Orphazyme A/SCompany announcementNo. 30/2022 Annual reportwww.orphazyme.com Company Registration No. 32266355
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Orphazyme Announces Publication of 2021 Financial Results and Annual Report
Orphazyme A/SCompany announcementNo. 31/2022www.orphazyme.comCompany Registration No. 32266355
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Notice to convene Annual General Meeting
Basel, 8 June 2022 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the European Commission has granted conditional marketing authorisation for the CD20xCD3 T-cell engaging bispecific antibody Lunsumio® (mosunetuzumab), for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) who have received at least two prior systemic therapies. Lunsumio is an off-the-shelf therapy that is readily available, so people do not have to wait to start treatment.
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European Commission approves Roche’s first-in-class bispecific antibody Lunsumio for people with relapsed or refractory follicular lymphoma
Quenton Tompkins family tree is deeply rooted in rural McCormick County, South Carolina.
His grandfather was a sharecropper in McCormick. His mother, who turns 88 this month, grew up as the youngest of 24 children. Branches of aunts, uncles, and cousins now stretch from Florida to Chicago.
And although 48-year-old Tompkins has heard plenty of stories, his family holds its secrets, too.
He didnt know until he was an adult that his grandfather died of leukemia. And hes still unsure if his fathers bout with prostate cancer runs in the family. Tompkins mother and her siblings have dealt with a range of health issues, including diabetes, heart attacks, and strokes, but he still doesnt know what killed his grandmother more than 70 years ago.
Those are questions I go through personally, said Tompkins, a lobbyist for the Medical University of South Carolina. Theres another side to knowing where you come from.
Twenty-two years ago, President Bill Clinton announced the completion of a draft version of the Human Genome Project, a breakthrough he described as the language in which God created life. He predicted that scientists, armed with genetic discoveries, would find cures for Alzheimers disease, cancer, Parkinsons disease, and diabetes in the coming years.
Clintons prediction, of course, hasnt yet come to pass. But researchers in Charleston are hopeful that a large genetics research project underway across South Carolina may help scientists address some of the states persistent health disparities, which disproportionately impact its Black residents and regularly rank among the nations worst.
The university health system intends to enroll 100,000 of South Carolinas 5 million residents in genetic testing over the next four years in hopes of better understanding how DNA influences health. Researchers also want to recruit participants who reflect the diversity of the states population.
Its an ambitious goal. With nearly 27% of South Carolina residents identifying as Black or African American, the MUSC genetics research project, called In Our DNA SC, would if successful accomplish something most other genetics research projects have failed to do. Historically, diverse participation in this type of research has been very low.
Theres a trust factor. Its plain and simple, said Tompkins, who is developing an outreach program for the project.
He referenced Henrietta Lacks, a Black woman in Baltimore whose cells were used without her or her familys knowledge for research purposes by doctors at Johns Hopkins University in the 1950s, and the Tuskegee syphilis study, conducted over nearly 40 years starting in the 1930s. Researchers deceived hundreds of Black men enrolled in the study, telling them they were being treated for syphilis when, in fact, they were left untreated, even after penicillin became widely available.
Those are still fresh in many peoples minds, Tompkins said. Weve come a long way from those stories it doesnt dismiss what happened but there are a lot more controls and oversight in place to ward those things off from happening again.
But its not only history feeding this distrust. Bias and racism evident in medicine today contribute to the problem.
Diversity in genetics research is so low that approximately 90% of participants in projects launched since the first sequencing of the human genome have been individuals of European descent or those who identify as white, said Dr. Shoa Clarke, a pediatric cardiologist and geneticist at Stanford University.
These numbers affect real-life health care. Clarke and others published research last year showing that a DNA-based tool used to assess a patients risk of developing high cholesterol works reliably well only when administered to those of Northern European descent. Thats because the tool was developed using information from genetic bio-banks largely made up of DNA from white people. And aside from a large DNA bank compiled by the Department of Veterans Affairs, this is generally the norm.
Human beings, regardless of race, are more than 99% genetically identical, but small variations and mutations passed down through generations can influence health outcomes in huge ways, Clarke explained.
Genetics is not the cause of health disparities, he said. But as we move toward using genetics in clinical settings, its very possible they could create new disparities.
In South Carolina, health disparities between Black and white patients are already acute, said Marvella Ford, a researcher at MUSCs Hollings Cancer Center in Charleston.
South Carolina compared to the rest of the country were usually in the bottom tier, Ford said. The prostate cancer mortality rate in South Carolina, for example, is 2 times higher for Black men than white men, she said.
When you look at most other chronic conditions, she said, you see the same thing.
She called the genetics project at MUSC a great opportunity to open the doors. Even so, the topic of recruiting Black research participants for genetics studies is complex.
Theres debate on how we should be doing this work, said Shawneequa Callier, an attorney and an associate professor of bioethics at George Washington University. Theres just so much diversity in Africa. Its the cradle of humanity.
Men and women transported to Charleston and other American port cities during the transatlantic slave trade came from a wide region of Africa mostly from West Central Africa, but in large numbers from regions farther north, too. Once in America, they were often separated and forced hundreds of miles apart. This explains why someone whose ancestors lived on one of South Carolinas barrier islands may have inherited different genetic variants than someone from a multigenerational Black family inland in McCormick County, just north of Augusta, Georgia.
Thats also why categorizing genetics research participants simply as Black or African American, without more context, may not yield particularly useful research insights, Callier said.
If you dont study the data and study it well, thats a real dereliction of ethical duty, Callier said.
Those who choose to participate in the MUSC project stand to benefit from it directly, its organizers said. After submitting a saliva sample, each participant will receive a report indicating if they have one or more of three genetic conditions that may put them at a higher risk for heart disease and certain cancers such as one of the BRCA mutations linked to breast cancer. If they test positive for one of these conditions, they will be connected at no cost to a genetics counselor, who can assist with information and treatment options related to a patients inherited risks. Participants will also learn where their ancestors likely lived.
The de-identified DNA data will then be used by researchers at MUSC, as well as those at Helix, a private California-based genomics company, which will process the saliva samples and extract the genetic information from each participants sample. Researchers at MUSC and Helix have indicated they hope to use the results to better figure out how DNA affects population health. Heather Woolwine, an MUSC spokesperson, said the project will cost $15 million, some of which will be paid to Helix. Hospital revenue will fund the research, she said.
Tompkins expects to receive a lot of questions about how it all will work. But hes used to questions. He said he encountered much of the same hesitancy when he helped set up MUSC covid testing and vaccine sites across the state. Many people regardless of race worried microchips or tracking technology had been embedded into the covid vaccines, he said.
Tompkins found that the key to persuading residents in rural parts of the state to consider the covid vaccine was to seek out invitations from trusted, local leaders, then set up events with them. South Carolinas covid vaccination rate remains lower than the national average, but Tompkins said some skeptics have been more receptive to MUSCs message because the hospital system has focused on building relationships with organizers outside Charleston. He hopes to use those relationships to spread word about the new genetics research project.
You have to build those relationships and find community champions that can help you open doors and gather people, he said. Then, its about letting them choose.
By Lauren SausserKaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.
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Addressing the 'Trust Factor': South Carolina Researchers Tackle Health Disparities Using Genetics - Physician's Weekly
It has been more than two years since the start of the global COVID-19 pandemic. Throughout that time, for some people, the infections became more frequent and hit closer to home. Their friends contracted coronavirus, and sometimes their children, grandparents and most of their co-workers too. It seemed to be only a matter of time before they would contract the virus as well but their luck never ran out it seems as if some people have never been knowingly infected with COVID-19 in over two years even after the wave of infections caused by the highly transmissible omicron variant.
If you ask them the reason, you'll hear all sorts of suppositions. For example, regular long trips on the underground will build up your resistance by repeatedly exposing you to small viral loads.
"This hypothesis falls in the realm of speculation," says Dr. Ulf Dittmer, director of the Institute of Virology at Essen University Hospital in Germany.
Some people not previously infected attribute it to scrupulously following COVID-19 precautions. Others thank their lucky stars for not contracting the virus from a contact person who later tested positive or while they partied at a club. Still, others wonder if they had an asymptomatic infection that wasn't detected, for instance before testing was widely available. Or maybe they did have symptoms but tested negative because the sample was collected improperly or the timing was inopportune.
Scientific attempts at an explanation go deeper, but there's no single definitive answer as to why some people still haven't caught COVID-19. A combination of factors could be the reason.
