StemCell Therapy

Removing one type of T cell from donor blood used for stem cell grafts could greatly reduce a serious complication called graft-versus-host disease in patients with leukemia, according to a new study.

Published today in theJournal of Clinical Oncology, the study reports that only 7% of leukemia patients who received stem cell transplants depleted of nave T cells developed chronic graft-versus-host disease, or GVHD, as compared to the 30% to 60% rate with standard of care treatment. About 70% of these patients developed the acute form of GVHD, but disease was typically mild and responsive to first-line corticosteroid agents.

For patients with leukemia and other blood diseases, transplantation of hematopoietic stem cells -- progenitor cells that can turn into any type of blood cell -- from a healthy donor can rebuild the body's blood manufacturing system. But this life-saving treatment also comes with risks. Stem cell grafts, which are collected from either the bone marrow or circulating blood, contain T cells that can cause GVHD by attacking host tissues.

Acute GVHD typically occurs within 100 days after transplantation and tends to affect the skin, liver and gastrointestinal tract. Most patients respond to corticosteroid drugs, but a substantial fraction require additional immunosuppression. Chronic GVHD usually develops later than the acute form and can affect many organs. This persistent version of the disease can be more difficult to treat, often requiring prolonged immunosuppression and reducing patient quality of life or causing death.

Removing all T cells from a graft prior to transplantation can reduce GVHD, but this approach is a double-edged sword. Previous studies found that patients were at higher risk of leukemia relapse or death because T cells also are important for killing cancer cells and fighting infections.

Researchers new strategy reduces these negative side effects by depleting grafts of inexperienced, nave T cells but retaining memory T cells, which protect against previously encountered pathogens.

The research team recruited 138 leukemia patients, including both adults and children, across three phase II clinical trials. They collected circulating blood from healthy donors who were immunologically matched to each patient and used a reagent to remove nave T cells. After chemotherapy and irradiation to kill cancer cells and make space for the transplant, patients received the nave T cell-depleted graft.

According to researchers the most striking finding was that just 7% of patients developed chronic GVHD compared with previously reported rates of 30% to 60%.

Importantly, nave T cell depletion did not appear to increase rates of leukemia relapse or fatal infections, although randomized control trials that compare different strategies are also needed to confirm these findings. The researchers have launched two such randomized phase II clinical trials for adult and pediatric leukemia patients.

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A New Strategy Could Turn the Tide in Stem Cell GVHD - Medical Device and Diagnostics Industry

Diabetes mellitus (DM) is a chronic metabolic disorder defined by insufficient secretion of insulin or insulin resistance. There are four major types of DM: type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, and monogenic diabetes.

Type 1 diabetes (also known as insulin dependent DM) is characterised by the autoimmune destruction of pancreatic -cells. This destruction of -cells results in a lack of production of insulin. Insulin is crucial to maintain healthy levels of glucose in the blood. The cause of this autoimmunity is not completely understood, but chronic hyperglycaemia (high blood glucose) can cause damage to blood vessels and nerves. If left untreated, hyperglycaemia can result in death.

In the UK, approximately 400,000 people are currently living with type 1 diabetes. In fact, the UK has one of the highest rates of type 1 diabetes in the world, for reasons that are currently unknown. Treatment for these individuals is traditionally via regular insulin injections to maintain normal blood sugar levels. Individuals with type 1 diabetes will have around 65,000 injections and measure their blood glucose more than 80,000 times in their lifetime.

Stem cell therapy [] utilises the potentiality of stem cells to differentiate into any cell type, in this case pancreatic -cells

To improve the quality of life of individuals with type 1 DM, there has been a wide range of treatment options explored. For example, clinical pancreas or islet transplantation has been considered a feasible treatment option. The first pancreas transplant was conducted by Dr Richard Lillehei in 1966, and up until 2015, more than 50,000 patients worldwide had received pancreas transplants according to the International Pancreas Transplant Registry. However, the worldwide shortage of pancreas donors and immune rejection has proved to be a major challenge to islet transplantation. Consequently, scientists have begun focusing on stem cell therapy as a method of treating type 1 DM.

Stem cell therapy is a form of regenerative medicine designed to repair damaged cells within the body. This form of medicine utilises the potentiality of stem cells to differentiate into any cell type, in this case pancreatic -cells. Embryonic stem cells (cells taken from an early mammalian embryo) are known as pluripotent cells. Pluripotency means that these cells have the ability to proliferate indefinitely, self-renew, and the capacity to differentiate into multiple types of adult cells. If scientists can place these embryonic stem cells under specific biological conditions, these stem cells can differentiate into pancreatic -cells.

The creation of VX-880 (an investigational stem cell derived therapy for pancreatic -cells) can be traced back to Dr Doug Melton, a stem-cell biologist at Harvard University in Cambridge, Massachusetts. He was a developmental neurobiologist until his six-month-old son was diagnosed with type 1 DM in the early 1990s. He then vowed to find a cure for the condition, leading to his entrance into the stem-cell field. 15 years later, Melton and his stem cell lab were able to successfully convert stem cells into islet cells. Meltons group published their methods in 2014. In 2015, Melton co-founded a start-up company which was acquired by Vertex in Boston, Massachusetts for US$950 million in September 2019.

The success of VX-880 in this singular patient has the potential to transform not only the lives of individuals with type 1 DM, but also the economic landscape of the disease

This method of treatment is currently undergoing clinical trials with Vertex Pharmaceuticals. Recently, Vertex announced that the first type 1 DM patient to be dosed with VX-880 saw their need for insulin disappear almost entirely. The patient was initially injected with a single infusion of the synthetic pancreatic -cells, and after 90 days was able to produce a steady flow of insulin and maintain insulin production after eating. The patient, Brian Shelton, told the New York Times that his treatment is like a miracle and it has given him a whole new life.

This is the first demonstration of a patient with type 1 DM achieving restored islet cell function from such a therapy. Vertex plans to enrol approximately 17 other participants for their early-stage trial. In its current form, VX-880 requires recipients to go on life-long immunosuppressants, therefore the therapys risk to benefit ratio may only be viable for those with the severest form of the disease. However, the success of VX-880 in this singular patient has the potential to transform not only the lives of individuals with type 1 DM, but also the economic landscape of the disease. Economically, this would transform those suffering with type 1 diabetes as it would be a one-time functional cure that could revolutionise the lives of these people.

As Brain Shelton said, this treatment could provide a new life for these patients. Type 1 diabetes can be an extremely debilitating disease that requires consistent monitoring and treatment. With VX-880, millions of people around the world could soon be free from insulin injections and glucose level monitoring, much like a miracle.

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Vertex type 1 diabetes vs stem cell therapy - The Boar

While acute lymphoblastic leukemia (ALL) was still the primary cause of death, researchers saw a steady increase in 2-year survival from 27.8% to 54.8% even as patient age at the time of relapse after allogeneic hematopoietic stem cell transplantation (HCST) increased.

Thanks to new treatment options and other strategies, the 2-year overall survival (OS) rate has doubled for patients with acute lymphoblastic leukemia (ALL) carrying the Philadelphia chromosome whose disease relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), according to a new study published Wednesday.

The findings, which the authors said are the largest study to date on real-world trends over time for this population, were published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

ALL by itself is an aggressive blood cancer, but patients with the Philadelphia chromosome have a worse prognosis and relapse after allo-HSCT about 30% of the time.

With new knowledge about how to manage these patients and reduce the risk of relapsesuch as through the use of tyrosine kinase inhibitor (TKI)-based maintenance therapy, regular monitoring for minimal residual disease, or a second allo-HSCTresearchers wanted to evaluate real-world data for this patient group over time.

The study was conducted by investigators from Acute Leukemia Working Party of the European Society of Blood and Marrow Transplantation (EBMT); the EBMT is a voluntary working group of more than 600 transplant centers that are required to report all consecutive HSCTs and follow-ups once a year.

The retrospective, registry-based, multicenter study included 899 patients 18 years and older with a first allo-HSCT for Philadelphia-positive B-cell ALL in their first complete remission and documented hematologic relapse after allo-HSCT between 2000 and 2019. Investigators divided the years into 4 time periods: 2000 to 2004, 2005 to 2009, 2010 to 2014, and 2015 to 2019.

The median ages at transplant and at relapse were 44 and 45.4 years, respectively, and there was a progressive increase in patient age at transplant (from 40.6 to 46.1 years; P = .007).

Over the 4 time periods, 116 patients relapsed between 2000 and 2004, 225 between 2005 and 2009, 294 between 2010 and 2014, and 264 between 2015 and 2019. There was also a statistically significant progressive increase in the use of matched unrelated donors, peripheral blood stem cells, reduced intensity conditioning (RIC), and in vivo T-cell depletion and a progressive decrease in total body irradiation (TBI).

For the entire group, the 2-year OS after relapse was 41.5% (95% CI, 38.0%-44.9%), but in univariate analysis, the 2-year OS after relapse jumped from 27.8% between 2000 and 2004 to 54.8% for 2015 to 2019 (P = .0001).

Overall, original disease was the cause of death in 68.5% of patients, followed by infections (14.3%) and graft-versus-host-disease. However, over time, original disease as the cause of death decreased, falling from 72.2% to 50% by 2019, while infections as the cause of death rose from 8.2% to 30.6%.

A second allo-HSCT within 2 years after relapse was performed in 13.9% of patients, resulting in a 2-year OS of 35.9%. In multivariate analysis, OS from relapse was positively affected by a longer time from transplant to relapse (P = .0006) and the year of relapse (HR, 0.71; P < .0033, for patients relapsing from 2005 to 2009; and HR, 0.37; P <.0001, for those relapsing from 2015 to 2019).

Explaining the improvements, the authors noted that RIC was used more often in recent years and TBI was used less frequently; with less-intense pretreatment, patients were likely able to withstand heavier treatments when they relapsed. In addition, these patients may have been more sensitive to later graft-versus-leukemia treatments at relapse, as they had received more T-celldepleted grafts.

In addition, these improvements in OS came despite a significant increase in patient age at the time of relapse (from 44 to 56 years).

"This effect is likely due to the greater efficacy of the novel targeted therapies, Ali Bazarbachi, MD, PhD, professor of medicine, associate dean for basic research, and director of the Bone Marrow Transplantation Program at the American University of Beirut, said in a statement. Besides newer TKIs, other strategies for therapy at relapse include monoclonal antibodies and chimeric antigen receptor T-cell therapy

"These large-scale real-world data can serve as a benchmark for future studies in this setting.

The study had some limitations. There was a lack of detailed information on minimal residual disease status and on the treatment of posttransplant relapse and its impact on survival improvement. There was also a lack of information on maintenance therapy, once a second remission was achieved.

Reference

Bazarbachi A, Labopin M, Aljurf M, et al. 20-year steady increase in survival of adult patients with relapsed Philadelphia-positive acute lymphoblastic leukemia post allogeneic hematopoietic cell transplantation. Clin Cancer Res. Published online January 12, 2021. doi:10.1158/1078-0432.CCR-21-2675

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Two-Year OS Doubles for Patients With Philadelphia-Positive Relapsed ALL After HSCT - AJMC.com Managed Markets Network

During a Targeted Oncology live event, Grzegorz S. Nowakowski, MD, discussed the case of a patient treated with tafasitamab plus lenalidomide in the second line for diffuse B-cell lymphoma.

Targeted OncologyTM: What are the options for second-line therapy in this patient with DLBCL?

NOWAKOWSKI: The current NCCN [National Comprehensive Cancer Network] guidelines [for patients who are not candidates for transplant] have gemcitabine [Gemzar] plus oxaliplatin [Eloxatin] plus or minus rituximab as a preferred regimen.1

Polatuzumab vedotin [Polivy] plus bendamustine [Treanda] plus rituximab is also included in the NCCN guidelines. Tafasitamab [Monjuvi] plus lenalidomide [Revlimid], which is another option, is FDA approved for second-line therapy and beyond. A lot of us in the field, in patients who are not willing to go for more intensive regimens [such as] transplant or CAR [chimeric antigen receptor] T-cell therapy, are looking more into these chemotherapy combinations, particularly if the patient progresses after chemotherapy. The idea is its going to be a different mode of action. CAR T-cell therapy is [used in the third-line setting] as of now. Again, this may change in the future.

What is the rationale behind the patient receiving this combination?

The FDA granted accelerated approval for the combination of tafasitamab and lenalidomide for relapsed or refractory DLBCL based on [results from] the L-MIND study [NCT02399085].2

Tafasitamab has a cool concept where the antibody cells target CD19, just as in CAR T-cell therapy and loncastuximab tesirine [Zynlonta], which is another recently approved antibody. There were initial developments before studying [CD19] where we felt it could be a good target, but some antibodies didnt work so well. Now there is this renaissance of interest in CD19-targeting agents such as CAR T-cell therapy, tafasitamab, and loncastuximab.

The [tafasitamab] antibody is engineered to have this enhanced Fc function that increases ADCC [antibody-dependent cellular cytotoxicity], ADCP [antibody-dependent cellular phagocytosis], and cell death. It causes direct cell death because CD19 is important in B-cell receptor signaling and not only in the immune system, but it gives some antisignaling properties as well.3

Lenalidomide has the properties of immune activation and microenvironment function and there are dozens of papers postulating many mechanisms of action for lenalidomide. Its very pleiotropic, but it does immune activation, and we know from R2 [lenalidomide plus rituximab] and other antibody combinations that it tends to synergize with the antibodies very well. This preclinical idea led to the development of the combination of this naked antibody and lenalidomide in patients with relapsed or refractory DLBCL.

Which trial data supported the approval of tafasitamab/lenalidomide?