"A number of hypotheses appear plausible," says Dr. Leif Erik Sander, director of the Department of Infectious Diseases and Respiratory Medicine at Charit University Hospital in Berlin.
First of all, it's important to bear in mind that a significant number of COVID-19 infections go largely or completely unnoticed. In a systematic review and meta-analysis published late last year in the Journal of the American Medical Association (JAMA) Network Open, the authors noted that about 40% of people with a confirmed COVID-19 diagnosis were asymptomatic at the time of the test. The finding was based on 95 international studies involving nearly 30 million people.
The frequency of testing obviously plays a role in detecting infections. If you're not tested regularly, there's a greater chance you won't become aware of a mild or asymptomatic infection.
And your genes can play a role too in whether or not you get COVID-19.
"There are people who, owing to genetic characteristics, can't easily be infected with malaria or HIV (the virus that causes AIDS), for instance. In certain gradations this will also be true of Sars-CoV-2," says Sander, adding that the genetic factors aren't completely understood, however.
As virologist Dittmer explains, human leukocyte antigens (HLA) molecules, which are encoded by a complex of genes, play an important part in the body's immune response to pathogens such as Sars-CoV-2. He adds that a person's blood group, too, not only influences disease severity but perhaps also susceptibility to infection with the virus.
The protection provided by vaccinations is probably often underestimated. Although levels of antibodies in your blood able to bind to and neutralize invading coronaviruses decline some time after injection with a vaccine, "protection nevertheless remains significant for months," Sander says. "That, too, reduces infections."
Immune responses to COVID-19 vaccines vary from person to person. "If the response is especially good, vaccination in combination with a previous infection with one of the four endemic common cold coronaviruses can also play a role," he suggests.
According to Dittmer, a particular subclass of antibodies has been found to provide especially good protection from a novel coronavirus infection. "Measuring them is complicated though, so for the time being no one will know whether they've got these antibodies or not," he says.
The fact that children who get COVID-19 tend to have either no or only mild symptoms is down to their generally having an innate immune response that's stronger than the immune response of adults, according to Sander. It's often "preactivated," so to say.
Another phenomenon worth mentioning is that for a few days after getting an infection, people are typically less susceptible to infection with another pathogen. "This is due in part to interferons, which are defensive proteins in mucous membranes that also reduce susceptibility to Sars-CoV-2 in the event of contact with it in that time window," Sander says.
He also notes that some people's immune system may rid their body of the virus very quickly: "In a Swedish study, researchers detected specific T-cells (a type of white blood cell that's part of the immune system) in people who didn't test positive after contact with infected household members a sign their immune system had indeed engaged Sars-CoV-2 even though an infection or antibodies against the virus weren't always detectable."
So what are we to conclude? If you think you've somehow managed to skirt a COVID-19 infection, you may already have one behind you. Or you may have benefited from certain temporary circumstances, as-yet-unexplained genetic factors and/or dumb luck.
"Just because you haven't had COVID-19 yet doesn't mean you're permanently safe," Sander warns. "A new coronavirus variant, or a different set of circumstances, can totally change that."
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Marine biologists at Scripps Institution of Oceanography at UC San Diego have created a line of sea urchins whose genetic makeup is fully mapped and can be edited to study human disease genes. The creation of these new research model organisms will accelerate the pace of marine biomedical research.
Sea urchins, like fruit flies or lab rats, have been an organism used in research for more than a century. Even before this breakthrough, sea urchins led to the discovery of a protein family known as cyclins that guides division of cells. That knowledge went on to become the basis of current cancer treatments and earned cyclins discoverers a Nobel Prize.
Now Scripps marine biologist Amro Hamdoun and colleagues have taken this research to a new level by developing lines of sea urchins that can be used as genetic models using the gene editing technology known as CRISPR. The modified sea urchins are derived from the fast-growing species, Lytechinus pictus, also known as the painted sea urchin.
The team describes its results June 6 in the journal Development.
Hamdoun said the new sea urchins could serve as a new workhorse organism in marine biomedical research, capable of being cultivated to adulthood in four to six months at room temperature. Presently many species of sea urchins are used around the world to study the developmental origins of diseases, and the effects of pollutants on human and marine health. But few can be grown in the lab and genetically modified like other lab animals. Having this new genetically enabled urchin could dramatically enhance the efficiency, reproducibility, and utility of those studies.
Sea urchins have long been a favorite model organism for marine biologists, but they have been bottlenecked by not having stable genetics, Hamdoun said. This work breaks that final barrier. This genetically enabled urchin will be an important resource for the large community of researchers who use urchins in their labs.
The research was an unexpected silver lining from the COVID pandemic which impacted operations in research labs around the country for more than two years. In the case of Hamdouns lab, team members developed a sense of mission that motivated them to continue with the work.
It gave us something positive to focus on, Hamdoun said. The team spent two years intently focused on solving the barriers to making a genetically enabled sea urchin. Once we figured out how to make the precise modifications we wanted, we next had to figure out how to efficiently culture the urchins and select the modified animals. It is a real testament to the groups dedication that they accomplished this despite the adverse circumstances. I like to think that while many people were home growing cool things like houseplants or sourdough starters, we were also growing something interesting, but it was a biomedical research animal.
Besides Hamdoun, co-authors of the study included Himanshu Vyas, Jose Espinoza, Catherine Schrankel, Kasey Mitchell, Katherine Nesbit, Elliot Jackson, Nathan Chang, Yoon Lee, and Deirdre Lyons of Scripps Oceanography as well as researchers from University of North Carolina Charlotte and Wilmington campuses.
The National Institutes of Health Program on Oceans and Human Health and the National Science Foundation funded the research.
COLUMBIA, Md., June 07, 2022 (GLOBE NEWSWIRE) -- Neon Bloom, Inc. (OTC: NBCO): Bazelet Health Systems, a wholly owned subsidiary of Neon Bloom, is proud to announce the endowment of a program known as cERI (cannabis Education & Research Initiative). The program encompasses the donation by Bazelet of federally legal cannabis genetics (genetically producing 0% THC) to DEA registered research entities, such as the National Center for the Development of Natural Products at the University of Mississippi and the broader qualified scientific community wishing to conduct, disseminate and support rigorous scientific research on the clinical effects of cannabis. The companys genetics are patented, compliant with the Controlled Substances Act (CSA) and are now available to all to conduct research with our genetics.
Global scientific research of the Cannabis Sativa L. plant has been illegal because of the Controlled Substance Act (CSA). The CSA has created a decades-long pent-up demand for the scientific research of the cannabis plant by qualified research entities. In 2016, the DEAannouncedthat it was amending its longstanding policies to allow additional parties to grow cannabis for clinical research purposes. Since that time, it amended its regulations in 2020 (which became effective in January 2021) to facilitate the cultivation of marihuana for research purposes and other licit purposes to enhance compliance with the Controlled Substances Act, including registering cultivators consistent with treaty obligations but has not legalized cannabis research. In fact, to date, the DEA has only acknowledged providing a MOA (Memorandum of Agreement) to just a handful of applicants to work together to facilitate the production, storage, packaging, and distribution of marijuana. (www.dea.gov). Meanwhile, human health and the global scientific community standby helpless, until now. Our genetic library of non-GMO, patented Cannabis Sativa L. plants offers access to cannabinoids such as Cannabigerol (CBG) with no existing THC or CBD, said Dr. Francisco Ward, NBPAS-PM&R/PM, Chief Medical Officer for Bazelet which makes us a prime candidate for research endeavors.
Having been involved with the DEA regarding its amendment to facilitate the cultivation of marihuana for research purposes and other licit purposes to enhance compliance with the Controlled Substances Act, I recognize and appreciate the DEAs unique implementation challenges. I am certain our patented cannabis plants and robust plant science program can immediately deliver value to their program, their researchers, and manufacturers. For decades worldwide, cannabis plants have been almost exclusively bred to yield higher and higher concentrations of Tetrahydrocannabinol (THC) which has fueled a multi-billion recreational and high THC medical marijuana industry. This breeding habit has caused the abandonment, if you will, of hundreds of compounds in the cannabis plant to the detriment of human health, scientific study, and federal law. We have developed an unprecedented plant genetic platform for the DEA that begins with registered, US plant patent approved, Cannabis Sativa L. plants as its foundation. Our unique genetic program will allow DEA registered research entities to unlock untold scientific and human health outcomes by accessing a full array of cannabinoids and compounds found in the Cannabis Sativa L. plant, such as Cannabigerol (CBG). Our program allows the DEA from here forward, the development of world-class cannabis genetics that began with registered, US patented cannabis genetics, says Michael Elzufon, CEO of the Bazelet Health Systems.
Through our cannabis Education & Research Initiative (cERI), we are opening our genetic library to DEA registered research entities, encouraging their rigorous scientific and medical research projects with federally legal cannabis products. With the DEA slow in issuing bulk manufacturer registrations, research projects remain on hold and our patented, federally compliant cannabis genetics are an immediate solution, said Dr. Ward. He added, I look forward to collaborating with colleagues, scientists, DEA bulk manufacturer applicants and patients everywhere, to study, innovate and access the potential of this plant in the areas of neurodegenerative diseases, auto-immune diseases, vascular diseases, psychiatric diseases such as addiction, delusional states, and PTSD.
About Neon Bloom: Neon Bloom, Inc. (OTC: NBCO), doing business as Bazelet Health Systems, Inc. ("Bazelet"), holds the exclusive license to grow in the United States a patented zero-THC, high CBG Cannabis sativa L plant which received United States Patent No. PP32,725 on January 5, 2021. The patented plant, which was named PAN2020, is remarkably high in Cannabigerol (CBG) with undetectable levels (zero percent) of both Cannabidiol (CBD) and Tetrahydrocannabinol (THC). Consistent with the company's mantra to create zero-THC products (the company's Cannabis-ZERO platform), Bazelet is actively developing non-GMO cannabis Sativa plants that produce zero-THC while being rich in CBG and other valuable cannabinoids. Bazelet is a wholly owned subsidiary of the public company that manufactures and markets PECSA, a patent-pending, proprietary full extract of the PAN2020 plant with other added proprietary ingredients. PECSA stands for Plant-based EndoCannabinoid System Activator. The EndoCannabinoid System is the premier regulatory center of the body affecting mental abilities, emotions, pain, inflammation, ne and metabolic functions with receptors found primarily in the brain and immune cells. The company's primary focus is to sell and market PECSA as a non-GMO, plant-based ingredient for the global food, drug, cosmetic, and tobacco industries. To meet the anticipated worldwide demand for PECSA, Bazelet has established a vertically integrated supply chain providing operational control from patented cannabis plants to proprietary patented plant processing to GMP-produced finished products, all with traceability from seed to sale. Bazelet grows patented plants in North America, Europe, South America, and the Middle East coming online in 2023. Processing and distribution facilities are located in the U.S. and Europe.
Disclaimer:This Press Release is for informational purposes, contains forward-looking statements based on current expectations, forecasts, and assumptions with information available to us as of the date hereof, and involves risks and uncertainties. This Press Release does not constitute an offer to sell or a solicitation of offers to buy any securities of any entity. Actual results may differ materially from those implied in forward-looking statements. Forward-looking statements include statements regarding our expectations, beliefs, intentions, or strategies regarding the future and can be identified by forward-looking words such as "anticipate," "believe," "could," "estimate," "expect," "intend," "may," "should," "would" or similar words. We assume no obligation to update the information included in this Press Release, whether from new information, future events, or otherwise.
CONTACT: Dr. Mat BlantonEMAIL: media@bazelethealth.comWEBSITE: http://www.bazelethealth.com
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Bazelet to Supply Its Federally Legal Cannabis Genetics to DEA Approved Research Entities for Rigorous Scientific Research on the Clinical Effects of...
June 8, 2022 | The pioneering OneK1K study in Australia has identified an immune fingerprint of seven autoimmune disorders using single-cell RNA sequencing (scRNA-seq). The general framework, which combines the scRNA-seq data with genotype data to classify individual cells, can be applied to many different diseases, including other autoimmune disorders, cardiovascular diseases, neuroinflammatory conditions, and cancer where the immune system is thought to play a role, according to Joseph Powell, director of cellular science at the Garvan Institute of Medical Research.
Selection of the original seven diseasesmultiple sclerosis, rheumatoid arthritis, lupus, type 1 diabetes, spondylitis, inflammatory bowel disease, and Crohns diseasewere based on their prevalence in the world of autoimmune diseases and high genetic component, he says. The study relied on scRNA-seq data from 1.27 million peripheral blood mononuclear cells collected from 982 healthy donors, many of whom carry the genetic loci found in people who have these diseases.
Take Crohns disease, which has molecular markers found on roughly 190 positions in the genome, Powell cites as an example. On average, patients collectively have roughly 90 risk alleles at those loci, but individually about 60. It is the difference between having 60 and 90 that takes you over the threshold and leads to occurrences of disease.
This phenomenon holds true for most every disease afflicting humans, which is why a big population group is ideal for gaining mechanistic insights on disease-associated genes, he continues. At the cellular level, genome regulation changes brought on by those genes are the same even if there is no clinical manifestation of disease.
Using a Mendelian randomization approach, Powell and his colleagues uncovered the causal route by which 305 loci contribute to autoimmune disease through changes in gene expression in specific cell types and subsetsand that these genetic mechanisms are the same for healthy individuals as in autoimmune disease cohorts. Results published recently in Science (DOI: 10.1126/science.abf30).
Single-cell RNA sequencing was used to look at genetic variants affecting gene expression in 14 different immune cell types, says Powell. It is the largest study to date linking disease-causing genes to specific types of immune cells.
Researchers developed a classification method based on the transcriptomic signature found in individual cells and aligned it back to what is currently understood about more common immune cell types at the top of the hierarchy (e.g., T cells, CD4, CD8, nave to memory B cells). Although 68 immune cells have been classified, they focused on those they were sure to find enough copies of across the OneK1K cohort to confidently link the genetic differences between people to the signatures in the cells.
Tissue-To-Tissue Variability
Powell says he has been interested in genetic control of gene expression, and its contribution to disease, for more than a decade now. For many years, this involved bulk RNA analysis that produces an average signal.
An important clue emerged when researchers began seeing how vastly different the genetics worked in one tissue versus another, he says. Only a few years ago, the Genotype-Tissue Expression Program (GTEx) of the National Institutes of Health examined RNA sequencing samples from 49 tissues of postmortem donors to characterize genetic associations for gene expression and found regulatory associations for almost all genes. Cell type composition was identified as a key factor in understanding gene regulatory mechanisms.
That study showed instances where genetic effects were seen in one tissue and not another, or generated completely different effects, Powell notes. It was published in 2020 when scRNA-sequencing was just emerging as a staple technologyand Powell had just started his computational genomics laboratory at the Garvan Institute.
We were stuck with this interesting question: If we see these differences between tissues, and know the tissues are comprised of really distinct cell types with really specific functional roles, and the transcriptomic cell signatures are different, can we try to create a system to undo the genetics we saw in tissue inside a cell? That led Powell and his colleagues to scale up their scRNA-sequencing efforts.
At the time, the vast amount of generated transcript data generated from 1,000 individuals would have made scRNA-sequence data entirely cost-prohibitive to generate. But Powell helped pioneer a biometric technique to pool cells from multiple samples, as well as a method to analyze the transcripts of individual cells that solved the challenge of determining what portion of them would provide the most useful information in defining a cell type.
Up until then, a few other groups had published studies using samples from perhaps 50 or 100 individuals suggesting signatures of disease, but they were all under-powered, says Powell. They could show genetic differences between cells, but they were all too under-powered to link them to disease, or to resolve why there were differences between cells.
Statistically speaking, disease fingerprints that capture the genetic heterogeneity of patients will never be fully defined, says Powell. But the OneK1K study has probably moved the needle from the 10th percentile to the 50th percentile on the saturation curve.
Powell is now aiming for the 95th percentile with a TenK10K study that will be seeking to enroll 10,000 individuals and generate single cell data on about 50 million cells. The multi-year initiative will involve partnerships with multiple hospitals across Australia, and both a healthy population group and patients newly diagnosed with autoimmune disorders, cardiovascular disease, and cancer.
Autoimmune diseases affect about one in 12 Australians, he notes. They are incurable and require lifelong treatments to minimize the damage. Patients often try many different treatments before finding one that works for them.
The genetic mechanisms are actually really generic, he says. You can learn a lot by linking what we see in [OneK1K study] data to what already know just about genetic positions in disease. Now, were taking those genetic positions from genome-wide association studies and will show mechanisms of action and specifically the cell types they are acting in.
Pure fundamental science is a major driver for the work, says Powell, knowledge creation for human disease... and making all the data publicly available. Since the Science paper published in April, he has been fielding multiple data requests daily.