L-MIND was a single-arm, phase 2 study [that enrolled patients who had] 1 to 3 prior regimens and who were either relapsing after transplant or were not eligible for transplant. The primary refractory patients were to be excluded, but because of changing definitions, they accrued, to some degree, to the study, and had pretty good results anyway.4

Tafasitamab is an infusion, just like other antibodies. Its given on days 1, 8, 15, and 22, for 1 to 3 cycles. In cycles 4 to 12, it is given every 2 weeks. Lenalidomide is given at 25 mg daily on days 1 to 25, [just as] in multiple myeloma. This is a different dose [from the R2 regimen], which is 20 mg, but the 25 mg was well tolerated, and this was based on the initial [pilot study]. After 12 cycles of therapy, patients received tafasitamab until disease progression.3,4

Frequently [we are asked] why we would plan on continuing forever. I was involved in the design of the study, and the salvage options for patients were quite limited for those who were not transplant eligible and some of the investigators asked why we would want to stop if it is working. We gave investigators discretion to [decide] whether the patient was benefiting from the treatment and to continue until disease progression. The primary end point of the study was overall response rate [ORR], which has frequently been the most reliable end point for the activity of the combination in this setting because it tends to have less bias in patient selection. The secondary end points were PFS [progression-free survival], duration of response [DOR], overall survival [OS], and so forth.4,5

There were some lenalidomide dose reduction studies where patients were given doses of 25 mg down to 5 mg using step reductions.5

This was a study of the [safety] population, and 81 patients were accrued overall. The median age was 72. The IPI risk score, Ann Arbor stage, and LDH results were typical for refractory DLBCL. Patients with primary refractory disease were supposed to be excluded, but 19 of 81 patients had it and 44 of 81 patients were refractory to prior therapies. Relatively few patients had a prior stem cell transplant and the majority were not eligible for it due to comorbidities, unwillingness to do so, or not responding to salvage therapy. [Not responding] to previous therapies was a major reason [for not getting a transplant].5

How did patients do on the L-MIND trial?

The ORR for this combination was quite high at greater than 60%, which is comparable with what we see in CAR T-cell therapy or intensive chemotherapy. So this was quite significant and impressive at the time the [results were] published. The CR [complete response] rate was even more impressive at 43%. Again, this was in patients who were relapsed or refractory, not transplant eligible, or those relapsing after transplant, so a 43% CR rate is high.5,6

As clinicians, we care about the DOR, too. So if you are a regulator, say at the FDA, you only worry about response rates because its less about patient selection, but clinicians like responses to be durable. The median PFS was 12.1 months.5 The median PFS doesnt fully reflect the activity of this regimen because it plateaus just after the median. CAR T-cell therapy data look very similar, too. For a relatively well-tolerated combination, these were very impressive results at the time of presentation. The median OS was not reached and, as with the PFS results, the OS also plateaued. So these were very impressive results in terms of DOR.

The patients in CR were primarily driving this benefit, but even the patients in PR [partial response] had [an approximately] 30% sustained response.6 The treatment was active in the patients treated both with 1 prior or 2 or more prior lines of therapy. Responses, particularly the CR rates, were somewhat higher in the patients who were on second-line treatment. This would be the patients who were not eligible for transplant.

Do you feel comfortable using this regimen in patients with GCB [germinal center B-celllike] subtypes because they were underrepresented in the study?

There was a whole debate about it. We believe that the combination of the antibodies and lenalidomide works well in GCB subtypes as well. It is a little bit different with single agents because the data showed response rates and activity were better in ABC [activated B-cell] or nonGCB subtypes of DLBCL, but in combination, there appeared to be less of a differential by cell of origin.

But in the [forest plot] analysis, both subtypes benefited. There was a trend toward a little bit of a high response rate in patients with the ABC subtype, but overall, the response rate was high in patients with GCB patients as well. I believe it was approximately 45% to 50% in both subtypes.

What about the R2 regimen? Do you prefer not to use it in GCB subtypes?

Yes, I prefer not to use it in GCB subtypes. [Results of] the ECOG-ACRIN E1412 study [NCT01856192] were recently published in the Journal of Clinical Oncology and I was a PI [principal investigator] in it.7 This study was looking at all-comers, so it was the only randomized frontline phase 2 study, where lenalidomide was added to R-CHOP. This one was cell-of-origin agnostic, so they could have the GCB or ABC subtype. There was [approximately] a 12% difference in PFS in this study and a favorable hazard ratio.

Another study, the ROBUST study [NCT02285062], was focused on patients with the ABC subtype.8 It didnt show a difference using different lenalidomide scheduled doses, though there were other patient selection issues in the study. As a single agent, lenalidomide is more active in the ABC subtype and I use it myself in clinical practice more in ABC or nonGCB subtypes. In combination with the antibodies, or even chemotherapy, this may not be necessarily true. Because most of these patients are already exposed to rituximab, I think based on the R2 study [results], they didnt see much of a differential based on cell of origin, which is a little bit disappointing, because we were hoping we could [use it to] select the high responders, but that didnt pan out. REMARC [NCT01122472] was a study done by a French group that used lenalidomide maintenance after R-CHOP but didnt track the cell of origin.

In fact, the GCB subtype tended to benefit more, and an idea was that maybe some microenvironment influences played a role. In my clinical practice, in nonGCB subtypes, I use a single agent, but for combination of the antibodies, the activity seems to be agnostic to cell of origin.

How does an anti-CD19 antibody downregulate the CD19 receptor?

There is limited information, but they did a study looking at the CD19 expression after tafasitamab exposure in chronic lymphocytic leukemia and [there was no impact] and in DLBCL as well. The CD19 expression is just a part of the story because you worry that a part of the CD19 molecule could be mutated and then the CAR T-cell agents would not bind or that part of the molecule could be missed because of alternative splicing or losing one of the exons because of the evolutionary pressure of the treatment. We did whole exome and RNA sequencing and saw no abnormalities within the CD19 cells. It appears to be expressed after tafasitamab exposure, and there are no point mutations, exon deletions, or other changes that would affect the integrity of CD19, to the best of our knowledge.

Of course, the best data would come from clinical evidence if we note that CAR T-cell therapy is working. In this study, only 1 patient proceeded with CAR T-cell therapy and had good clinical benefit and was in remission last time I saw the data. So it appears that in anecdotal experiences CAR T-cell therapy will still work in those patients.

The opposite is true, too. There is a huge interest now in this combination and [whether] it will be active in post CAR T-cell relapses. Lenalidomide as a single agent is frequently used in this setting. How active will this combination be in postCAR T-cell relapse? We know that lenalidomide is active. A lot of patients with CAR T-cell relapses will still have CD19, so we believe that is also an option, but more data will be needed.

Do patients tolerate the 25-mg lenalidomide dose in combination with tafasitamab, or is the dose modified often?

[Approximately] 30% of patients will have to drop to 20 mg, particularly with subsequent cycles. The nice thing for lenalidomide is that you can use the growth factor support because it is primarily neutropenia that causes some of the dose reductions. Studies are different from real life, so in the real world we always have some patients who are already cytopenic from the previous therapy. I usually support them with a growth factor, and sometimes I start my patients at 20 mg. The dosing intensity of lenalidomide seems to be important, though.

I wouldnt very liberally decrease it because there appears to be some dose relation to the response, at least as a single agent in a refractory setting in DLBCL in contrast to follicular [lymphoma], but somewhere from 15 mg to 20 mg is the golden spot for response.

The 25 mg was used in those studies as a single agent, so, about one-third of patients did require dose reductions. If you use this combination, you follow the lenalidomide package inserts, and if you need to reduce because of creatinine clearance, you reduce the lenalidomide or if you see significant neutropenia despite the growth factor used, then you can reduce on a subsequent cycle to 20 mg, or interrupt and reduce to 20 mg.

Does patient preference weigh into the decision to choose finite therapy vs therapy until progression of disease in the second-line setting?

Yes, it comes down to the patients preference. I dont practice in the community, so I dont have more experience with this. We have this policy at Mayo Clinic that [any clinician] from around the world can call us at any time for advice about their patients. So, routinely, we are getting quite a few phone calls from those who are responsible for patients with lymphoma, or for any other disease type from outside, and practitioners call asking what to do.

I am always surprised by how many patients do not want to proceed with CAR T-cell therapy or stem cells or even clinical trials, which we often have here, because of the preference of being near the local center. Travel is not always possible and some patients want to stay where they are, which is a very reasonable option.

Are there trials comparing this with transplant or something lenalidomide alone?

We did 2 things to differentiate this from lenalidomide alone. A study called RE-MIND [NCT04150328] with close matching of the patients with real-world data showed that the combination was definitely much more active than lenalidomide alone. [We knew this] but wanted to double-check in a very close-matched cohort. A confirmatory study for this is [the frontMIND study (NCT04824092), which is a frontline study that compares] R-CHOP as standard therapy vs R2-CHOP plus tafasitamab.

I am the principal investigator globally for this study, and one of the reasons why we designed it this way was there was some activity already from randomized phase 2 studies using lenalidomide. It was safe and effective and also the doublet was already approved, so it was logical to move it forward.

However, the biggest [issue we had when] presenting this concept to some regulatory authorities was that we were a little bit naive in the past, thinking that adding 1 drug at a time is going to move the bar a whole lot. R-CHOP already has 5 different compounds, so I think the sixth one probably is not going to move the bar a whole lot. There are some studies that failed, I think, 1 drug at a time. So the ambitious plan here is to add a doublet. But the study is designed to capture very high-risk patients, [meaning] IPI 3 and above. Its looking at the highest-risk population and is adding doublet on top of R-CHOP. There are some study centers in the United States that are in the process of either opening or even have it open currently.

Could tafasitamab/lenalidomide be moved to the first-line setting with more targeted agents as chemotherapies are eliminated?

Yes. There is a pilot study led by my colleague Dr [Jason] Westin at [The University of Texas MD Anderson Cancer Center]. He is basically pioneering the so-called smart-start, or smart-stop now, where he is adding exactly this combination to R-CHOP. The question is: Can he strip some of the chemotherapy agents [such as anthracyclines]?

[The patient] tried to shorten and then to remove different cytotoxic drugs with the idea that maybe over time he can develop a chemotherapy-free regimen. [Results of] the initial pilot study have shown this combination plus ibrutinib [Imbruvica] is producing high response rates. He still added chemotherapy later because he was worried that he may miss the possibility of curing the patient, but after initial feasibility, he is slowly stripping chemotherapy. We may get there one day.

What are the similarities and differences of loncastuximab tesirine and tafasitamab?

I think cross-study comparisons are usually difficult. I am very cautious always when comparing different study results because the patient population is not always the same. I happen to be involved with the FDA in different reviews and I do believe that the response rate is what tends to reflect the most activity and is less dependent on patient selection, though not completely.

The ORR of loncastuximab is [approximately] 50% or very close to that. The DOR appears to be a little bit shorter, but this could be due to patient selection, so it looks very encouraging. It has a little bit of a different adverse event [AE] profile. At this point it doesnt have as strong a follow-up as this study, so we dont know if the same very encouraging plateaus in responding patients will be seen with it.

Maybe its going to happen, but it is more of a traditional cytotoxic therapy that is directed like polatuzumab. It works more on the immune microenvironment in immune activation. There is this renaissance of CD19 targeting and for CAR T-cell therapies, all the approved products target CD19, and now loncastuximab and tafasitamab.

I usually tell the industry to not develop any more agents targeting CD19. We have enough. There are some other good targets, too. Some of the CAR T-cell therapies are targeting different molecules on the surface.

How many of these patients on the L-MIND trial stopped therapy early? What is the safety profile of combination lenalidomide and tafasitamab?

The primary reason for stopping therapy early was disease progression because some patients just didnt respond. The toxicities were primarily hematologic, which is consistent with what you would see with lenalidomide. Nonhematologic AEs [included] fatigue and diarrhea, but nothing striking or unusual. Discontinuation of combination [therapy due to] AEs was seen in 12% of the patients [n = 10/81].5

A comparison of the AEs of combination therapy vs monotherapy showed the hematologic and other toxicities were driven by lenalidomide. Tafasitamab alone had [an approximate] 27% ORR and when combined with lenalidomide the response rate doubles, so theres a true synergy between those drugs.

The monotherapies are quite well tolerated. Some patients can develop neutropenia, as was seen in the monotherapy trials, but overall the toxicity is minimal for the antibody alone.

What is the rapidity of the response for this regimen? Who wouldnt be eligible for it?

The first evaluation was done after 2 cycles of therapy, so within 8 weeks the response was right there. The response is quite brisk. If I had any concern about putting [a patient] on lenalidomide, it would be for reasons such as it can cause some rashes as seen previously with lenalidomide combinations, so with previous hypersensitivity, I probably would not [use it].

If patients have very rapidly progressive symptoms, I may stabilize them with radiation or some other treatment first, maybe hydroxysteroids, rituximab, or something such as that just to remove the disease burden before I start this combination. I expected that the responses would be dipping over time, but the responses were brisk and happened after 2 cycles of therapy.

REFERENCES

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Nowakowski Considers CD19 Therapy in Transplant-Ineligible DLBCL - Targeted Oncology

Jen Psaki clashed with a Fox News reporter when he questioned why Joe Biden still referred to Covid-19 as a pandemic of the unvaccinated.

The White House press secretary pounded Pete Doocy with virus statistics after he highlighted the large number of vaccinated Americans suffering breakthrough infections.

It was Mr Doocys first press briefing back after he suffered a breakthrough infection himself.

I understand that the science says that vaccines prevent death, said Mr Doocy.

But Im triple-vaxxed, still got Covid. Youre triple-vaxxed, still got Covid. Why is the president still referring to this as a pandemic of the unvaccinated?

Ms Psaki reminded Mr Doocy that she had only suffered minor symptoms after getting Covid-19 following vaccination.

There is a huge difference between that and being unvaccinated, she said bluntly.

You are 17 times more likely to go to the hospital if youre not vaccinated, 20 times more likely to die.

So yes, the impact for people who are unvaccinated is far more dire than for those who are vaccinated.

Mr Doocys questioning of Ms Psaki came just days after his own father, Steve Doocy of Fox & Friends, explained he viewed the vaccine like a bullet-proof vest.

He said on Fox News that while the vest may not stop a bullet from hitting the person wearing it, it wont let the bullet kill you.

The United States has now seen more than 60.2m Covid cases during the pandemic, and 836,000 deaths.

With the Omicron variant still surging in the US, the daily average of Covid-19 hospitalisations for the week ending January 4 was 16,458, says the CDC.

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Psaki demolishes Doocy with stats as he tries to claim covid now an illness of the vaccinated - newsconcerns

Early in the coronavirus pandemic, alarming reports suggested that COVID-19 was more than just a severe respiratory disease. Clinicians quickly learned that the disease could have a dire impact on cardiovascular health and sometimes seemed to attack the heart directly.

Over the following months, hypotheses and speculation gave way to a solid understanding of the cardiovascular risks associated with a COVID-19. Viral infections are notorious for putting added pressure on the system in the form of inflammation, which in turn leads to adverse health outcomes such as cardiovascular injury or disease and strokes, but early data suggested that SARS-CoV-2 is exceptional.