The more translational outcome is the possibility that the catalogue of genetic mechanisms will be useful in predicting which treatments will work best for individual patients, Powell says. To test that hypothesis, Powells lab is in the process of conducting a series of retrospective and prospective signal-seeking studies using currently marketed drugsstarting with immunotherapy treatment of cancer.
If successful, patients will one day be able to get a very cheap test costing literally tens of dollars [in Australia anyway] to guide the clinical decision-making of their treating physician, Powell says. We think that across a population we will be able to move the efficacy of a drug from, say, 30%which is pretty common for immunotherapy and a lot of inhibitory drugs in autoimmune diseaseto 50% or 60%. Even a 10-percentile gain for a single drug would be remarkable in terms of patient impact, he adds.
Along the way, the molecular mechanisms of disease are being unearthed at the cellular RNA level and that data could be shared with pharmaceutical companies to inform their early-stage drug development work, including which targets to take forward to phase 1 clinical trials, says Powell. Already, four pharma companies and one biotech have approached him about just such partnering opportunity, which would additionally aid them in the selection of patient groups for treatment trials.
Scientific strides have been a team effort by many committed individuals, he says, crediting the 16 co-authors on the latest study hailing from Sydney, Hobart, Melbourne, Brisbane, and San Francisco. They consider themselves part of the larger, decade-long movement toward open science, marked by transparency, open communication, and access to the data and computer code used to reach conclusions.
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Genetic Control Of Autoimmune Disease Mapped To Cellular Level - Bio-IT World
Alameda County Superior Court Judge Jo-Lynne Q. Lee set a hearing on nationally recognized plaintiffs firm Maune Raichle French Hartley & Mudd. LLCs motion for protective order in a pending asbestos case in which the defendants experts wanted to perform genetic testing. The case is John Lohmann and Suzanne Lohmann v. Aaon, Inc., et al. Alameda County Superior Court Case No. RG21098862. In this case, the plaintiffs filed their action in May 2021 in Alameda County against several defendants alleging that Mr. Lohmann contracted mesothelioma occupationally during his career as a refrigeration equipment mechanic beginning in the early 1970s largely in California.
After appearing in the action, the defendants retained pathology experts who wanted to use Mr. Lohmanns medical data for non-litigation purposes without Mr. Lohmanns permission, because the experts believed that the information would advance science. To conduct this testing, counsel for designated defense counsel moved for discovery of Mr. Lohmanns original cytology/pathology slides and paraffin blocks and subpoenaed his health care providers. The court ordered production of those original materials. According to the plaintiffs counsel, production of Mr. Lohmanns pathology and genetic material during litigation does not thereby permit outside, personal research and analysis. Multiple defendants disagreed, however, and contend that evidence produced during litigation enters the public domain and is thereafter not protected by discovery law.
As a result, on January 7, 2022 the plaintiffs filed for a protective order under California Code of Civil Procedure 2025.420, arguing that they never discussed with defense counsel the terms by which Mr. Lohmanns pathology material was to be used. The plaintiffs asked Alameda County Superior Court to block defendants from compiling medical data for the benefit of a third partys medical database or research project. Defendants, in their written opposition and during oral argument, contend that there is no authority barring medical research on data derived during litigation. Defendants also contend that the plaintiffs are incorrectly relying on Californias discovery statutes, which only govern how the evidence is obtained, not how it can be used. Defendants also argue that research evidence derived from litigation is relevant not only for diagnosis, treatment, and cause, but also helps determine the plaintiffs damages. For example, the defendants cite to scientific research showing that patients with the BAP-1 mesothelioma marker respond better to treatment and tend to have longer life expectancies than those patients without this marker. Defendants wish to present this evidence to the jury as they decide Mr. Lohmanns claim for future medical costs and damages for shortened life expectancy.
Up until last year, defendants and the plaintiffs in Alameda County operated under an informal discovery agreement regarding a plaintiffs pathology materials. However, with more and more defense experts looking to see if a plaintiff, like Mr. Lohmann, had the BAP-1 mesothelioma marker, the Maune firm revoked this informal agreement citing privacy and concerns over genetic testing of their clients materials. Their concerns were largely centered on the actions of longtime defense pathology expert, Dr. Victor Roggli, who published an article in 2020 describing an individual previously represented by the Maune firm.[1] According to the Maune firm, Dr. Rogglis use of their clients medical data in his non-litigation research was improper. In regard to the testing for BAP-1 in particular, the plaintiffs in Lohmann are attempting to block it arguing that it has questionable value in a mesothelioma case. The plaintiffs imply in their motion that the defendants are hoping to use published research linking BAP-1 mutations and certain asbestos exposures in litigation.
It is now up to Alameda County Superior Court to decide whether these defendants and the Dr. Rogglis of the world can, legally under the Discovery Act, use a plaintiffs medical data for their own non-litigation purposes without first obtaining the plaintiffs permission. The Court has requested additional briefing from the parties on this subject before it will make this determination. Defendants are urging the Court to retain an independent expert to examine this issue.
For the Lohmann case, the hearing on the plaintiffs protective order did not go forward after the Defendants stipulated that none of their experts intended to use any of Mr. Lohmanns medical information outside of litigation.
So, for now at least, this issue has been tabled until the next case. But, if and when Alameda County does make a ruling on this issue, its decision will have a significant impact on genetic defenses for mesothelioma cases in California and, likely, elsewhere in the nation as well. The courts eventual opinion will decide whether asbestos defendants can use a plaintiffs medical data in third-party research that could potentially help gather information useful to defendants defenses to damages claims in future asbestos cases.
[1] Mujahed T, Tazelaar HD, Sukov WR, Halling KC, Davila JI, Glass C, Pavlisko EN, Strickland KC, Roggli V, Haque M, Mneimneh W, Carter E, Galateau-Salle F, Glidden D, Garcia-Kennedy R, Larsen BT. Malignant Peritoneal Mesothelioma Arising in Young Adults With Long-standing Indwelling Intra-abdominal Shunt Catheters. Am J Surg Pathol. 2021 Feb 1;45(2):255-262. doi: 10.1097/PAS.0000000000001574. PMID: 32826527.
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Alameda County Awaits Key Decision Regarding The Use of Genetic Testing in Asbestos Cases - JD Supra
The lack of diversity in genomic research could mean Africans are missing out on potential life-changing care for chronic health disorders, according to a new study published inNature Medicine.
Genetic risk scores are a tool used to estimate an individuals risk of developing a disease, based on genetic factors. Researchers are able to find out someones genetic risk score by examining a populations genetic data and linking genetic factors to various health outcomes to indicate how likely they are to experience certain conditions.
These genetic risk scores are thought to revolutionise medicine by making it possible for people to receive treatments in line with their genetic make up, as well as for early identification and prevention of diseases. However, due to the small numbers of genetic studies involving African people, there is not currently enough information to create accurate genetic risk scores to predict their vulnerability to illnesses such as heart diseases.
The study, led by researchers from theMRC/UVRI and the London School of Hygiene & Tropical Medicine (LSHTM) Uganda Research Unit in collaboration with those from the University of Witwatersrand in South Africa, used genetic data from 1.4 million people of diverse ancestry across sub-Saharan Africa to examine how the use of diverse and representative data can impact our ability to predict disease risk.
The team found that when genetic data from the African American population was included in genomic studies, the genetic risk score estimates were five times more accurate for people with African ancestry, compared to when data from European ancestry was used.
African Americans only comprise 1.1% of global genomic studies. These findings emphasise the importance of including Africans genetic information in genomic studies in order to gain more accurate information about genetic risk factors for disease, and better control the growing trend of chronic health disorders in Africa.
Segun Fatumo, Associate Professor of Genetic Epidemiology & Bioinformaticsat theMRC/UVRI and LSHTM Uganda Research Unit said: "Currently, genomic studies include primarily individuals with European ancestry. This means genetic risk scores in predicting risk of disease, while applicable to the European population, is not accurate or reliable for those of African ancestry. It is crucial that we address this lack of diversity in genomic data. More genomic research is required to produce genetic risk scores that are relevant and representative of the genetic diversity in African populations due to age, lifestyle, environment, and other genetic factors."
Researchers used data from Uganda and South Africa to gather genetic information using genetic risk scores to identify people within continental African populations with high and low fat levels. Their findings identified a number of inherent features in African populations, including that the genetic risk scores were more accurate for people living in urban settings in South Africa than for those in Uganda, due to differences in age, lifestyles, environments and genetics.
Additionally, by including well-known risk factors, such as age, gender, body mass index (BMI) and type 2 diabetes in the estimation of genetic risk scores, the classification of people with either high or low risks improved by 42%.
This was in contrast to conventional risk factors reported in European-based studies such as age, gender, and body mass index as significant contributors to identifying people with high and low fat levels. These findings also demonstrate that a standard genetic risk score cannot be applied across different ethnicities and nations in Africa due to genetic variability and other factors which affect risk such as age, lifestyle and environment.
The team also divided the population into three categories to indicate whether they have a low, medium or high risk of developing a disease. This could help clinicians and genetic specialists to evaluate an individuals risk of disease, especially those at high risk of developing chronic diseases.
Early diagnosis and treatment is one of the best ways to reduce the chances of developing chronic diseases such as heart and blood vessel disorders. The lack of diversity in genetic studies, and those that include African people in particular, has slowed progress in calculating individuals susceptibility to illnesses, which in turn slows their path to diagnosis and treatment.
Although genetic risk scores are not extensively used by health professionals at the moment, the researchers believe these findings provide hope for enhancing clinical care in Africa. Knowing how likely an individual is to get a disease could help them take preventative steps to diagnose it earlier, when it is easier to treat, or even cure. According to the researchers, this is crucial for detecting those who are at risk of having high levels of body fat in the future.
Dr. Tinashe Chikowore, from the University of the Witwatersrand and an author of this study, said: "Advocating for greater diversity in genetic studies will guarantee that Africa is not left out of future precision medicine initiatives, which are crucial in identifying people who are more or less susceptible to contract chronic infections."
Reference:KamizaAB, Toure SM, Vujkovic M, et al. Transferability of genetic risk scores in African populations. Nat Med. 2022. doi: 10.1038/s41591-022-01835-x
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Diversity in Genetic Research Is Key to Enhancing Treatment of Chronic Diseases in Africa - Technology Networks
Colorado State University researchers are partnering with the American Hereford Association to support cattle producers and the beef industry in finding sustainable solutions to environmental and economic challenges.
The new research aims to enhance understanding of genetic differences in seedstock relative to enteric methane production and nitrogen excretion while identifying selection tools that can help reduce beef's carbon and environmental footprint.
"We're excited to begin this cooperative research agreement with Colorado State University,"says Jack Ward, executive vice president of the American Hereford Association, one of the largest beef breed associations in the United States. "It leverages decades of research and data collected by AHA members aimed at characterizing genetics associated with production efficiency, which plays a key role in environmental and economic sustainability."
Environmental and economic challengesDirect emissions from the animal agriculture sector account for 3.8% of U.S. greenhouse gas emissions, according to the Environmental Protection Agency. Enteric methane accounts for approximately 27% of methane emissions in the U.S.
Methane emission, as a genetic trait in cattle, appears to be moderately heritable with genetic correlations to economically relevant production traits, such as measures of growth, dry matter intake and various estimates of feed efficiency.
Worldwide attention is also focusing more intently on nitrogen a byproduct of rumen fermentation. Previous research suggests genetics play a significant role in nitrogen excretion by cattle, and when selected for, an individual animal's environmental footprint can be reduced.
"We know genetic improvement of our industry is driven by gains made in the seedstock sector. One only needs to look at changes in carcass meat yield and quality over the last two decades to realize the potential for improvements in seedstock genetics to transform the entire beef industry,"says Animal Sciences Professor Mark Enns, a beef cattle geneticist and key member of the research team.
Sustainable solutions"Often, we hear criticism leveled at the beef industry regarding greenhouse gas emissions and the impact of cattle on the environment, but with little context,"Enns says. "Cattle also sequester carbon and contribute to environmental health. This project will contribute to the beef cattle industry's goal of demonstrating carbon neutrality by 2040."
Given the Hereford breed's inherent genetic advantages associated with production efficiency, Ward says documenting the relationship between traits associated with efficiency and greenhouse gas emissions is logical next step for the breed and the industry.
"Beef industry stakeholders including the National Cattlemen's Beef Association have committed to improving the environmental impact of U.S. cattle production. This project aims to develop a selection tool for the American Hereford Association and the broader cattle industry that helps producers identify genetics that will have reduced greenhouse gas emissions without sacrificing animal productivity,"says Kim Stackhouse-Lawson, director of CSU AgNext, a pioneering research collaborative developing sustainable solutions for animal agriculture.
By leveraging existing animal performance data and monitoring animal emissions, Stackhouse-Lawson explains the goal is to identify genetic traits that influence environmental emissions from individual animals and then develop selection indices that can be used to reduce the environmental impact of cattle, while maintaining, and ideally improving economic returns to producers.
"This project will also position the American Hereford Association as a sustainability leader in the beef industry through the development of genetic selection tools that can identify and inform breeders of genetics that meet climate goals without sacrificing quality, performanceand efficiency," says Stackhouse-Lawson.
Further, Enns notes the project has potential to pave new paths of revenue for cattle producers. These could include such things as verified sustainable production claims, in addition to commonly discussed carbon credits.
Supporting the beef industryThe U.S. beef cattle industry has a long history of demonstrating extraordinary gains in efficiency over time, using genetics, technology and management to produce more beef with fewer cows and less land.
"This research will help us identify ways to magnify the gains the industry has already achieved," Ward says.
"CSU is involved in this project because we are passionate about beef production and the beef industry, and the societal benefits it brings from the upcycling of human-inedible plant materials and byproducts into high-quality protein,"Enns says. "From a genetic improvement standpoint, CSU has a long history of new trait development and delivery of selection tools to the industry. As such, we feel we have much to contribute in this realm, striving to produce cattle that meet consumer demands, yet have a smaller environmental footprint."
Source: Colorado State University, whichis solely responsible for the information provided, and wholly owns the information. Informa Business Media and all its subsidiaries are not responsiblefor any of the contentcontained in this information asset.
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CSU partners with American Hereford Association on genetics research - Beef Magazine
A new study adds to our understanding of polar bears and brown bears' linked evolutionary histories.
Scientists have known this for a while, but the current study used a larger dataset to eke out additional detail, including DNA from an old polar bear tooth.
(Photo : HENNING BAGGER/Ritzau Scanpix/AFP via Getty Images)
The fact that these creatures were separated into different species did not prevent them from mating, as per ScienceDaily.
This has been known for some time, but the current study uses a larger dataset, including DNA from an old polar bear tooth, to elucidate the details.
The result that emerged is riddled with difficulties akin to those that have plagued human progress.
According to Charlotte Lindqvist, Ph.D., a specialist in bear genetics and associate professor of biological sciences at the University at Buffalo College of Arts and Sciences, the establishment and maintenance of species may be a chaotic process.
What's going on with polar bears and brown bears is a good analogy for what we're learning about human evolution: species separation may be imperfect.
They're witnessing multidimensional genomic mixing as diverse groups of archaic humans married with descendants of contemporary humans as more old genomes from historical population groups, particularly Neanderthals and Denisovans, have been discovered.
Another system in which this occurs is between polar bears and brown bears.
They discovered evidence of polar bear-brown bear interbreeding that preceded the study of an ancient polar bear, Lindqvist said.
Furthermore, the findings revealed a complex, entangled evolutionary history between brown and polar bears, with gene flow mostly from brown bears to polar bears.
According to the lead author, scientists previously believed that modern humans and Neanderthals evolved from a shared ancestor, and then divided into different species.
Then, she explained, researchers discovered Neanderthal DNA in current Eurasian individuals, showing that modern human groups got an influx of Neanderthal genes at some point during their common evolutionary history.
Lindqvist added that it was only afterward that scientists realized that this genetic intermingling had also enriched Neanderthal populations with current human DNA.
Interbreeding, she noted, may be complicated and not always a one-way track.
Also Read:Consequences of Climate Change: Polar Bear Population Shrinking Due to Arctic Sea Ice Melt
(Photo : JEAN CHRISTOPHE VERHAEGEN/AFP via Getty Images)
The polar bear has long been assumed to have arisen lately from its lower-latitude sister species, the brown bear, based on fossil and mitochondrial DNA data, as per the study "Polar and brown bear genomes reveal ancient admixture and demographic footprints of past climate change," that was published in the journal Proceedings of the National Academy of Sciences of the United States (PNAS).
Full mitochondrial generation sequencing, for example, has suggested a 150-kya split in these species' maternal lineages and affirmed a notably special connection between the polar bear and a hereditarily secluded population of brown bears from Alaska's Alexander Archipelago's Admiralty, Baranof, and Chichagof Islands.