It turns out that COVID-19 can involve a variety of cardiovascular health outcomes. Scientists from the CDC COVID-19 Response Team found that COVID-19 patients have a 16-fold increase in the risk of developing the inflammatory conditions myocarditis and pericarditis while they had COVID-19. Research published in JAMA Neurology in July 2020 identified 31 strokes among 1,683 COVID-19 patients admitted to the emergency room at two New York City hospitals, a 7.6-fold greater risk than for those who were admitted for flu. This estimate has fallen a bit as more data have accrued, but the trend is holding that SARS-CoV-2 presents a greater risk of stroke than other viruses, especially among older patients with preexisting health complications, study author and Weill Cornell Medical College neurologist Alexander Merkler tells The Scientist. Similarly, research published in The Lancet in July found that COVID-19 patients are three times more likely to have a heart attack in the week after their diagnosis than healthy controls. Many of these cardiovascular outcomes have the potential to become chronic health issues, especially among older patients or those with medical conditions such as diabetes and hypertension, according to a literature review published in Circulation Research.

Its not uncommon to see these cardiovascular manifestations take effect in patients with underlying heart disease or patients with severe COVID, Aeshita Dwivedi, an assistant professor of cardiology at Lenox Hill Hospital in New York tells The Scientist.

Throughout the pandemic, scientists have been probing health records, examining patient tissue, and analyzing viral genomes in order to understand how SARS-CoV-2 affects the cardiovascular system. In addition to the high levels of inflammation associated with COVID-19, the disease can also cause hearts to enlarge as a result of how much harder they have to work during the infection, which can in turn lead to heart failure, notes Northwestern University cardiology professor Robert Bonow, who is also the editor-in-chief of JAMA Cardiology. And several studies involving autopsies and biopsies of the heart muscle and stem cell models found evidence of heart cells infected with SARS-CoV-2, indicating that the coronavirus seems to be able to injure the heart directly as well as indirectly. Meanwhile, scientists are still grappling with the possible implications of long COVID, which remains enigmatic because reliable data sets are only now starting to emerge. Also unknown is whether Omicron, now the dominant variant in the United States, will affect the heart any differently than prior variantsthe best data available are still too preliminary to draw conclusions.

Manish Bansal, a cardiologist at the Medanta hospital in India, points out that overall rates of cardiovascular events related to COVID-19 are low. So, these figures should not lead to fear, he writes in an email, but yes, at [the] population level, they are worrisome because COVID-19 has affected millions of people and therefore the absolute burden of cardiovascular events is going to be large.

SARS-CoV-2 may be unique in the level of risk it poses to the heart, but like other viruses, many of the cardiovascular risks associated with COVID-19 stem from severe inflammation, researchers tell The Scientist. UVA Health emergency cardiologist William Brady says the increase in cardiovascular health problems that doctors report encountering likely stems from the fact that COVID-19 causes particularly severe inflammation compared to other viruses. Even in the absence of a direct assault on the heart, severe inflammation is bad news for the cardiovascular system due to the added strain it imposes on the heart and the bodys vasculature.

Indeed, viral inflammation like that caused by the coronavirus seems to increase ones risk of dying from any cause by accelerating the aging process, Brigham and Womens Hospital physician and infectious disease specialist John Ross tells The Scientist over email. He cites a 2015 study in PLOS ONE that scoured the health records of 160,481 patients to link biomarkers of an inflammatory responseincluding C-reactive protein, albumin, and neutrophilsto a heightened risk of all-cause mortality. In the case of SARS-CoV-2, the inflammation occurs all around the body, not just in the lungs as seen with the respiratory inflammation caused by the flu. That inflammation doesnt spare any part of your body, Dwivedi says.

In addition to injuring the body directly, this inflammatory response can also trigger programmed cell death: infection activates the apoptosis-directing gene caspase-8, according to an analysis of postmortem lung samples published last October.

Early on in the pandemic, SARS-CoV-2 became notorious for its ability to cause cytokine storms, severe immunological responses to infection that attack a pathogen so ferociously that they damage the bodys organs. A literature review published last March in Frontiers in Immunologysuggests that the cytokine storms caused by SARS-CoV-2 are different from and more dangerous than those caused by influenzas and other coronaviruses. These storms are unusually bad in COVID-19, J. David Spence, a neurologist and stroke prevention expert at the Robarts Research Institute, tells The Scientist. Specifically, a Sciencestudy determined how SARS-CoV-2 infections cause dysregulation of the antimicrobial type-I interferons secreted by immune cells to fight pathogens. That leads to not only a greater number but also a greater variety of cytokines being released into the system, which results in greater immunological havoc than with other infections.

The inflammation caused by COVID-19 may be more severe than that caused by other viruses, but inflammation alone cant explain all of COVID-19s cardiovascular effects. COVID-19 causes symptoms that are different from and more diverse than those of other respiratory diseases, which is why its much more complicated than the average pneumonia or influenza, says Bonow.

He explains that COVID-19 cytokine storms cause a hyper coagulable state that increases the risk of blood clots, stroke, and heart attacks. In this storm-induced coagulable state, Spence says that platelets aggregate together, creating plugs that can get stuck in the heart or elsewhere in the circulatory system and restrict or block blood flow, although the mechanism behind the formation of these plugs hasnt been determined yet. Bonow suggests that cytokine storms contribute in some way to this coagulable state and what he calls intense blood clotting during COVID-19.

Theres also accumulating evidence that the coronavirus can infect human cardiomyocytes, the hearts muscle cells. However, several of the studies probing this direct infection phenomenon were inconclusive, experts say. Its difficult to draw conclusions from stem cell models because the human body behaves very differently from cells in a dish, Cincinnati Childrens Hospital molecular cardiovascular biologist Kelly Grimes tells The Scientist in an email, and squirting a ton of virus on some cardiomyocytes isnt a good model for how those cells might encounter the virus in the body.

As of yet, its unclear whether viral infection of heart cells is causing any of COVID-19s symptoms or factoring into disease severity, Grimes adds. Determining if the cells get directly infected by the virus will allow us to understand if the dysfunction were finding in them is a primary or secondary effect of the virus.

So, is there a direct injury effect of the virus on the myocardium? says Brady. I think the thought is yes there is, but . . . we need to understand more about the direct effect of the virus on the myocardium. Thats not conclusively sorted out.

However the damage is inflicted, if the heart muscle, or myocardium, suffers injury, it could lead to a large number of people with weak hearts over time, potentially leading to chronic health conditions or an uptick in heart attacks in the future, Bonow says.

Multiple researchers tell The Scientist that they expect to see the bulk of these problems among patients who had underlying health issues before catching COVID-19. But Brady notes that theres not a scientific consensus regarding whether COVID-19 causes new cardiovascular issues that wouldnt have happened on their own or if its inducing these health problems among those who had preexisting risk factors.

More generally, as they look toward the future of the pandemic and beyond, researchers are now trying to chase down the diseases long-term implications, Bonow says. I think theres still a lack of understanding of what long COVID is all about, he says. Everybodys in the knowledge-gathering stage regarding longer-term effects at this point.

However, the general consensus within the scientific literature is that COVID-19 cases are associated with an uptick in cardiovascular health problems in the long run. An April 2021 paper from the American College of Cardiology highlights patient reports of cardiopulmonary symptoms such as fatigue long after their coronavirus infections waned, and an October review in Nature Reviews Cardiologysuggests that long COVID can cause an increased risk of heart palpitations and arrhythmias.

Maybe it shouldnt be that surprising that COVID, which causes a very severe and very prolonged inflammatory state, is associated with a high risk of heart problems over a long period of time, Ross says. However, Bonow notes, determining whether a cardiovascular complication was caused by an acute injury that happened to manifest later on or if its actually tied to long COVID is difficult. Part of the difficulty, says Dwivedi, is that long COVID is really a diagnosis of exclusion, meaning that clinicians need to rule out the myriad other explanations for a patients symptoms before attributing them to a past SARS-CoV-2 infection.

Several clinicians tell The Scientist that theyve witnessed an increase in cardiovascular health issues among the general population as the pandemic progressed. Indeed, research published in the American Heart Association journal Circulation in May of last year identified an atypical annual increase in deaths caused by heart disease and cerebrovascular diseases in 2020. These could stem from a drop in the number of doctor visits among people who wanted to avoid hospitals lest they get exposed to the coronavirus, experts say.

The confusion surrounding long COVID illustrates how much is left to learn about COVID-19 across the board. The first cases of the disease emerged at the end of 2019, and while it may not feel that way to those living through the pandemic, two years is an extremely short time when it comes to determining the long-term effects of a new disease.

For most other diseases, we have years and years of data, says Dwivedi. This diseasebarely any time has passed by.

When it comes to prevention and mitigation of cardiovascular outcomes caused by COVID-19, all eyes are on the continued performance of the various vaccines approved for use.

As with the long-term effects of COVID-19, its too early in the pandemic to know whether vaccines will help stave off secondary health outcomes such as cardiovascular complications in people who get breakthrough infections. Figuring out whether thats the case is a top priority for many researchers and clinicians, experts tell The Scientist, but not nearly enough time has passed since the vaccine rollout began to offer a definitive answer. Still, many offered up the hypothesis that vaccination will, in fact, help prevent problems including strokes, heart attacks, and heart disease, pointing to the vaccines ability to lessen the severity of SARS-CoV-2 infections.

If I were to be a betting person, I would say the incidence of cardiovascular complications should be lower in patients after vaccination, says Aeshita Dwivedi, an assistant professor of cardiology at Lenox Hill Hospital in New York. The vaccine kind of blunts the severity of the disease, so it can be hypothesized that vaccination should reduce the cardiovascular burden of COVID. But its a little too soon to say.

Columbia University neurologist Mitchell Elkind, a former president of the American Heart Association, agrees. He tells The Scientistthat most complications are associated with the course of the disease. It stands to reason that vaccination will lessen the chance of any secondary cardiovascular complication of COVID.

Continued here:
Doctors and Researchers Probe How COVID-19 Attacks the Heart - The Scientist

Two D.C.-area families shared their stories about how the blood you donate could help save the life of their children.

Courtesy Falon Beck

Courtesy Rebecca Carrado

Courtesy Rebecca Carrado

Courtesy Falon Beck

What Rebecca Carrado wants potential blood donors to know

Donate blood and who does it help? It might be the baby born so small her mom described her as looking like a gummy bear or the twin teenagers who need routine transfusions to survive.

What makes this current blood shortage a true crisis is the fact that weve seen a record low blood supply for several months, said Ashley Henyan of the American Red Cross.

Normally, the Red Cross maintains a five-day supply of blood but right now, there is less than a one-day supply of certain blood types, putting doctors in the difficult situation of having to choose who gets treatment and who, unfortunately, has to wait for a transfusion, she said.

Donated blood was available when Rebecca Carrado, of Woodsboro, Maryland, needed an emergency C-section 26 weeks into her pregnancy. She delivered 1-pound, 10-ounces Hayden, who is now 12 years old. But before Hayden was well enough to go home, she needed nine transfusions.

It never crossed my mind that blood would not be available to save my daughters life, Carrado said. Luckily, it wasnt something then that we had to be concerned with. But it is something now. I see the blood shortage today and whats going on in our country.

How impossible it would be to make a bad decision as to who gets blood donated to them to save their life, she said.

Receiving transfusions of donated blood every two-and-a-half weeks is routine for Sophia and Olivia Dikeman, 13, of Cecil County, Maryland.

The girls, diagnosed with Diamond Blackfan Anemia as toddlers, dont produce red blood cells on their own. A cure will only come with successful blood marrow or blood stem cell transplants for each of them.

Without blood donations, it would be a matter of life and death for them, mom Falon Beck said of the girls who turn 14 next Tuesday.

Talking this week via Zoom, Olivia raised her arm to the camera to show the bruise from Mondays transfusion. The girls said its boring taking four to six hours each time to refuel, but they can bring homework.

I can feel when I need it, Sophia said of the transfusions. Im tired, not as active and I get headaches a lot too. Not every time. Sometimes I get headaches but not all the time. It depends how low I am.

Both the girls like playing softball and enjoy playing and watching basketball and golf. Their favorite subject in school is math because it challenges them.

After I get my blood, I feel like I have energy and I dont get headaches, Olivia said.

Sophia and Olivia want to grow up to be nurses like their mother who works in the emergency department; but they want to focus on kids like the nurses who have helped them. Their father, Ernie, is a firefighter. The couple met when Falon was taking in patients Ernie was delivering in ambulances.

Falon and I met helping other people, and the twins, with their story, are going to be helping other people, Ernie Beck said. He talked about raising awareness about both the need for blood donations and for people to register to potentially be a match for a blood stem cell donation.

Ernie Beck explains how someone acting to help his daughters can impact hundreds of lives

Falon Beck said shes grateful for people who donate blood.

My family donates, but I found out today that only 37% of the population is able to donate and of that 37, only 10% actually donate blood, Falon Beck said.

Carrado and her husband, both City of Frederick police officers, donate blood regularly with Hayden sitting alongside. At 12, shes too young to donate but knows all about the process and why its important.

It takes a very small amount of time out of your day to give a gift of life and to give blood or platelets that are so desperately needed to keep families safe and healthy and to keep loved ones together, Rebecca Carrado said.

Much like theres been a disruption in blood donations, registering people for eligibility to be blood stem cell donors has lagged tremendously, said Beth Carrion, an account manager with Be The Match. You could literally be the cure Olivia and Sophia are looking for.

People 18 to 40 years old can register for the blood stem cell registry by texting CURELIVSOPH to 61474 or by going to the Be The Match website.

Appointments to donate blood with the American Red Cross can be made online. Inova Blood Donor Services also schedules appointments online to collect blood to distribute throughout the D.C. area.

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Who does donated blood that's direly needed help? - WTOP

Omicron is spreading rapidly throughout the U.S. and Dr. Anthony Fauci, the chief medical advisor to the President and the director of the National Institute of Allergy and Infectious Diseases, said this week the variant will "find just about everyone." He reminded people about the importance of getting vaccinated. "Omicron, with its extraordinary, unprecedented degree of efficiency of transmissibility, will ultimately find just about everybody," Dr. Fauci told J. Stephen Morrison, senior vice president of the Center for Strategic and International Studies. "Those who have been vaccinated and boosted would get exposed. Some, maybe a lot of them, will get infected but will very likely, with some exceptions, do reasonably well in the sense of not having hospitalization and death." As the surge continues to rage through the country, Eat This, Not That! Health talked to Dr. Katie Passaretti, MD, vice president and enterprise chief epidemiologist at Atrium Health about where Omicron is most contagious and why the variant is causing hospitalization rates to go up. Read onand to ensure your health and the health of others, don't miss these Sure Signs You've Already Had COVID.

Dr. Passaretti explains, "Omicron and really all strains of COVID spread MOST effectively in crowded areas, enclosed spaces, especially those with poor ventilation. Concerts and indoor sporting events are where I would stay away from. Spectators at either event are yelling, shouting and singing. They are emitting respiratory secretions that as we know fly freely to the people around you."

RELATED: COVID Symptoms to Watch For This Month

Dr. Passaretti suggests, "Crowded bars and indoor parties are another place I would avoid. When people take their masks off to eat or drink that is a barrier coming down that prevents the spread of omicron. Also, people tend to be in close proximity at these events. If there is food that is out for people to choose from that is another opportunity for there to be transmission. Stay masked up as much as possible if you are considering being at one of these locations."

RELATED: Virus Expert Just Issued New Omicron Warning

"Crowded workplaces are not always avoidable," Dr. Passaretti says. "While many employers are having employees work remotely, there are some jobs that must be done in person. Sometimes where these jobs are there is little chance for optimal distancing from other employees or customers. For people at these jobs, I would also have them consider double masking with a medical grade mask and any other type of mask on top."

RELATED: Dr. Fauci Says if You Have COVID, Do This

The vaccine for COVID has been effective in preventing death and severe illness and with Omicron so highly contagious, Dr. Passaretti urges people to get vaxxed, especially if you're in an Omicron hotspot like the places mentioned above. "For all of these locations, people must consider getting vaccinated and boosted if they are already fully vaccinated. Each of the vaccines have been proven to be effective in preventing the likelihood of becoming seriously ill and unfortunately hospitalized."

RELATED: The Best Things to Take If You Get COVID

Dr. Passaretti states, "Vaccines and boosters are not 100% effective in the best of circumstances, but they do a very good job at what we need them to do, which is prevent severe disease and hospitalization. In order to stem the tide of Omicron, people need to mask up, even consider double masking since it is extremely transmissible. Do whatever you can to keep yourself safe and away from areas that may make you vulnerable to getting Omicron."

RELATED: This Can Help "Stop" Dementia, New Study Says

According to Dr. Passaretti, "Omicron is the newest strain of COVID but it's still the COVID virus different strains act differently due to mutations or changes in the genetic makeup that can impact things like how well the virus binds to human cells or how well it evades our immune system. Both of these factors can impact how easily the virus is spread in a population or transmissibility. We are still learning about omicron, but early data suggests that omicron may spread more than other recent variants because it is somewhat better at evading our immune system. Vaccines and prior infection still help protect the individual but not quite as well as we have seen with prior COVID variants and that allows it to spread more effectively."

RELATED: Ways to "COVID-Proof" Your Life As Much as Possible

Dr. Passaretti explains, "We are still learning about the severity of illness with omicron but early data from South Africa and the UK do suggest that less people end up severely ill. Having said that the increased transmissibility and marked increase in cases still translates into more people being hospitalized. In addition, our vaccination rates in the US and certainly booster uptake leave a lot to be desired. Yet again we are seeing our hospitals fill up with unvaccinated individuals who get infected with Omicron. This combination of vaccination and booster rates being lower than we'd like and an increased number of cases/transmissibility translates into a very challenging situation in healthcare right now."

RELATED: I'm an ER Doctor and Beg You Don't Enter Here

Follow the public health fundamentals and help end this pandemic, no matter where you liveget vaccinated or boosted ASAP; if you live in an area with low vaccination rates, wear an N95 face mask, don't travel, social distance, avoid large crowds, don't go indoors with people you're not sheltering with (especially in bars), practice good hand hygiene, and to protect your life and the lives of others, don't visit any of these 35 Places You're Most Likely to Catch COVID.

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Places Where Omicron is Most Contagious Eat This Not That - Eat This, Not That

Researchers atUniversity Health Network (UHN) and the University of Toronto have received $24 million to advancetechnology to repair and rebuild organs outside the bodyfor patients in need.

The project, led byShaf Keshavjee, is one of only seven across Canada selected to receive funding in the Government of CanadaNew Frontiers in Research Fund(NFRF) Transformation competition, following an international consultation.

"The Ex Vivo Lung Perfusion (EVLP) system we developed here in Toronto has revolutionized lung transplantation in the past decade. Now, it's been translated around the world to increase lung transplant access and it's being extended to other organs," says Keshavjee, a professor and vice-chair for innovation in thedepartment of surgeryin U of Ts Temerty Faculty of Medicinewho is surgeon-in-chief at UHN and a senior scientist atToronto General Hospital Research Institute.

"With this transformative grant, we now have the opportunity to take ex vivo technology to the next level, where we can repair and rebuild organs for transplant."

Atul Humar, director of the AjmeraTransplant Centre(photo byTim Fraser)

Over 4,500 people in Canada are currently waiting for an organ transplant, and more than 270 die each year as the need for transplant greatly exceeds availability.

Ex vivo perfusion systems use specialized machines to maintain, evaluate and treat organs before transplant. They have a huge impact on increasing the number of organs that can be considered for transplant.

TheToronto Lung Transplant Program,led by Keshavjee, has used this technology to double the number of lung transplants performed and lives saved at UHN.

"The New Frontiers grant will allow us to advance applications for lungs and further develop ex vivo systems for other organs, such as liver, kidney, heart and pancreas," says Atul Humar, a co-principal investigator on the project, professor in thedepartment of medicineat U of T and director of theAjmera Transplant Centre at UHN.

Brad Wouters, UHN's executive vice president, science and research, notes that this major grant will enable multidisciplinary teams to develop new, cutting-edge approaches to extend the time that donated organs can be used, and also enable treatment and repair of unsuitable organs to allow treatment of more patients.

It will also help the teams refine and improve equitable organ allocation guidelines for all patients, he adds.

The advancements that this team has made and their continued success is made possible by support from provincial and federal governments, industry partners, external charitable agencies, generous philanthropy from the UHN Foundation and our incredible patient partners, says Wouters, who is also a professor in thedepartment of radiation oncologyat U of T. This award recognizes the tireless efforts of the team, and this support, which have been key to achieving global impact.

The New Frontiers Research Fund was designed to support large-scale, Canadian-led interdisciplinary research projects with the potential to realize real and lasting change.

The fund falls under the strategic direction of theCanada Research Coordinating Committeeand is administered by the Tri-Agency Institutional Programs Secretariat on behalf of Canada's three research granting agencies: theSocial Sciences and Humanities Research Council, theCanadian Institutes of Health Researchand theNatural Sciences and Engineering Research Council.

Over the course of this project, the team of over 20 researchers at U of T, UHN, national and international partner sites will develop sophisticated ex vivo platforms to:

Longer ex vivo preservation prior to transplant will enable many world-first therapeutic applications that will, ultimately, create more organs for clinical transplant.

One example is to use gene therapy to make an organ more like the recipient's cells and help to address the current hurdle of organ rejection by the immune system. Researchers at UHN are also working on changing an organ's blood type so the sickest people can get access to the next available organ, instead of waiting for one that exactly matches their blood a delay that currently can take several months before a match is found.

Another transformative goal is to use medicines and light therapies in the ex vivo circuit to eliminate viral or bacterial infections that previously prevented an organ to be considered for transplant.

"This grant gives us a unique opportunity to extend personalized medicine to every organ group," saysMarcelo Cypel, a professor in the department of surgery at U of T and surgical director of the Ajmera Transplant Centre, who is also a co-principal investigator on the project.

"Not only will it enable longer preservation, this research will let us treat and improve organs. It has the potential to change the paradigm in the field of transplantation."

The change will include several advanced applications, such as the engineering of new organs using stem cells with the goal to make organs available for all in need. Significant progress has already been made in generating new kidneys, lungs and tracheae (windpipe), and their applications will be tested further during the six-year project term.

With the involvement of a multidisciplinary team housed in a world-class centre at UHN, the project will bring personalized medicine to transplant, and go beyond solid organs.

Siba Haykal, plastic and reconstructive surgeon and project co-principal investigator, will lead research involving vascularized composite allotransplantation the transplant of limbs, face, trachea and composite tissues, such as skin and muscles.

"These are very delicate tissues that can't survive outside the body for very long and are very susceptible to rejection," she explains, adding that the current treatment involves high doses of life-long anti-rejection medication for transplant recipients.

Haykal and the team want to develop a system to preserve limbs and tissues out of the body without blood flow for longer periods. This will enable the application of new cell therapies to adapt these tissues to the recipient prior to surgery.

"Whether they have been disfigured by burns or from trauma or cancer, if they've had an amputation and need prosthetic limbs or if they require a new airway, transplantation provides hope for these patients who currently don't have many options," says Haykal, who is an assistant professor in the department of surgery at U of T.

"If we can use techniques that reduce the amount of anti-rejection medication and maybe one day get to a stage where they don't need it anymore, that would have a huge impact on the patient's quality of life."

Humar adds, "I have seen so many people who have literally been at death's door and have been completely turned around by transplant and live a full and healthy life. If we can offer that to more patients, then for me that would be an incredible achievement.

"This funding will also help us disseminate our knowledge, and facilitate other hospitals across Canada and around the world build upon what we're doing at UHN."

This story wasoriginally postedon the University Health Network website.

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UHN and U of T receive $24-million federal grant for transplant research - News@UofT

Ethical statement, study design and allocationEthical statement

Approval was obtained from the ethical committee of Faculty of Medicine, Mansoura University (No. R21.05.1328) in accordance with principles of laboratory animal care NIH publication revised 1985 (Code number: 2020107). Reporting of all experimental procedures complied with recommendations in ARRIVE guidelines.

Randomized, placebo-controlled, blinded animal study was conducted. The sample size was calculated using G power 3.9.1.4 software, to detect a 0.7 effect size between the null hypothesis and the alternative hypothesis with significance level of 0.05 and a power of 0.85, using a one-way ANOVA F-test. Twenty seven male Wistar rats, 100120g, were maintained in a controlled temperature (2426C), relative humidity of 6080% and on a 12-h lightdark cycle for one week acclimatization. Rats were randomly allocated using list randomizer (https://www.random.org/lists) into 3 groups with 9 rats/group as follow; Group1: served as a control, Group 2: represented diabetic rats, and Group 3: denoted as the treated group in which the diabetic rats received intraperitoneal (IP) injection of 100mg/kg/3 times a week GA (Sigma-Aldrich, St Louis, MO, USA) for 8 weeks33,34.

After overnight fasting, rats assigned to groups 2 and 3 were injected with (50mg/kg/ip) of freshly prepared streptozotocin (STZ) dissolved in citrate buffer, pH 4.5 (STZ, Sigma Chemical Co., St. Louis, MO, USA) while, the control animals in group 1 were injected by an equal volume of the buffer by the same qualified person35. Three days after the STZ injection, animals with stable fasting blood glucose levels at>250mg/dl were considered diabetic.

After eight weeks of treatment, all rats were anesthetized with Xylazine (5mg/kg, ADWIA Co. S.A.E 10 of Ramadan city, Egypt) and Ketamine (40mg/kg, Segmatec Pharmaceutical Industries Co., Egypt) injection into the peritoneum (IP) and euthanized by decapitation (at 8 am to minimize the circadian effect)36,37 and the SMG tissues were collected. The right halves were processed for the histological analysis, and the left halves were snap frozen in liquid nitrogen and kept at 80C until used for oxidative stress estimation, RT-PCR and ELISA techniques.

The 4m sections of paraformaldehyde-fixed and paraffin-embedded SMG tissues were stained with hematoxylin and eosin (H&E). For the semithin sections, tissue biopsies were dehydrated through an ascending series of ethanol (to 100%) and then washed in dry acetone and embedded in epoxy resin then stained with toluidine blue.

The protein expression of SIRT1 (Bioss Antibodies, USA, 1:200), ET-1 (Bioss Antibodies, USA, 1:200), AQP1 (Scervicebio Co., USA, 1:1000), AQP4 (Scervicebio Co., USA, 1:1500), AQP5 (ABclonal, USA, 1:200) and autophagy biomarkers LC3 (Abcam, USA, 1:1200), P62 (ABclonal, USA, 1:200) were determined in each group by incubating tissue sections in primary antibodies overnight followed by incubation with secondary antibodies to perform IHC. The visualization of slides was detected using 3,3-Diaminobenzidine (DAB, Abcam, USA), and counterstained with hematoxylin. Then, the sections were analyzed and photographed using an Olympus microscope (Japan) with installed camera. The positive reaction was thresholded and calculated in relation to the surface area using Image J. The data were then decoded and statistically analyzed.

The SMG tissue was homogenized with sodium phosphate buffer, centrifuged, and the supernatant was used for the biochemical analysis. Oxidative stress markers; reduced glutathione (GSH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured spectrophotometrically38,39.

Rat Beclin-1 ELISA Kit (MBS733192) and Rat LC3II ELISA kit (MBS169564) were used for quantitative measurement of Beclin-1and LC3II protein levels in the SMG homogenate according to the manufacturers instructions.

Total RNA was extracted from SMG samples, and then RNA quality and purity were assured. Then cDNA was synthesized from RNA. The cDNA was amplified and used in SYBR Green Based Quantitative Real-Time PCR. For Relative Quantification (RQ) of LC3 gene expression, a primer with Gene Bank Accession No. NM_022867.2, Forward sequence: 5-ACG-GCT-TCC-TGT-ACA-TGG-TC-3 and Reverse sequence: 5-GTG-GGT-GCC-TAC-GTT-CTG-AT was used. And for AQP5, a primer with Gene Bank Accession No. NM_012779.2 was used. The forward primer sequence was 5-GGGCCATCTTGTGGGGATCT-3 and the reverse primer sequence was 5-CCAGTGAGAGGGGCTGAACC-3. The RQ of both genes expression was performed using comparative 2Ct method, where the amount of the target genes mRNA were normalized to an endogenous reference gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and relative to a control40.

Data were tested for normal distribution by ShapiroWilk test. Quantitative data were analyzed using Graph Prism 8 (GraphPad Software, Inc., CA, USA) to test the significance between different groups using analysis of variance (ANOVA) followed by Tukeys test. Data were presented as meanstandard error (SE). Significance was inferred at P<0.05.

Originally posted here:
Glycyrrhizic acid ameliorates submandibular gland oxidative stress, autophagy and vascular dysfunction in rat model of type 1 diabetes | Scientific...

Four years ago, a small Philadelphia biotech company won U.S. approval for the first gene therapy to treat an inherited disease, a landmark after decades of research aimed at finding ways to correct errors in DNA.