A new, higher comprehensive genome for a polar bear that lived 115,000 to 130,000 years ago in Norway's Svalbard island was also created by the scientists.
The ancient polar bear's DNA was recovered from a tooth belonging to a subfossil jawbone presently kept at the University of Oslo's Natural History Museum.
Researchers predicted that polar bears and brown bears split into separate species around 1.3 to 1.6 million years ago, revising previous estimates by some of the same experts.
The age of the divide has been and continues to be a source of discussion among scientists, with historical interbreeding and a lack of fossil evidence for old polar bears among the variables that make the dating difficult to pin down, according to Lindqvist.
Related article:'Highly-Predatory' Brown Bear Killed 28 Newborn Reindeers After Waking From Hibernation
2022 NatureWorldNews.com All rights reserved. Do not reproduce without permission.
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Unraveling the Tangled History of Polar Bears to Brown Bears Using Genetic Sequencing - Nature World News
Conceiving a child is like playing the lottery. Given any two parents, there are 70 trillion possible genetic combinations that any one of their children could inherit.
This genetic diversity can make siblings really different from one another, for instance, in terms of their education, income, and lifespan.
Any attempt to study or address inequality in society must consider the impact of genetic inequality.
PAIGE HARDEN: Conceiving a child is like a giant Powerball. If we think about any two parents, there are 70 trillion possible genetic combinations that any one of their children could inherit. So siblings are really different from one another, in their education, in their income, even lifespan. And genetics is part of the reason why. But to study things like genetics in relation to education or intelligence or personality, has long been a really controversial area of research. For many people, the idea of genetic differences between us is hard to reconcile with what they think of as equality.But if we care about inequality that is tied to accidents of people's birth, the kind of stroke of luck over which they have no control, then we should care about genetic inequality, because it is one of the major sources of inequality in this country.
My name is Paige Harden. I'm a professor of psychology at the University of Texas at Austin. And I recently wrote a book called "The Genetic Lottery: Why DNA Matters for Social Equality."
I think what a lot of people don't realize is that all humans are over 99% genetically the same, regardless of their racial group. Even those differences don't fall along racial lines. So most of our DNA we have in common. That remaining less than 1%, however, is really scientifically interesting, because many of the psychological, behavioral, physical differences between us are related to that tiny fraction of our genome that differs between us. How can we figure out which genetic variants are associated with some of the psychological differences that we care about? Your risk for schizophrenia, your risk for depression, how far you go in school. I think a big part of the power of genetics is as a tool to help us understand the environment.
What are the social environments, the school contexts, the parenting environments that can turn on or turn off genetic risk? So if I'm at genetic risk for doing poorly in school, is there something about the school environment that can buffer me against that risk, such that I still go on to do well in my math class, such that I still go on to do well in college? So we're interested in bringing together the biological differences but also an understanding of the environment to see how they combine to shape children's lives.
This work, connecting genetics to things like education, continues to be controversial because people fear 'eugenics.' And that's the idea that genetic differences underlie some natural hierarchy of value, and that genetic information should be used to sort of slot people into their place or station in life. White supremacist groups will be eager consumers of genetic research in order to justify their narratives around biological hierarchy. But if scientists that have egalitarian values avoid the topic, then the only people who are consuming it and talking about what it means are these ideological extremes.
The predominant response to the eugenic perspective has been what I call 'Genome-blindness.' And that's really the idea that we should avoid talking about biological or genetic differences between people. The fear is that if something's genetic, it's natural and there's nothing we can do about it. So let's not talk about genetics lest people give up on the idea of changing social policy. And that doesn't bear out under the science. Things can be influenced by genetics, but still responsive to the environment. A great example is if you wear eyeglasses.
That's something that is genetically-caused, that we fix not by CRISPRing your genome or selecting your embryo, but by giving you an environmental intervention that you wear on your face. So, I think we can think of the antidote to eugenics not being genome-blindness, but being 'anti-eugenics.' There's a really great example of anti-eugenic policy in the United States, and that's the Americans with Disabilities Act.
If you go into an ADA compliant building, there has to be an elevator there. What's being equalized is not their functioning, so someone might still not be able to walk, they might still be in a wheelchair. What's being equalized is their ability to participate with dignity in a public space. In order to accomplish that, you actually have to recognize differences between people. What if we took that anti-eugenic disability justice perspective when we're crafting policies?
I am an egalitarian.I think of social inequality as a moral and political problem to be fixed. But at the same time, I think that biological differences between us are real and make a difference for our lives. I'm out here saying, 'Science doesn't neatly fit into ideology.' What we need to do is think about what our values are, what does the science say, and then take both of those things seriously when we're crafting policies.
Originally posted here:
Your genes affect your education. Here's why that's controversial. - Big Think
ATTR-CM (transthyretin amyloid cardiomyopathy) is a rare heart condition that can lead to heart failure. However, with an early and accurate diagnosis, ATTR-CM is often treatable.
One big question that patients have is what caused this disease? As with many serious health issues, sometimes its hard to pinpoint exactly, but usually this disease is caused by your type of lifestyle/diet, genetics, or a mix of both.
Whether you have been diagnosed early or very late in the game with this condition, changing your lifestyle habits is crucial to extending how long you can live with this type of heart disease, especially when your heart becomes too weak to effectively pump blood throughout the body.
Because ATTR-CM is often misdiagnosed or diagnosed long after symptoms first appear, it has been difficult to establish a reliable life expectancy for the condition if it is diagnosed and treated early in the disease progression.
ATTR cardiomyopathy is, unfortunately, an under-diagnosed condition, says New York cardiologist Aeshita Dwivedi, MD, who adds that greater awareness of ATTR-CM is leading to more diagnoses, which is also resulting in people starting treatment earlier in the disease process.
Some of what you will need to know can be learned by participating in a cardiac rehabilitation program. If you have been diagnosed with ATTR-CM ask your doctor about prescribing you rehab to learn about diet, exercise, medication adherence and other aspects of living with a heart condition.
Related: How Lifestyle Changes Can Help With Managing Heart Failure
Dr. Dwivedi explains that when confronted with the signs of ATTR-CM, like those of heart failure, its essential that you begin working closely with your cardiologist and follow the doctors advice about medication, checkups, lifestyle, and give thoughtful consideration to discussions of procedures, such as having a pacemaker or pump implanted.
Getting Diagnosed with ATTR-CM
Number one would be to see your doctor regularly, Dr. Dwivedi says. It is important to seek medical care for this condition, because we have good options and can change lives. Second would be talk to your doctor if any of your symptoms change. You would rather know sooner rather than later, before things get worse and when you may need hospitalization.
Related: What is the Heart Condition, ATTR-CM? What are the Symptoms?
She also recommends shifting to a heart-healthy diet that includes limited sodium intake and fats. This diet will help you achieve and maintain a healthy weight. Exercise is also important, though your capacity for physical activity will be limited. Be sure to discuss your exercise limits and concerns with your doctor or a cardiac rehab specialist.
Getting your steps in for the day and doing moderate activities very important, Dr. Dwivedi says. If exercise is new to you and you are unsure where to start, reach out to your doctor for a supervised exercise program for you to get comfortable being active.
In general, people with a family history of heart disease or other conditions should be extra vigilant for symptoms of ATTR-CM, which include those associated with heart failure, including:
There are two types of ATTR-CM:
Males are at higher risk than females for both types of ATTR-CM. And while hereditary ATTR-CM may present with symptoms at a young age, older adults are generally at higher risk for both types.
Bottom line, regardless of how you got to this point, what matters is that your condition has been accurately assessed, and you are in the care of a doctor who can try to help you achieve the best case scenario situation while living with ATTR-CM.
Contributing by SurvivorNet staff.
Learn more about SurvivorNet's rigorous medical review process.
ATTR-CM (transthyretin amyloid cardiomyopathy) is a rare heart condition that can lead to heart failure. However, with an early and accurate diagnosis, ATTR-CM is often treatable.
One big question that patients have is what caused this disease? As with many serious health issues, sometimes its hard to pinpoint exactly, but usually this disease is caused by your type of lifestyle/diet, genetics, or a mix of both.
Because ATTR-CM is often misdiagnosed or diagnosed long after symptoms first appear, it has been difficult to establish a reliable life expectancy for the condition if it is diagnosed and treated early in the disease progression.
ATTR cardiomyopathy is, unfortunately, an under-diagnosed condition, says New York cardiologist Aeshita Dwivedi, MD, who adds that greater awareness of ATTR-CM is leading to more diagnoses, which is also resulting in people starting treatment earlier in the disease process.