Since then, most of the world's largest pharmaceutical companies have invested in gene therapy, as well as cell therapies that rely on genetic modification. Dozens of new biotech companies have launched, while scientists have taken forward breakthroughs in gene editing science to open up new treatment possibilities.

But the confidence brought on by such advances has also been tempered by safety setbacks and clinical trial results that fell short of expectations. In 2022, the outlook for the field remains bright, but companies face critical questions that could shape whether, and how soon, new genetic medicines reach patients. Here are five:

Food and Drug Administration approval of Spark Therapeutics' blindness treatment Luxturna a first in the U.S. came in 2017. A year and a half later, Novartis' spinal muscular atrophy therapy Zolgensma won a landmark OK.

But none have reached market since, with treatments from BioMarin Pharmaceutical and Bluebird bio unexpectedly derailed or delayed.

That could change in 2022. Two of Bluebird's treatments, for the blood disease beta thalassemia and a rare brain disorder, are now under review by the FDA, with target decision dates in May and June. BioMarin, after obtaining more data for its hemophilia A gene therapy, plans to soon approach the FDA about resubmitting an application for approval.

Others, such as CSL Behring and PTC Therapeutics, are also currently planning to file their experimental gene therapies with the FDA in 2022.

Approvals, should they come, could provide important validation for their makers and expand the number of patients for whom genetic medicines are an option. In biotech, though, approvals aren't the end of the road, but rather the mark of a sometimes challenging transition from research to commercial operations. With price tags expected to be high, and still outstanding questions around safety and long-term benefit, new gene therapies may prove difficult to sell.

A record $20 billion flowed into gene and cell therapy developers in 2020, significantly eclipsing the previous high-water mark set in 2018.

Last year, the bar was set higher still, with a total of $23 billion invested in the sector, according to figures compiled by the Alliance for Regenerative Medicine. About half of that funding went toward gene therapy developers specifically, with a similar share going to cell-based immunotherapy makers.

Driving the jump was a sharp increase in the amount of venture funding, which rose 73% to total nearly $10 billion, per ARM. Initial public offerings also helped, with sixteen new startups raising at least $50 million on U.S. markets.

Entering 2022, the question facing the field is whether those record numbers will continue. Biotech as a whole slumped into the end of last year, with shares of many companies falling amid a broader investment pullback. Gene therapy developers, a number of which had notable safety concerns crop up over 2021, were hit particularly hard.

Moreover, many startups that jumped to public markets hadn't yet begun clinical trials roughly half of the 29 gene and cell therapy companies that IPO'd over the past two years were preclinical, according to data compiled by BioPharma Dive. That can set high expectations companies will be hard pressed to meet.

Generation Bio, for example, raised $200 million in June 2020 with a pipeline of preclinical gene therapies for rare diseases of the liver and eye. Unexpected findings in animal studies, however, sank company shares by nearly 60% last December.

Still, the pace of progress in gene and cell therapy is fast. The potential is vast, too, which could continue to support high levels of investment.

"I think fundamentally, investment in this sector is driven by scientific advances, and clinical events and milestones," said Janet Lambert, ARM's CEO, in an interview. "And I think we see those in 2022."

The potential of replacing or editing faulty genes has been clear for decades. How to do so safely has been much less certain, and concerns on that front have set back the field several times.

"Safety, safety and safety are the first three top-of-mind risks," said Luca Issi, an analyst at RBC Capital Markets, in an interview.

Researchers have spent years making the technology that underpins gene therapy safer and now have a much better understanding of the tools at their disposal. But as dozens of companies push into clinical trials, a number of them have run into safety problems that raise crucial questions for investigators.

In trials run by Audentes Therapeutics and by Pfizer (in separate diseases), study volunteers have tragically died for reasons that aren't fully understood. UniQure, Bluebird bio and, most recently, Allogene Therapeutics have reported cases of cancer or worrisome genetic abnormalities that triggered study halts and investigations.

While the treatments being tested were later cleared in the three latter cases, the FDA was sufficiently alarmed to convene a panel of outside experts to review potential safety risks last fall. (Bluebird recently disclosed a new hold in a study of its sickle cell gene therapy due to a patient developing chronic anemia.)

The meeting was welcomed by some in the industry, who hope to work with the FDA to better detail known risks and how to avoid them in testing.

"[There's] nothing better than getting people together and talking about your struggles, and having FDA participate in that," said Ken Mills, CEO of gene therapy developer Regenxbio, in an interview. "The biggest benefit probably is for the new and emerging teams and people and companies that are coming into this space."

Safety scares and setbacks are likely to happen again, as more companies launch additional clinical trials. The FDA, as the recent meeting and clinical holds have shown, appears to be carefully weighing the potential risks to patients.

But, notably, there hasn't been a pullback from pursuing further research, as has happened in the past. Different technologies and diseases present different risks, which regulators, companies and the patient community are recognizing.

"We're by definition pushing the scientific envelope, and patients that we seek to treat often have few or no other treatment options," said ARM's Lambert.

Last June, Intellia Therapeutics disclosed early results from a study that offered the first clinical evidence CRISPR gene editing could be done safely and effectively inside the body.

The data were a major milestone for a technology that's dramatically expanded the possibility for editing DNA to treat disease. But the first glimpse left many important questions unanswered, not least of which are how long the reported effects might last and whether they'll drive the kind of dramatic clinical benefit gene editing promises.

Intellia is set to give an update on the study this quarter, which will start to give a better sense of how patients are faring. Later in the year the company is expecting to have preliminary data from an early study of another "in vivo" gene editing treatment.

In vivo gene editing is seen as a simpler approach that could work in more diseases than treatments that rely on stem cells extracted from each patient. But it's also potentially riskier, with the editing of DNA taking place inside the body rather than in a laboratory.

Areas like the eye, which is protected from some of the body's immune responses, have been a common first in vivo target by companies like Editas Medicine. But Intellia and others are targeting other tissues like the liver, muscle and lungs.

Later this year, Verve Therapeutics, a company that uses a more precise form of gene editing called base editing, plans to treat the first patient with an in vivo treatment for heart disease (which targets a gene expressed in the liver.)

"The future of gene editing is in vivo," said RBC's Issi. His view seems to be shared by Pfizer, which on Monday announced a $300 million research deal with Beam Therapeutics to pursue in vivo gene editing targets in the liver, muscle and central nervous system.

With more and more cell and gene therapy companies launching, the pipeline of would-be therapies has grown rapidly, as has the number of clinical trials being launched.

Yet, many companies are exploring similar approaches for the same diseases, resulting in drug pipelines that mirror each other. A September 2021 report from investment bank Piper Sandler found 21 gene therapy programs aimed at hemophilia A, 19 targeting Duchenne muscular dystrophy and 18 going after sickle cell disease.

In gene editing, Intellia, Editas, Beam and CRISPR Therapeutics are all developing treatments for sickle cell disease, with CRISPR the furthest along.

As programs advance and begin to deliver more clinical data, companies may be forced into making hard choices.

"[W]e think investors will place greater scrutiny as programs enter the clinic and certain rare diseases are disproportionately pursued," analysts at Stifel wrote in a recent note to investors, citing Fabry disease and hemophilia in particular.

This January, for example, Cambridge, Massachusetts-based Avrobio stopped work on a treatment for Fabry that was, until that point, the company's lead candidate. The decision was triggered by unexpected findings that looked different than earlier study results, but Avrobio also cited "multiple challenging regulatory and market dynamics."

Read the rest here:
5 questions facing gene therapy in 2022 - BioPharma Dive

It was either die or do this transplant, Mr. Bennett said before the surgery, according to officials at the University of Maryland Medical Center. I want to live. I know its a shot in the dark, but its my last choice.

Dr. Griffith said he first broached the experimental treatment in mid-December, a memorable and pretty strange conversation.

I said, We cant give you a human heart; you dont qualify. But maybe we can use one from an animal, a pig, Dr. Griffith recalled. Its never been done before, but we think we can do it.

I wasnt sure he was understanding me, Dr. Griffith added. Then he said, Well, will I oink?

Xenotransplantation, the process of grafting or transplanting organs or tissues from animals to humans, has a long history. Efforts to use the blood and skin of animals go back hundreds of years.

In the 1960s, chimpanzee kidneys were transplanted into some human patients, but the longest a recipient lived was nine months. In 1983, a baboon heart was transplanted into an infant known as Baby Fae, but she died 20 days later.

Pigs offer advantages over primates for organ procurements, because they are easier to raise and achieve adult human size in six months. Pig heart valves are routinely transplanted into humans, and some patients with diabetes have received porcine pancreas cells. Pig skin has also been used as a temporary graft for burn patients.

Two newer technologies gene editing and cloning have yielded genetically altered pig organs less likely to be rejected by humans. Pig hearts have been transplanted successfully into baboons by Dr. Muhammad Mohiuddin, a professor of surgery at University of Maryland School of Medicine who established the cardiac xenotransplantation program with Dr. Griffith and is its scientific director. But safety concerns and fear of setting off a dangerous immune response that can be life-threatening precluded their use in humans until recently.

Link:
In a First, Man Receives a Heart From a Genetically Altered Pig - The New York Times

By Allison Proffitt

January 13, 2022 | At the JP Morgan Healthcare Conferencebeing held virtually again this yearpharma and biotech companies gave overviews of their 2021 business and their views of the future. Here are the highlights we noted from presentations from Regeneron, 10X Genomics, and Invitae

Regeneron: Investing in Antibodies

Regeneron CEO and founder Leonard Schleifer reported 20% top line growth for the company in 2021if you exclude their covid antibodies. With the REGEN-COV monoclonal antibody treatment for Covid-19, the company saw 83% growth year over year.

Schleifer touted diversified growth drivers for Regeneron in the future. Their oncology suite has seen success, they said, and they particularly highlighted opportunities to reach oncology targets via drug combinations.

Co-founder and CSO George Yancopoulos spent his time highlighting the Regeneron Genetics Center, which has sequenced more than two million volunteers to date, all of whom have linked their electronic health record to the genetic data, he said. The work has already led to genetic drug targets and changes in clinical trial design, he added.

He emphasized the future of the Regeneron Genetic Medicine initiative, taking the data gleaned from the RGC and combining it with external partner expertise to develop genomic medicines. Partnerships are a key strategy in Regenerons efforts here, and Yancopoulos mentioned Alnylam, Intellia, and Decibel specifically. We are well-positioned to be at the forefront of the next wave of biotech innovation. While still in its infancy, we think that these ground-breaking technologies such as siRNAs, CRISPR-based therapies, as well as virally-directed gene therapy have the potential to be just as large as the biologics are today, Yancopoulos said.

But perhaps the largest target in Regenerons future plans are Covid-19 antibodies. The biggest growth driver for the company last year is essential to overcoming the pandemic, argued Yancopoulos. The most vulnerable part of the entire population, the immunocompromised, which represent about 5-10 million people in America alone, dont respond wellor at all!to vaccines. If youre giving everybody else boosters twice a year, what are you going to be doing for these people who are more vulnerable because they dont have any ability to fight back to the virus, he said. This is where we think essentially giving them a surrogate immune systema surrogate antibody responsesuch as we can with our monoclonal antibodies can really help these individuals.

10X Genomics: News for In Situ

Serge Saxonov, CEO and co-founder of 10X Genomics, summarized the landscape of single-cell sequencing and announced a new in situ product. Weve been making significant advances across many different areas spanning hardware, chemistry, and softwarepushing the state of the artand we will put these advances into the new platform we will bring to market, Saxonov said.

The new Xenium platform will be a single molecule RNA and protein platform offering subcellular resolution, high-throughput, analysis suite, and pre-designed and custom panels. Saxonov declined to give further details, but said a technology access program is expected for 2022 and commercial availability in 2023. It will be designed for ease of use, robustness, and throughput. As will all our products, our overarching goal for Xenium is that it just works, he added.

It was a refrain he mentioned several times as evidence for 10Xs success. We dont constrain our thinking to any particular technology or any particular platform. We start with biology, think critically about where the world is going, what are the big questions, the big capabilities that the world is going to need, and we work backward to figure out what technologies and products were going to build, Saxonov said. We strive to delight our customers. One thing that were particularly proud of is that our customers often tell us that our products just work. That quality, that ease-of-use is actually a result of tons of innovation and advanced technology innovation that goes into making our products. We do the hard work on the backend so for the customer its easy. It just works.

Besides Xenium, Saxonov focused on highlighting ease-of-use improvements to the companys Chromium and Visium platforms. For Chromium, 10X is launching new kits to enable analysis of fixed tissues. In general, samples need to be collected, packaged, transported, and prepared for single-cell analysis, all within a day or less to maintain cell viability, Saxonov said. The companys new Fixed RNA Profiling Kit will let users fix tissues at time of collection, so the patterns of gene and protein expression are chemically frozen in place, he said, using a common fixation technique along with new assay chemistry. Once the tissue is fixed, samples can be shipped, stored, and processed in batch without rush. We expect this product to be a significant enabler, especially for translational and pharma customers, Saxonov said. Its expected to be available mid-2022.

He also announced two antibody and T-cell receptor products, both of which will be available in the second half of 2022. BEAM-Ab enables general antibody discovery and BEAM-T empowers discovery of optimal T cells for hyper-personalized cancer cell therapy. Now, Saxonov said, anyone will be able to discovery excellent antibodies with minimal effort.

For Visium, 10Xs spatial genomics platform, Saxonov announced Visium CytAssist coming later this year. The hardware tool is meant to bridge the worlds of histology and genomics by transferring molecules from pre-mounted standard glass slides to Visium slides, simplifying sample handling and adapting Visium to pre-existing histology workflows.

At the place and time of their choosing, the customer can preview and choose the best tissue section for their Visium assay, and initiate Visium workflow through CytAssist, Saxonov said. CytAssist will open up tissue sample archives currently stored on glass slides for Visium analysis.

Invitae: Launching A Patient-Owned Data Network

Sean George announced Invitaes new open-ended, multi-sided, patient-owned and controlled network of data to be used to increase the utility of the genomic information. Built on top of Invitaes September acquisition of Ciitizen for $325 million, the Ciitizen Patient Network is available now to Invitaes business partners and individuals and will help pool health information in one place for patients to use as they wish. Whats really important about this, George repeated, is that, it is 100% patient owned, patient controlled, consented, and fully trusted. Wherever that information is going to go, it will be at the behest of the patient and only at the behest of the patient.

The network is the next step in Invitaes longstanding vision of genome management, George said. Its not so much about a single test itself, but about a package of information that can be delivered to the right place at the right time.