Some of what you will need to know can be learned by participating in a cardiac rehabilitation program. If you have been diagnosed with ATTR-CM ask your doctor about prescribing you rehab to learn about diet, exercise, medication adherence and other aspects of living with a heart condition.
Related: How Lifestyle Changes Can Help With Managing Heart Failure
Dr. Dwivedi explains that when confronted with the signs of ATTR-CM, like those of heart failure, its essential that you begin working closely with your cardiologist and follow the doctors advice about medication, checkups, lifestyle, and give thoughtful consideration to discussions of procedures, such as having a pacemaker or pump implanted.
Getting Diagnosed with ATTR-CM
Number one would be to see your doctor regularly, Dr. Dwivedi says. It is important to seek medical care for this condition, because we have good options and can change lives. Second would be talk to your doctor if any of your symptoms change. You would rather know sooner rather than later, before things get worse and when you may need hospitalization.
Related: What is the Heart Condition, ATTR-CM? What are the Symptoms?
She also recommends shifting to a heart-healthy diet that includes limited sodium intake and fats. This diet will help you achieve and maintain a healthy weight. Exercise is also important, though your capacity for physical activity will be limited. Be sure to discuss your exercise limits and concerns with your doctor or a cardiac rehab specialist.
Getting your steps in for the day and doing moderate activities very important, Dr. Dwivedi says. If exercise is new to you and you are unsure where to start, reach out to your doctor for a supervised exercise program for you to get comfortable being active.
In general, people with a family history of heart disease or other conditions should be extra vigilant for symptoms of ATTR-CM, which include those associated with heart failure, including:
There are two types of ATTR-CM:
Males are at higher risk than females for both types of ATTR-CM. And while hereditary ATTR-CM may present with symptoms at a young age, older adults are generally at higher risk for both types.
Bottom line, regardless of how you got to this point, what matters is that your condition has been accurately assessed, and you are in the care of a doctor who can try to help you achieve the best case scenario situation while living with ATTR-CM.
Contributing by SurvivorNet staff.
Learn more about SurvivorNet's rigorous medical review process.
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Did My Lifestyle or Genetics Cause ATTR-CM? Learning More About This Heart Condition That Often Goes Misdiagnosed - SurvivorNet
Introduction
Gene therapy has become an emerging treatment modality for both inherited and acquired diseases. Therapeutic genes can be delivered into the nuclei of target cells via viral and non-viral vectors. The viral vector approach utilizes the natural ability of viruses to infect human cell genomes. Viral pathologic genetic sequences are replaced by the desired therapeutic genes, and target cells are then infected with the modified viruses leading to incorporation of the therapeutic material into the nuclei. The non-viral vector approach uses different chemical and physical methods to deliver the therapeutic genetic material.1
While gene therapy is used to treat inherited diseases with loss of function mutations, it can also be used to treat acquired diseases. Target cells are infected with therapeutic genes which encode for specific drugs, so that the infected cells can produce the desired drugs in vivo.2 This concept has considerable potential; patients can be treated once, and their tissues are transformed into bio-factories that produce the medications indefinitely.
The eye is considered a good candidate for gene therapy; it is small and compartmentalized, requires relatively small numbers of vectors/gene copies, and has special immune response features that can favor viral-mediated gene therapy.3 Gene therapy for ocular diseases has already been approved by the United States Food and Drug Administration (FDA) to treat pediatric patients with Leber congenital amaurosis harboring a particular gene deficiency, named RPE65.4 Multiple promising clinical trials are currently being conducted for many other ocular diseases, described below.
Similar to every novel approach, gene therapy has its own set of challenges. Insertional oncogenesis, an inadvertent activation of oncogenes by insertion of transduced genetic material near proto-oncogenes, is a potential limiting factor.5 The irreversibility and unpredictable longevity of gene therapy effects highlights the lack of control once the treatment is administered.6
Different vector types and subtypes induce variable immune and inflammatory responses. These responses can nullify the effect of gene therapy or prevent repeated therapy in the same patient. In addition, different modes of delivery, whether intravitreal, subretinal or suprachoroidal, induce variable immune and inflammatory reactions. Given the etiological complexity of these responses and their detrimental effect on gene therapy efficacy, many studies have tried to analyze the factors that influence these responses.
Recently available data from clinical trials have shown that ocular gene therapy has been associated with severe ocular inflammation with resultant vision loss. Therefore, in this review, we would like to discuss ocular gene therapy with special focus on the resultant immune and inflammatory reactions in the light of the recent updates.
Viral vectors that are used for ocular gene therapy include adenovirus (AV), adeno-associated virus (AAV), and lentivirus. Non-viral vectors utilize different chemical and physical methods to deliver naked genetic material into the cells.1
Adenovirus is a double-stranded deoxyribonucleic acid (DNA) virus that can efficiently transduce dividing and non-dividing cells. It can induce a high amount of protein production by inserting numerous copies of the same gene into a cell.7 Adenovirus offers multiple advantages, including broad range of tissue tropism (transduction of both retina and anterior segment), a well-characterized genome, ease of genetic manipulation, capacity of carrying large genes, non-replicative nature in a host, and producibility at a large scale.3,7
Although adenovirus was the first vector to be evaluated in clinical trials, it is not currently used in ocular gene therapy clinical trials except for one trial studying retinoblastoma. Adenovirus has fallen out of favor due to the resulting robust immune response that causes inflammation and elimination of the transduced cells.8 Severe side effects have been reported using adenovirus, as severe as death of a patient with systemic fever and liver damage in a clinical trial for metabolic disease.9 Although it does not usually replicate inside hosts, a replication-competent virus can be inadvertently created by combination of adenoviral derived vectors with pre-existing adenoviral genome in the targeted cells, causing active systemic adenoviral infection in the patient.10
Adeno-associated virus (AAV) is the most commonly used vector for ocular gene therapy trials. AAV is a small (25 nm), replication defective, single-stranded DNA, non-enveloped virus belonging to the Parvoviridae family. It has been evaluated as a gene therapy vector for metabolic, hematological, ophthalmological, muscular, infectious disorders, and cancers.11 Currently, 13 different AAV serotypes have been identified in primates. They differ in their capsid components and display variable cellular tropism, transduction efficiency, and immunogenicity.7
Bennett et al have reported that AAV2 and AAV8 can infect retinal cells from the vitreous, but it was limited to the inner retina.12 AAV2 has also been used effectively through a subretinal injection to transduce retinal pigment epithelium (RPE) in a number of gene therapy trials and animal models.3,4 For AAV8, subretinal delivery leads to efficient photoreceptor transduction.13,14 AAV2 is commonly used in ocular gene therapy trials and is the vector used in the first FDA-approved ocular gene therapy voretigene neparvovec-rzyl (Luxturna) for Leber congenital amaurosis.4
AAVs deliver the genetic material as an extragenomic circular episome and do not integrate it into the human genome. This mechanism significantly decreases the risk of insertional oncogenesis. Similar to adenovirus, AAVs can also infect dividing and non-dividing cells.15,16 AAVs limited capacity to carry large-sized genetic material restricts their use in gene delivery for some diseases that are coded by large genes such as Usher syndrome.17
Unlike adenoviruses, AAVs generate relatively mild innate and adaptive immune responses, which allow for stable long-term transgene expression.13,15,18,19 These characteristics make AAV vectors particularly suited for applications in a variety of chronic ocular diseases.