For several care areasnewborn and rare disease, reproductive and womens health, and oncologyGeorge reported that by the end of the year, Invitae will have the most comprehensive offering on the market for risk testing, counseling tools, therapy selection, and next steps and monitoring. He flagged cardiovascular disease, neurodegenerative disease, and pharmacogenomics as areas for future investment and develop for Invitae.

The companys efforts to create a platform of tests and counseling options and build a network of partners have laid the groundwork for sharing genetics on a global scale to diagnose more patients and bring therapies to market earlier.

We do presently have some of our own testing competitors accessing that data and running analyses on it to whatever ends. Its up to them and to the patients that own that data. But we believe that is the nature of this kind of network that has to be in place to really drive us into genome management in the future, George said.

At the genome management phase of the platform, George predicts costs will be driven down and data will moved into the hands of ecosystem players that can develop more therapies. We have ambitions, in the future, not just to work with healthcare ecosystem partners, not just to work with healthcare data partners, but eventuallyas we move into the era of genome managementit is all of retail, all of tech, anybody with a device, anybody who can bring anything to the table to help an individual understand and navigate a specific point of their healthcare journey, he said. We believe that this kind of patient network will be fundamental in enabling that in the future, and we couldnt be more excited to be launching this today.

Link:
Antibodies, Easy Single-Cell, Genomics for All: Notes from the JP Morgan Healthcare Conference - Bio-IT World

What if we could help threatened wildlife better adapt to the intractable threats many species are facing from challenges like climate change and disease?

The United Nations has warned that about a million animal and plant species are at risk of extinction. In response, conservation breeding programs are ramping up to boost and protect populations.

The problem is that while conservation breeding can prevent extinction, it doesnt allow threatened species to survive in the wild in the face of these difficult to mitigate threats.

So, while it is critical that we address climate change and diseases, we also need to be urgently looking at way to make it easier for species to live with the threats.

This is where Targeted Genetic Intervention (TGI) comes in.

TGI works by adapting methods that are successfully used in agriculture and medicine in which an individuals genetics are tweaked in ways that, when passed on to the wider population through breeding, can change the traits of a species to improve its survival.

Read more

Two of the most promising approaches in this toolkit include artificial selection and synthetic biology.

Artificial selection has been used for thousands of years in animal and plant breeding to produce pets, farm animals and agriculture crops with desired features.

This has led to the development of many of the animals and plants we now rely on for food or companionship like dairy cattle, rice and Golden Retrievers.

These approaches were even lauded by English naturalist Charles Darwin for their astonishing ability to generate from wolves our domesticated dogs which are as different as Chihuahuas and Great Danes.

Today, advances in genomic approaches have made artificial selection methods considerably more sophisticated than in Darwins day. We can now use genomic information to predict what traits an animal will have with an approach known as genomic selection.

Genomic selection may be a game changer for endangered wildlife because it allows for the development of informed breeding strategies that promote adaptation.

It works by first understanding and identifying what genetic features make members of a species more adapted to an environment or threat than others. This is usually done by exposing individuals in a reference population to the threat (like heat stress or infectious disease) and then measuring their response.

Read more

We then look for genes that are present in individuals that resist and survive the threat. This genetic information can be used to predict which animals in the breeding population are better adapted to survive a given threat based on their own genotype.

Over time, the use of genomic selection as a breeding strategy can increase the average ability of these individuals in the breeding population to survive by promoting adaptation in captivity.

The ability to use this sort of genomic prediction data based on discrete groups of individuals is a major advantage because it means that risky activities, like exposing a population to a disease or other infection as part of a trial, can be performed separately in laboratories away from the critical breeding populations.

Synthetic biology is newer and more controversial than artificial selection. It includes methods like transgenesis and gene editing.

While these methods frequently figure in science fiction and are sometimes feared for their unintended consequences, the real science of synthetic biology is gaining traction in the conservation community due to its many benefits.

Additionally, a recent public opinion survey conducted by the Commonwealth Scientific and Industrial Research Organisation (CSIRO) indicates that the public are moderately-to-strongly supportive of use of synthetic biology approaches for conservation.

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Synthetic biology can be used to introduce lost or novel genes and tweak specific genetic features of an organism without changing other characteristics, which often occurs with less targeted approaches like artificial selection.

Transgenesis does this by incorporating foreign DNA from a different species into the genome. Gene editing is more subtle and works by inducing the organism itself to knock out or replace targeted genes.

American Chestnut trees, corals and black-footed ferrets are just some of the species that synthetic biology methods are currently being trialled to assist with restoration. American Chestnut trees, in particular, are a great success story for the use of synthetic biology for conservation.

This species was driven to virtual extinction in North America after the introduction of the Asian Chestnut Blight fungus in the late 1800s.

Various approaches have been tested to increase resistance to this pathogen with varying degrees of success, but since the tree lacks natural resistance, the most effective approach to date has involved using transgenesis to introduce a new disease-tolerant gene from wheat.

This has produced American Chestnut trees that appear to be blight tolerant. Trial plantings of these trees in American forests may soon start, pending regulatory approval.

Read more

My research group at the University of Melbourne was recently awarded grants from the Australian Research Council (here and here) to test TGI approaches in various Australian frogs vulnerable to extinction.

Many frogs in Australia and globally are threatened by the devastating fungal disease chytridiomycosis. This disease is caused by the introduced fungus Batrachochytrium dendrobatidis and unfortunately few options exist for restoring frogs susceptible to this disease to the wild.

We are working with various institutions including Zoos Victoria and the Taronga Conservation Society to investigate if TGI approaches can be used to increase chytridiomycosis resistance in Australian frogs.

We are currently working on the iconic Southern Corroboree frog (Pseudophryne corroboree) and, in the next few years, we intend to add additional species like the Green and Golden Bell frog (Litoria aurea) and Northern Corroboree frog (Pseudophryne pengilleyi).

Its imperative that we as a community investigate the application of TGI approaches for conservation as in some cases they may be the only way to restore a species in the wild.

Read more

But with this comes the responsibility of the public, government and scientists to not only fund research on TGI, but to also make sure that it is done responsibly with careful consideration to all entities impacted and with proper evaluation of all potential risks.

Since TGI for conservation is a new concept, species modified by TGI should be evaluated to ensure that induced genetic changes increase survival and that the organisms pose no risk to the environment by occupying a different niche or position in the food chain.

Given the scale and seriousness of the challenge in conserving our wildlife, and given the established efficacy of TGI, its an approach that we cant afford to ignore.

The ideas introduced in this article are discussed in more detail in our recent article in the journal Trends in Ecology and Evolution. Dr Koschs co-authors are Anthony W. Waddle, Dr Caitlin A. Cooper, Professor Kyall R. Zenger, Professor Dorian J. Garrick, Associate Professor Lee Berger, and Professor Lee F. Skerratt.

The southern corroboree frog genome is being sequenced for the researchers by the Vertebrate Genomes Project.

Banner: Getty Images

View post:
Using genetics to conserve wildlife - Pursuit

At a Glance

Approximately 1,800 children in the United States die from sudden, unexplained causes each year, most while asleep. When it happens in children under 1 year of age, it's called sudden infant death syndrome (SIDS). In children 1 year of age or older, its called sudden unexplained death in children (SUDC). While SIDS cases outnumber SUDC cases by four to one, research funding and published studies for SIDS have dwarfed that for SUDC.

A research team led by Drs. Richard Tsien and Orrin Devinsky at the NYU Grossman School of Medicine sought to identify genetic mutations that might contribute to SUDC. To do so, they sequenced DNA from 124 SUDC cases and their parents. DNA was extracted from samples collected through the SUDC Registry and Research Collaborative.

NIHs National Institute on Drug Abuse (NIDA) and National Institute of Mental Health (NIMH) supported the work. Results appeared in Proceedings of the National Academy of Sciences on December 28, 2021.

The team first sequenced whole exomes, the 1% of the human genome that codes for proteins. There werent enough subjects to uncover genetic associations in a broad, initial analysis. The researchersthen focused on 137 genes associated with heart or seizure disorders, both of which can trigger sudden death.

They found that in SUDC cases, these genes contained significantly more mutations than would be expected by chance. Most were de novo mutations, meaning that while they were found in the child, they werent found in either parent. A handful of potentially harmful mutations in these genes occurred in parents. In such cases, the mutation also showed up in the offspring 80% of the timeagain, more often than would be expected by chance.

The researchers identified 11 particular mutations that were likely to cause health problems. These mutations were estimated to contributed to death in 9% of cases. Many of the mutations occurred in a cluster of genes that regulate calcium in neurons and heart muscle cells. Calcium changes in these cells control nerve signal transmission and muscle contraction. Mutations in one of the genes, RYR2, have been linked to heart problems. Mutations in another, CACNA1C, have been linked to a rare disorder, called Timothy syndrome, that can affect the heart, limbs, muscle, and brain.

The results suggest that altered calcium signaling may play a significant role in SUDC. They also highlight the importance of de novo mutations for SUDC risk. Studies in larger samples might reveal additional genetic risk factors. Identifying these risk factors is the first step towards developing life-saving medical interventions.

Our study is the largest of its kind to date, the first to prove that there are definite genetic causes of SUDC, and the first to fill in any portion of the risk picture, Tsien says. Along with providing comfort to parents, new findings about genetic changes involved will accumulate with time, reveal the mechanisms responsible, and serve as the basis for new treatment approaches.

by Brian Doctrow, Ph.D.

Funding:NIHs National Institute on Drug Abuse (NIDA) and National Institute of Mental Health (NIMH); SUDC Foundation; Finding a Cure for Epilepsy and Seizures (FACES); Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

Read this article:
Genetics of sudden unexplained death in children - National Institutes of Health

Full-Year 2021 Galafold Revenue of ~$306M, Representing 17% YoY Growth

Expect Double-Digit Growth (15-20%) of 2022 Galafold Revenue with $350M-$365M in Global Sales

U.S. and EU Regulatory Reviews Underway for AT-GAA in Pompe Disease

AT-GAA Global Launch Preparations Accelerating

Cash Flow and Balance Sheet Sufficient to Achieve Self-Sustainability and Profitability by 2023

PHILADELPHIA, Jan. 10, 2022 (GLOBE NEWSWIRE) -- Amicus Therapeutics (Nasdaq: FOLD), a patient-dedicated global biotechnology company focused on developing and commercializing novel medicines for rare diseases, today provided its preliminary and unaudited 2021 revenue, corporate updates, and full-year 2022 outlook and revenue guidance.

Corporate Highlights:

Global revenue for Galafold (migalastat) in 2021 reached $306 million driven by strong new patient accruals and sustained patient adherence, representing a year-over-year increase of 17%.

AT-GAA regulatory reviews are underway: In the U.S., the Food and Drug Administration (FDA) accepted for review the Biologics License Application (BLA) for cipaglucosidase alfa and the New Drug Application (NDA) for miglustat, the two components of AT-GAA. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of May 29, 2022 for the NDA and July 29, 2022 for the BLA. In the EU, the Marketing Authorization Applications (MAA) were submitted and validated in the fourth quarter by the European Medicines Agency (EMA).

AT-GAA launch preparations are accelerating: Development of global launch plans, targeted investments in additional personnel, and launch inventory are fully underway as company believes AT-GAA can rapidly become the new standard of care treatment regimen for people living with Pompe disease.

Pipeline of next generation genetic medicines to advance through both internal efforts and creation of R&D focused new company, Caritas Therapeutics.

Cash Flow and Balance Sheet sufficient to achieve self-sustainability and profitability in 2023. Through careful management of expenses, the Company is on the path to achieve self-sustainability and profitability in 2023 as it executes on the global Galafold expansion and prepares for AT-GAA global launch.

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John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, Inc., stated, In 2021, Amicus made great strides for people worldwide living with rare diseases through the broad execution of our annual strategic priorities. Despite the resurgence of COVID with Delta and Omicron variants, the Galafold business remains very strong, and we delivered on our full year revenue guidance and expect robust growth this year driven by strong adoption across the globe for our Fabry disease precision medicine. We are underway with the global regulatory reviews and launch preparations for AT-GAA in Pompe disease with high expectations that this novel medicine has the potential to become the new standard of care in Pompe disease treatment and the potential to address unmet needs for thousands of Pompe patients in the years ahead. We see further opportunity ahead to impact the lives of those living with rare disease through our genetic medicine business and capabilities. Together, Amicus is in a stronger position than ever and we remain steadfast on our mission of transforming the lives of people living with rare, life-threatening conditions and creating significant value for our shareholders.

Bradley Campbell, President and Chief Operating Officer of Amicus Therapeutics, Inc., stated, We are looking ahead to transforming Amicus into a leading global rare disease biotechnology company led by two innovative therapies that we believe meaningfully impact the lives of people living with Fabry and Pompe disease. This year we will be focused on continuing to bring Galafold to patients around the world and delivering on the anticipated approval and launch of AT-GAA.

Amicus is focused on the following five key strategic priorities in 2022:

Continued double-digit Galafold growth (15-20%) with revenue of $350M to $365M

Secure FDA approval and positive CHMP opinion for AT-GAA

Initiate successful, rapid launch in the U.S. for AT-GAA

Advance best-in-class next generation genetic medicines and capabilities

Maintain strong financial position on path to profitability

Mr. Crowley and Mr. Campbell will discuss the Amicus corporate objectives and key milestones in a presentation at the 40th Annual J.P. Morgan Healthcare Conference on Wednesday, January 12, 2022, at 3:45 p.m. ET. A live webcast of the presentation can be accessed through the Investors section of the Amicus Therapeutics corporate website at http://ir.amicusrx.com/events.cfm, and will be archived for 90 days.

Full-Year 2021 Revenue Summary and 2022 Revenue Guidance

Global revenue for Galafold in full-year 2021 was approximately $306 million, preliminary and unaudited, representing a year-over-year increase of 17% from total revenue of $260.9 million in 2020. Full-year revenue benefited from a positive currency impact of approximately $7 million. Fourth quarter Galafold revenue was approximately $84 million, preliminary and unaudited.

For the full-year 2022, the Company anticipates total Galafold revenue of $350 million to $365 million. Double-digit revenue growth (15-20%) in 2022 is expected to be driven by continued underlying demand from both switch and nave patients, geographic expansion, the continued diagnosis of new Fabry patients and commercial execution across all major markets, including the U.S., EU, U.K., and Japan.

The current cash position is sufficient to achieve self-sustainability and profitability in 2023.

Updates and Anticipated Milestones by Program

Galafold (migalastat) Oral Precision Medicine for Fabry Disease

Sustain double-digit revenue growth in 2022 of $350 million to $365 million

Continue geographic expansion

Registry and other Phase 4 studies ongoing

AT-GAA for Pompe Disease

U.S. Prescription Drug User Fee Act (PDUFA) action date of May 29, 2022 for the NDA and July 29, 2022 for the BLA

EU Committee for Medicinal Products for Human Use (CHMP) opinion expected in late 2022

Continue to broaden access through early access plans in the U.K., Germany, Japan, and other countries

Ongoing supportive studies, including pediatric and extension studies

Gene Therapy Pipeline

Advance IND-enabling studies, manufacturing activities, and regulatory activities for the Fabry disease gene therapy program towards an anticipated IND in 2023

Progress preclinical studies, manufacturing activities, and regulatory activities for the Pompe disease gene therapy program

Discontinue CLN6 Batten disease gene therapy program following review of long-term extension study data. It was recently determined that any initial stabilization of disease progression at the two-year time point was not maintained through the long-term extension study. Amicus plans to further analyze and share the Phase 1/2 data with key stakeholders in the CLN6 Batten disease community and work with the community to support continued research efforts to find better treatments and cures which are so desperately and urgently needed

Advance CLN3 Batten disease program with the higher dose, different promoter, and intra-cisterna magna (ICM) route of delivery pending further Phase 1/2 clinical data and pre-clinical data expected in 2022. These data will inform timeline for commencement of any pivotal clinical study

About GalafoldGalafold (migalastat) 123 mg capsules is an oral pharmacological chaperone of alpha-galactosidase A (alpha-Gal A) for the treatment of Fabry disease in adults who have amenable galactosidase alpha gene (GLA) variants. In these patients, Galafold works by stabilizing the bodys own dysfunctional enzyme so that it can clear the accumulation of disease substrate. Globally, Amicus Therapeutics estimates that approximately 35 to 50 percent of Fabry patients may have amenable GLA variants, though amenability rates within this range vary by geography. Galafold is approved in over 40 countries around the world, including the U.S., EU, U.K., Japan and others.

U.S. INDICATIONS AND USAGEGalafold is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data.

This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

U.S. IMPORTANT SAFETY INFORMATION

ADVERSE REACTIONSThe most common adverse reactions reported with Galafold (10%) were headache, nasopharyngitis, urinary tract infection, nausea and pyrexia.

USE IN SPECIFIC POPULATIONSThere is insufficient clinical data on Galafold use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

It is not known if Galafold is present in human milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Galafold and any potential adverse effects on the breastfed child from Galafold or from the underlying maternal condition.

Galafold is not recommended for use in patients with severe renal impairment or end-stage renal disease requiring dialysis.

The safety and effectiveness of Galafold have not been established in pediatric patients.

To report Suspected Adverse Reactions, contact Amicus Therapeutics at 1-877-4AMICUS or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

For additional information about Galafold, including the full U.S. Prescribing Information, please visit https://www.amicusrx.com/pi/Galafold.pdf.

EU Important Safety InformationTreatment with Galafold should be initiated and supervised by specialists experienced in the diagnosis and treatment of Fabry disease. Galafold is not recommended for use in patients with a nonamenable mutation.

Galafold is not intended for concomitant use with enzyme replacement therapy.

Galafold is not recommended for use in patients with Fabry disease who have severe renal impairment (<30 mL/min/1.73 m2). The safety and efficacy of Galafold in children less than 12 years of age have not yet been established. No data are available.

No dosage adjustments are required in patients with hepatic impairment or in the elderly population.

There is very limited experience with the use of this medicine in pregnant women. If you are pregnant, think you may be pregnant, or are planning to have a baby, do not take this medicine until you have checked with your doctor, pharmacist, or nurse.

While taking Galafold, effective birth control should be used. It is not known whether Galafold is excreted in human milk.

Contraindications to Galafold include hypersensitivity to the active substance or to any of the excipients listed in the PRESCRIBING INFORMATION.

Galafold 123 mg capsules are not for children (12 years) weighing less than 45 kg.

It is advised to periodically monitor renal function, echocardiographic parameters and biochemical markers (every 6 months) in patients initiated on Galafold or switched to Galafold.

OVERDOSE: General medical care is recommended in the case of Galafold overdose.

The most common adverse reaction reported was headache, which was experienced by approximately 10% of patients who received Galafold. For a complete list of adverse reactions, please review the SUMMARY OF PRODUCT CHARACTERISTICS.

Call your doctor for medical advice about side effects.

For further important safety information for Galafold, including posology and method of administration, special warnings, drug interactions and adverse drug reactions, please see the European SmPC for Galafold available from the EMA website at http://www.ema.europa.eu.

About Fabry Disease

Fabry disease is an inherited lysosomal disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A), which results from mutations in the GLA gene. The primary biological function of alpha-Gal A is to degrade specific lipids in lysosomes, including globotriaosylceramide (referred to here as GL-3 and also known as Gb3). Lipids that can be degraded by the action of alpha-Gal A are called "substrates" of the enzyme. Reduced or absent levels of alpha-Gal A activity lead to the accumulation of GL-3 in the affected tissues, including heart, kidneys, and skin. Accumulation of GL-3 and progressive deterioration of organ function is believed to lead to the morbidity and mortality of Fabry disease. The symptoms can be severe, differ from person to person, and begin at an early age.

About Amicus Therapeutics

Amicus Therapeutics (Nasdaq: FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases. For more information please visit the companys website at http://www.amicusrx.com, and follow us on Twitter and LinkedIn.

Forward Looking Statement

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 relating to preclinical and clinical development of our product candidates, the timing and reporting of results from preclinical studies and clinical trials, the prospects and timing of the potential regulatory approval of our product candidates, commercialization plans, manufacturing and supply plans, financing plans, and the projected revenues and cash position for the Company. The inclusion of forward-looking statements should not be regarded as a representation by us that any of our plans will be achieved. Any or all of the forward-looking statements in this press release may turn out to be wrong and can be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding the goals, progress, timing, and outcomes of discussions with regulatory authorities, and in particular the potential goals, progress, timing, and results of preclinical studies and clinical trials, including as they are impacted by COVID-19 related disruption, are based on current information. The potential impact on operations from the COVID-19 pandemic is inherently unknown and cannot be predicted with confidence and may cause actual results and performance to differ materially from the statements in this release, including without limitation, because of the impact on general political and economic conditions, including as a result of efforts by governmental authorities to mitigate COVID-19, such as travel bans, shelter in place orders and third-party business closures and resource allocations, manufacturing and supply chain disruptions and limitations on patient access to commercial or clinical product. In addition to the impact of the COVID-19 pandemic, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in our business, including, without limitation: the potential that results of clinical or preclinical studies indicate that the product candidates are unsafe or ineffective; the potential that it may be difficult to enroll patients in our clinical trials; the potential that regulatory authorities, including the FDA, EMA, and PMDA, may not grant or may delay approval for our product candidates; the potential that we may not be successful in commercializing Galafold in Europe, Japan, the US and other geographies or our other product candidates if and when approved; the potential that preclinical and clinical studies could be delayed because we identify serious side effects or other safety issues; the potential that we may not be able to manufacture or supply sufficient clinical or commercial products; and the potential that we will need additional funding to complete all of our studies and manufacturing. Further, the results of earlier preclinical studies and/or clinical trials may not be predictive of future results. Statements regarding corporate financial guidance and financial goals and the attainment of such goals. With respect to statements regarding projections of the Company's revenue and cash position, actual results may differ based on market factors and the Company's ability to execute its operational and budget plans. In addition, all forward-looking statements are subject to other risks detailed in our Annual Report on Form 10-K for the year ended December 31, 2020 and the Quarterly Report filed on Form 10-Q for the quarter ended September 30, 2021. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, and we undertake no obligation to revise or update this news release to reflect events or circumstances after the date hereof.

CONTACT:

Investors: Amicus Therapeutics Andrew FaughnanExecutive Director, Investor Relationsafaughnan@amicusrx.com(609) 662-3809

Media: Amicus Therapeutics Diana Moore Head of Global Corporate Communicationsdmoore@amicusrx.com(609) 662-5079

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Amicus Therapeutics Reports Preliminary 2021 Revenue and Provides 2022 Strategic Outlook and Revenue Guidance - Yahoo Finance

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Maze Therapeutics, a company translating genetic insights into new precision medicines, today announced a $190 million financing led by Matrix Capital Management with participation from General Catalyst, a16z Bio+Health, Woodline Partners, Casdin Capital, City Hill Ventures, Foresite Capital, Driehaus Capital Management, Moore Strategic Ventures, Terra Magnum Capital Partners, NS Investments and several others. Maze was launched in 2019 with a financing led by Third Rock Ventures and ARCH Venture Partners, with participation from GV, Foresite Capital, Casdin Capital, Alexandria Venture Investments and other undisclosed investors and has since generated nine programs and two joint-ventures. In conjunction with the financing, Maze also announced that Matrix Capital Managements Andy Tran has joined the companys board of directors.

Over the past year, Maze has generated data across multiple disease areas and modalities, said Jason Coloma, Ph.D., president and chief executive officer of Maze. I am confident that Maze has emerged at precisely the right moment with the right people to execute on an ambitious and important mission, and I am proud of our team for the progress made in our pipeline to date. As we transition to a clinical-stage company, we believe this financing provides important resources to advance our pipeline and to uncover new genetic associations to develop precision medicines for patients with genetically defined diseases.

We think Mazes unique approach that fuses deep human genetics with a platform that can deliver end-to-end computational chemistry informed drug discovery has the potential to generate a continuous stream of precision therapies in complex disease areas that have long been underserved and lack meaningful treatment options, said Andy Tran, investor at Matrix Capital Management and incoming Maze board director. We have been impressed by the rapid progress from idea to program this world-class team of drug hunters and computational biologists has made and look forward to supporting the company in this next wave of growth.

Proceeds from the financing will be used to support advancement of the companys nine precision medicines programs for both rare and common genetically defined diseases with high unmet need, including its three most advanced programs, MZE001 for the treatment of Pompe disease, its APOL1 program for the treatment of chronic kidney disease and its ATXN2 program for the treatment of amyotrophic lateral sclerosis (ALS). The company expects MZE001 to enter the clinic in the first half of 2022. Proceeds will also be used to further expand Maze Compass, the companys purpose-built, end-to-end platform that seeks to take advantage of scientific advancements in genetics, genomics and data science to expedite drug discovery by focusing on variant functionalization to develop new small molecule and biologic therapies for patients with genetically based disorders.

Charles Homcy, M.D., chairman of the board and partner at Third Rock Ventures, commented, The foundational vision of Maze was focused on applying learnings from the evolving landscape of genetic insights and the role they play in disease and translating that knowledge into new medicines where other approaches have fallen short. With the combination of its Compass platform, an exceptional team and this latest financing, I believe Maze is well-positioned to realize the potential of its vision and the true impact we may be able to make for many patients.

About Maze Therapeutics

Maze Therapeutics is a biopharmaceutical company applying advanced data science methods in tandem with a robust suite of research and development capabilities to advance a pipeline of novel precision medicines for patients with genetically defined diseases. Maze has developed the Maze CompassTM platform, a proprietary, purpose-built platform that combines human genetic data, functional genomic tools and data science technology to map novel connections between known genes and their influence on susceptibility, timing of onset and rate of disease progression. Using Compass, Maze is building a broad portfolio, including wholly owned programs targeting Pompe disease, chronic kidney disease and amyotrophic lateral sclerosis, as well as partnered programs in cardiovascular and ophthalmic diseases. Maze is based in South San Francisco. For more information, please visit mazetx.com, or follow us on LinkedIn and Twitter.

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Maze Therapeutics Announces $190 Million Financing to Support the Advancement of Nine Precision Medicine Programs and Compass Platform for Genetically...

I said, I am an RNA scientist. I can do anything with RNA, Dr. Karik recalled telling Dr. Weissman. He asked her: Could you make an H.I.V. vaccine?

Oh yeah, oh yeah, I can do it, Dr. Karik said.

Up to that point, commercial vaccines had carried modified viruses or pieces of them into the body to train the immune system to attack invading microbes. An mRNA vaccine would instead carry instructions encoded in mRNA that would allow the bodys cells to pump out their own viral proteins. This approach, Dr. Weissman thought, would better mimic a real infection and prompt a more robust immune response than traditional vaccines did.

It was a fringe idea that few scientists thought would work. A molecule as fragile as mRNA seemed an unlikely vaccine candidate. Grant reviewers were not impressed, either. His lab had to run on seed money that the university gives new faculty members to get started.

By that time, it was easy to synthesize mRNA in the lab to encode any protein. Drs. Weissman and Karik inserted mRNA molecules into human cells growing in petri dishes and, as expected, the mRNA instructed the cells to make specific proteins. But when they injected mRNA into mice, the animals got sick.

Their fur got ruffled, they hunched up, they stopped eating, they stopped running, Dr. Weissman said. Nobody knew why.

For seven years, the pair studied the workings of mRNA. Countless experiments failed. They wandered down one blind alley after another. Their problem was that the immune system sees mRNA as a piece of an invading pathogen and attacks it, making the animals sick while destroying the mRNA.

Eventually, they solved the mystery. The researchers discovered that cells protect their own mRNA with a specific chemical modification. So the scientists tried making the same change to mRNA made in the lab before injecting it into cells. It worked: The mRNA was taken up by cells without provoking an immune response.

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How The mRNA Vaccines Were Made: Halting Progress and Happy Accidents - The New York Times

BETHESDA, Md., Jan.12, 2022 /PRNewswire/ --The ACMG Annual Clinical Genetics Meetingwill be a hybrid event in 2022 with the options to attend in person in Nashville or online. This meeting continues to provide groundbreaking research and the latest advances in medical genetics, genomics and personalized medicine. The 2022 ACMG Annual Clinical Genetics Meeting will offer media a firsthand look at what is shaping the future of genetics and genomics in medicine and will offer a variety of engaging and interactive educational formats and types of sessionsfrom Scientific Sessions and Workshops to TED-Style Talks, Case-based Sessions, Platform Presentations and Short Courses.

Interview those at the forefront in medical genetics and genomics, connect with new sources, and get story ideas on the clinical practice of genetics and genomics in healthcare today and for the future. Learn how genetics and genomics research is being integrated and applied in medical practice. Topics include artificial intelligence in genetics, gene editing, cancer genetics, direct-to-consumer genetic testing, exome sequencing, pre- and perinatal genetics, the importance of diversity, equity and inclusion in the study of genetics, biochemical/metabolic genetics, genetic counseling, health services and implementation, legal and ethical issues, therapeutics and more.

Credentialed media representatives on assignment are invited to cover the ACMG Annual Meeting Hybrid Event on a complimentary basis. Contact Reymar Santos at [emailprotected]for the Press Registration Invitation Code, which will be needed to register at http://www.acmgmeeting.net.

Abstracts will be available online in February. All attendees will have access to session recordings until April 30.

A few 2022 ACMG Annual Meeting highlights include:

Program Highlights:

Two Short Courses Available Starting on Tuesday, March 22:

Cutting-Edge Scientific Concurrent Sessions:

Social Media for the 2022 ACMG Meeting: As the ACMG Annual Meeting approaches, journalists can stay up to date on new sessions and information by following the ACMG social media pages on Facebook,Twitterand Instagramand by usingthe hashtag #ACMGMtg22 for meeting-related tweets and posts.

The ACMG Annual Meeting website has extensive information at http://www.acmgmeeting.netand will be updated as new information becomes available. All plenaries plus one session per time block are currently planned for streaming.

About the American College of Medical Genetics and Genomics (ACMG) and ACMG Foundation

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is the only nationally recognized medical professional organization solely dedicated to improving health through the practice of medical genetics and genomics, and the only medical specialty society in the US that represents the full spectrum of medical genetics disciplines in a single organization. The ACMG is the largest membership organization specifically for medical geneticists, providing education, resources and a voice for more than 2,400 clinical and laboratory geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. ACMG's mission is to improve health through the clinical and laboratory practice of medical genetics as well as through advocacy, education and clinical research, and to guide the safe and effective integration of genetics and genomics into all of medicine and healthcare, resulting in improved personal and public health. Four overarching strategies guide ACMG's work: 1) to reinforce and expand ACMG's position as the leader and prominent authority in the field of medical genetics and genomics, including clinical research, while educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease; 2) to secure and expand the professional workforce for medical genetics and genomics; 3) to advocate for the specialty; and 4) to provide best-in-class education to members and nonmembers. Genetics in Medicine, published monthly, is the official ACMG journal. ACMG's website (www.acmg.net) offers resources including policy statements, practice guidelines, educational programs and a 'Find a Genetic Service' tool. The educational and public health programs of the ACMG are dependent upon charitable gifts from corporations, foundations and individuals through the ACMG Foundation for Genetic and Genomic Medicine.

Kathy Moran, MBA[emailprotected]

SOURCE American College of Medical Genetics and Genomics

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Introduction

Long QT syndrome (LQTS) is defined by a prolonged QT interval accompanied by morphological abnormalities in the T and/or U waves on the electrocardiograph (ECG).1 The primary clinical symptom of LQTS is syncope produced by ventricular arrhythmias.24 The clinical diagnosis of LQTS is based on a combination of the patients medical and family history, as well as the 12-lead ECG.5 According to the guidelines, LQTS diagnosis can be made in case the QTc is more than 460ms, and the patient presents some antecedents, most notably a family history of SCD and unexplained syncope.6

LQTS can be classified into two types based on its etiology: congenital LQTS (cLQTS) and acquired LQTS (aLQTS). While the former is a relatively rare genetic cardiovascular disease with a low incidence rate (1/2000-1/3000),7 the latter is frequently subsequent to electrolyte disorders, cardiomyopathy, cerebrovascular accidents, and autonomic dysfunction.

The pathogenesis of cLQTS is related to the mutation of genes encoding for ion channels, such as KCNH2,3,8 KCNQ1,2,9 TRPM4,1012 and so on, and causing ion channel dysfunction with reduced repolarization ion flow and/or increased delocalization ion flow, which in turn leads to prolonged repolarization. Among ion channel genes, mutations in KCNQ1 and KCNH2, which encode voltage-gated K+ channels involved in cardiac action potential (AP) repolarization are most common,10 followed by mutations in SCN5A which encode voltage-gated Na (1.78%), while mutations in other genes including TRPM4 are rare (below 1% of LQTS).11 Dr. Hof and colleagues were the first to hypothesize that TRPM4 mutations cause long QT syndrome, and they detected four TRPM4 variants, including c.1321 G >A, c.1495 C >T, c.1496 G >C, and c.2531 G >A, with no changes in the key LQTS genes.11

Herein, we reported a Chinese proband with cLQTS with a new mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) in the TRPM4 with the hope that this report may be helpful in future genetic studies and prospective, genetically informed research.

A 75-year-old male was implanted with a permanent pacemaker 18 years ago due to a local diagnosis of bradycardia characterized by recurrent syncope since the age of 20, yet postoperative syncope continued to occur. Syncope occurred again a day before admission, and then he was taken to our hospital. Electrocardiography (ECG) at disease onset indicated sinus bradycardia, anterior wall T wave changes with visible u waves (Figure 1).

Figure 1 The admission ECG showed sinus bradycardia with QTc interval 432ms and U wave.

On admission, the following vital signs were recorded: blood pressure of 135/88mmHg, pulse rate of 59 beats per minute, the body temperature of 36.4C, and breathing rate of 18 beats per minute. Physical examination revealed no evidence of heart failure or pathological nervous system features.

After admission, repeated electrocardiograms suggested prolonged QT intervals, sinus bradycardia, and T wave changes (Figure 2). Ambulatory ECG also showed sinus bradycardia (mean heart rate 59 beats), prolonged QT interval (540ms), and torsade de pointes (Figure 3). Whats more, the electrodes on the patients pacemaker were discovered to be depleted for nearly five years. Laboratory data showed a slightly elevated level of troponin, as well as N-terminal-pro-brain natriuretic peptide, while other laboratory indexes including hepatic and renal function, electrolytes, coagulation, and inflammatory indexes were normal. We also performed a cranial MRI on this patient, and no neurological lesion was found that could cause syncope. Echocardiography indicated no abnormalities in cardiac structure, and the left ventricular ejection fraction was 61%. Moreover, selective coronary angiography was performed, indicating that the patient has no apparent pathological stenosis in the coronary arteries.

Figure 2 (AC) During the hospitalization, the ECG showed the dynamic changes of T wave; the longest QTc interval was 540ms.

Figure 3 Electrocardiogram monitoring shows torsion de pointes tachycardia.

According to the above results and the diagnostic criteria of LQTS, a highly suspected diagnosis of LQTS was finally made (Rating 6.5 out of 5).1,13,14

Then the etiology of LQTS was further explored. For no acquired LQTS associated risk factors such as electrolyte disorders, cardiomyopathy, cerebrovascular accidents, and autonomic dysfunction were found in the patients previous medical history and related examinations after admission, we are suspicious of the patients Genetics of LQTS.

After obtaining the informed consent, we conducted whole-exome sequencing (WES) on the patient and his family to confirm our diagnosis. Gene testing revealed that the patient carried a TRPM4 heterozygous shift mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133). Moreover, WES analysis of his family members revealed that his sister carried the same TRPM4 mutation as the patient (Figure 4), but his two brothers and son did not. Regrettably, the probands parents have all died, and hence their genes have not been obtained.

Figure 4 The results of genetic testing showed the proband and his sister carried a TRPM4 heterozygous shift mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) (A), while his two brothers and son did not (B).

Because of the high risk of sudden cardiac death, we recommend implanting a cardioverter defibrillator (ICD) for the patient. Due to economic reasons, the patient refused. Due to the patients strong preference for cautious treatment, we administered Shengsong Yangxin Capsule as a placebo.

cLQTS is a rare cardiac disorder inherited in an autosomal trait, with an estimated incidence of 1:20001:3000.7 It is accepted that cLQTS is a rare ion channelopathy, and a host of genes were described to be responsible for LQTS. So far, 15 genes with more than 7000 mutations have been considered to be associated with cLQTS.15 Among the six genes encode for a pore-forming ion channel, while others encode for regulatory subunits or proteins. Mutations in KCNQ1 (3035%) and KCNH2 (2530%) encoding voltage-gated K+ channels involved in cardiac action potential (AP) repolarization are the most common among ion channel genes,10,14 followed by mutations in SCN5A, which encode voltage-gated Na+ (1.78%).11,14 In comparison, mutations in other genes, including TRPM4 are rare (below 1% of LQTS).11,12,14

As far as the pathology of LQTS, it is generally known that QT duration depends on both ventricular AP duration and AP propagation within the ventricle and ion channel dysfunction with reduced repolarization ion flow and/or increased delocalization ion flow leads to prolonged repolarization. According to a sack of animal experiments on TRPM4, TRPM4 affects cardiac electrophysiological activity through nonselective cation permeability, which leads to cLQTS.11 Unfortunately, additional research is required to decipher the biological mechanism underlying TRPM4-induced loss of function of nonselective cation permeability.

Above all, gene test counts for cLQTS. The importance of gene detection for cLQTS lies in exploring its pathogenic mechanism and its treatment, for the drugs targeted specific ion channels can be used with exerting maximal effects.

In our case, a new mutation site on TRPM4 (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) was discovered through whole-exon detection, which can provide a brand-new direction for gene screening of patients with cLQTS and further complements its diagnostic criteria. As for the detail of gene tests, we used PolyPhen2 to predict whether a new mutation is damaging to the resultant protein function. And then, according to the relevant literature, we did consider that TRPM4 is as same amino acid change as a previously established pathogenic variant regardless of nucleotide change after searching the OMIM database. But the absence of the literature for molecular pathology makes us failure to achieve the information of damaged protein. At last, combined clinical history, ECG, and the results of gene test, it was suspected that TRPM4 mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) was the pathogenic variant.

In the treatment of cLQTS, beta-blockers effectively prevent cardiovascular disease and ventricular arrhythmia, and ICD implantation is regarded as the ultimate therapy.16 Because of the high risk of sudden cardiac death, we recommend implanting a cardioverter defibrillator (ICD) for the patient. Due to economic reasons, the patient refused, and we administered a placebo.

The incidence of cLQTS is very low, with the incidence of LQTS caused by TRPM4 being even lower, leading to less research on the gene TRPM4. Therefore, we reported a new mutation in TRPM4 (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) to provide more evidence for gene screening, to improve the detection rate of healthy gene carriers or patients in the early incubation stage, thereby providing further complements to the clinical data of the study about TRPM4. Notwithstanding its limitation such as lack of this patients past clinical data that can help to compare the symptom before and after the permanent pacemaker implantation, detailed information of the pedigree of this patients parents and so on, this report does hopefully serve as useful feedback information for genetic pathogenesis of cLQTS caused by TRPM4 variants.

cLQTS, congenital long QT syndrome; LQTS, long QT syndrome; ECG, electrocardiograph; AP, action potential; ICD, implanting cardioverter defibrillator; WES, whole-exome sequencing; TRPM4, transient receptor potential melastatin 4; aLQTS, acquired LQTS.

All relevant data supporting the conclusions of this article are included within the article.

The need for institutional ethics approval for this case report was waived. Written informed consent was obtained from the patient for publication of this case report and accompanying images.

The patient has provided informed consent for the publication of the case. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Dr. Rui Huang and Dr. Yinhua Luo are co-first authors for this study.

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

This work was supported in part by the National Natural Science Foundation of China (82160072) and the Science and Technology Support Project of Enshi Science and Technology Bureau (D20210024).

The authors declare that they have no conflicts of interest.

1. Vohra J. The long QT syndrome. Heart Lung Circ. 2007;16(Suppl 3):S5S12. doi:10.1016/j.hlc.2007.05.008

2. Beiyin G, Tingliang L, Lei Y, et al. Head-up tilt test induces T-wave alternans in long QT syndrome with KCNQ1 gene mutation: case report CARE-compliant article. Medicine. 2020;99(20):e19818.

3. Henk-Jan B, Lucia B. Orgasm induced torsades de pointes in a patient with a novel mutation with long-QT syndrome type 2: a case report. Eur Heart J Case Rep. 2018;2(2):yty062.

4. Joel G, Kinsley H, Amanda W, et al. Recurrent torsades with refractory QT prolongation in a 54-year-old man. Am J Case Rep. 2018;19:1515.

5. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):19321963. doi:10.1016/j.hrthm.2013.05.014

6. Priori SG, Blomstrm-Lundqvist C, Mazzanti A, et al. [2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death]. Kardiol Pol. 2015;73(10):795900. Croatian. doi:10.5603/KP.2015.0190

7. Zumhagen S, Stallmeyer B, Friedrich C, et al. Inherited long QT syndrome: clinical manifestation, genetic diagnostics, and therapy. Herzschrittmacherther Elektrophysiol. 2012;23(3):211219. doi:10.1007/s00399-012-0232-8

8. Du F, Wang G, Wang D, et al. Targeted next generation sequencing revealed a novel deletion-frameshift mutation of KCNH2 gene in a Chinese Han family with long QT syndrome: a case report and review of Chinese cases. Medicine. 2020;99(16):e19749. doi:10.1097/MD.0000000000019749

9. Motoi N, Marehiko U, Ryota E, et al. A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report. BMC Med Genet. 2017;18(1):16.

10. Amin AS, Pinto YM, Wilde AA. Long QT syndrome: beyond the causal mutation. J Physiol. 2013;591(17):41254139. doi:10.1113/jphysiol.2013.254920

11. Hof T, Liu H, Sall L, et al. TRPM4 non-selective cation channel variants in long QT syndrome. BMC Med Genet. 2017;18(1):31. doi:10.1186/s12881-017-0397-4

12. Guinamard R, Bouvagnet P, Hof T, et al. TRPM4 in cardiac electrical activity. Cardiovasc Res. 2015;108(1):2130. doi:10.1093/cvr/cvv213

13. Hayashi K, Konno T, Fujino N, et al. Impact of updated diagnostic criteria for long QT syndrome on clinical detection of diseased patients: results from a study of patients carrying gene mutations. JACC Clin Electrophysiol. 2016;2(3):279287. doi:10.1016/j.jacep.2016.01.003

14. Neira V, Enriquez A, Simpson C, et al. Update on long QT syndrome. J Cardiovasc Electrophysiol. 2019;30(12):30683078. doi:10.1111/jce.14227

15. Tester DJ, Ackerman MJ. Genetics of long QT syndrome. Methodist Debakey Cardiovasc J. 2014;10(1):2933. doi:10.14797/mdcj-10-1-29

16. Betge S, Schulze-Bahr E, Fitzek C, et al. [Long QT syndrome causing grand mal epilepsy: case report, pedigree, therapeutic options, and review of the literature]. Nervenarzt. 2006;77(10):12101217. German. doi:10.1007/s00115-006-2118-7

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A Novel Mutation in the TRPM4 Gene | RRCC - Dove Medical Press