Around 70% of the normal population have preexisting antibodies (Abs) against AAV2. On the other hand, AAV8 was isolated from non-human primates (NHPs). Therefore, there is a lower percentage of humans with Abs against it (around 38%).20 The presence of antiviral Abs has been correlated with minimal or absent gene expression following gene therapy.21 Thus, the use of AAV8-based vector therapy has the potential to be more effective than AAV2. However, there is still cross-reactivity of anti-AAV Abs against different serotypes.21
AAVs can be rapidly eliminated by the humoral immune response in patients who have previously been exposed to the virus.22 The immune reactions include induction of neutralizing antibodies that reduce the number of capsids reaching the target cells, innate immune pathways silencing the gene cassette within the host cell, and cell-mediated T-cell immune responses against foreign protein expression.18
Lentivirus is a complex, single-stranded ribonucleic acid (RNA) retrovirus that has been studied as a vector. Similar to the two previous vectors, it possesses the ability to induce a stable transduction in both dividing and non-dividing cells in a broad range of target organs.23 Lentiviral vectors are derived from primate lentiviruses human immunodeficiency virus (HIV), equine infectious anemia virus (EIAV) and simian immunodeficiency virus.3 Lentiviruses integrate their complementary DNA (reverse-transcribed RNA) into the chromosome of target cells enabling sustained gene expression but, like all integrative systems, can increase the risk of insertional mutagenesis and oncogenesis.7,24 They can be manufactured in high numbers and their genome can be deleted to reduce the inflammatory response. They also have high transgene carrying capacity allowing delivery of large-sized therapeutic genes that cannot be packed into AAV vectors. Such viral composition is particularly useful for diseases with large causative genes such as Stargardt disease and Usher syndrome.22,25,26
Lentiviruses are possibly more immunogenic than AAVs.27 Binley et al found that 5 out of 6 non-human primates that were injected with EIAV in their subretinal space developed a peripheral perivascular retinal whitening. However, this whitening (which probably represented a form of intraocular inflammation) was transient and resolved with treatment.28 In general, multiple studies have shown that lentiviruses are relatively safe and can result in effective and sustained gene transduction for a significant time.2830
Non-viral vectors were developed as an alternative to viral vectors to avoid their associated immune responses. Non-viral vectors are used to transfer large DNA-like plasmids, small DNA (eg, oligodeoxynucleotides), and RNA molecules through different chemical and physical methods.31
Chemical methods include lipid-based delivery systems, polymers, and cell-penetrating peptides. They form nano-complexes with the genetic material that can either penetrate the cell membrane or be endocytosed. These complexes also protect genetic material from premature degradation. Nanoparticles carrying genetic material have been shown to effectively transduce the outer retina if injected subretinally.6,32
Physical methods are more variable and technically utilize different approaches to facilitate the genetic materials delivery into the cells. Examples are electrical pulses, ultrasound, magnetic fields, gene guns, and lasers. High voltage short electrical pulses (electrotransfection) are highly efficient in transducing the ciliary body to produce the desired drug autonomously.6,32,33
The main advantages of non-viral methods include the lower risk of immune stimulation and insertional mutagenesis (as most do not integrate with chromosomes), the ability to deliver a large amount of genetic materials, and the ease of production. Short-term expression of the transduced genetic material can be considered as a major disadvantage of this method.6,32
The eye constitutes an excellent site for gene therapy due to its anatomy, ease of access, immune-privileged state, which limits the immune responses and inflammatory reactions against the delivered genetic product, and tight blood-ocular barriers that limit the systemic exposure of the drug. Its relatively small size also grants a minor volume of drug to have effective results. In addition, the assessment of treatment implications can be performed non-invasively via diagnostic imaging, and the second eye can be used as a control group.34 Several studies are focusing on possible gene therapies for an array of ocular diseases from the cornea to the retina. A summary of completed and/or current ocular gene therapy clinical trials can be found in Table 1.
Gene therapy has been studied as a potential treatment option for both inherited and non-inherited corneal diseases. Examples of studied non inherited diseases for gene therapy were Herpes simplex keratitis (HSK), dry eye Sjogrens syndrome (SS), corneal graft rejection, and corneal neovascularization.35 Mucopolysaccharidosis (MPS), Meesmann epithelial corneal dystrophy, ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome, aniridia, and Fuchs endothelial corneal dystrophy are among the inherited diseases where corneal gene therapy is applied in several animal studies.35
As 72% of the cases with primary open-angle glaucoma are hereditary and there is a monogenic inheritance component in juvenile-onset open-angle glaucoma, gene therapy may be beneficial.36 Preclinical and Phase I studies have shown that gene therapy using small interference RNA (siRNA) that suppresses 2-adrenergic-receptor synthesis, via topical drops, might be effective in lowering intraocular pressure (IOP) in glaucoma patients. Phase II studies have also been conducted.3739
Because the retina is fragile in patients with X-linked Retinoschisis XLRS, the risk for subsequent retinal detachments increases following gene therapy if performed via the subretinal route. Therefore, the intravitreal route is preferred for the transfer of vectors in this condition.40 There are currently two clinical trials in which the AAV vector expressing RS1 gene is delivered intravitreally to XLRS patients. The preliminary results were reported that the gene product was well tolerated, and ocular adverse events, including dose-related inflammation, resolved using topical and oral corticosteroids.41
Stargardt disease is caused by ABCA4 mutations leading to accumulation of lipofuscin pigment inside the RPE causing degeneration of both RPE and photoreceptor cells.42 A phase I/II clinical trial investigated the utility of EIAV-vector carrying the ABCA4 gene that is delivered through the subretinal route, but it was terminated in 2015.43 Other clinical trials for Stargardt Disease are being planned.
Choroideremia occurs secondary to a mutation in the CHM gene leading to progressive RPE and photoreceptor cell death.44 There are some challenges for gene therapy in choroideremia, including insufficient resemblance of animal models to functional and morphological manifestations of the disease, and uncertainty of which retinal layer is affected most.45,46 Gene therapy outcomes for choroideremia have been less successful than RPE65-related Leber congenital amaurosis (LCA).47 There are currently nine clinical trials registered on ClinicalTrials.gov evaluating interventional gene therapies for these patients all of which use AAV vectors. Only one of them uses the intravitreal route, and the remaining eight deliver the drug subretinally.
Retinitis Pigmentosa (RP) is a heterogeneous disease, and it occurs in an autosomal recessive (AR) pattern in 5060% of the cases.48 The most common genes include RPGR (retinitis pigmentosa GTPase regulator) which accounts for ~70% of X-linked RP; rhodopsin (RHO) which causes ~25% of AD RP, and the Usherin2A (USH2A) gene that is linked to approximately 20% of AR RP.49 Currently, there are multiple clinical trials assessing different viral and non-viral vectors, through intravitreal and subretinal injections, for different types of RP.
A novel approach, which is described as optogenetic therapy, is also under investigation for retinitis pigmentosa. It is based on delivering genetic information that codes for light sensitive proteins to non-photoreceptor retinal neurons such as ganglion cells, rendering them sensitive to light stimulation and hence, bypassing the photoreceptors. This approach has the potential to improve visual perception in cases of RP and other inherited retinal diseases where the photoreceptors are severely damaged.50
Usher syndrome displays AR inheritance with different large-sized causative genes, including MYO7A, USH2A and GPR98. Similar to Stargardt disease, lentiviruses are required to deliver the large-sized genetic material.51,52 A single clinical trial was conducted for Usher syndrome with a mutation in MYO7A gene using a lentivirus vector through a subretinal injection, but it was terminated.53 Recently, a promising phase I/II clinical trial was initiated to evaluate the safety and tolerability of an intravitreal RNA antisense oligonucleotide for Usher syndrome.54
For achromatopsia, there are six different gene mutations (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6) of which CNGA3 and CNGB3 are the most common.55 Clinical trials are being conducted targeting these two genes with an AAV vector through subretinal injection.
Leber congenital amaurosis (LCA) is an AR disease with mutations in numerous genes. LCA2 occurs specifically due to RPE65 gene mutations, a gene expressed highly in RPE cells. Despite the significant visual impairment in LCA, retinal cells and photoreceptors are relatively spared.56 Therefore, RPE65-mediated LCA has shown to be a favorable candidate for ocular gene therapy as it requires a certain amount of viable cells to be effective. The FDA approved the first gene therapy for ocular disease following the Phase III clinical trial of AAV2-hRPE65v2 (voretigene neparvovec, Luxturna) that evaluated the efficacy and safety of bilateral sequential subretinal injections to both eyes in patients with LCA.4
The trial with voretigene neparvovec involved 29 pediatric patients older than 3 years with LCA and visual acuity of 20/60 or less. Participants were randomized (2:1) to intervention or control groups. The results of this trial have demonstrated that voretigene neparvovec ameliorated functional vision in RPE65-mediated LCA, and there were no treatment-related serious adverse events. Mild ocular inflammation was reported in only two patients (10%) which was resolved. The authors did not provide details regarding how the ocular inflammation was managed.4
Different vector therapy trials are being conducted for both non-neovascular and neovascular AMD. The safety of subretinally delivered lentiviral EIAV vector expressing endostatin and angiostatin for neovascular AMD has been established with well-tolerated doses, no dose-limiting toxicities, and little to no ocular inflammation.30 Intravitreal injection of AAV carrying aflibercept gene has also shown very promising results in controlling neovascular AMD disease activity.57 Additional studies are being conducted to confirm the potential role and utility of vector therapy, via various approaches, including subretinal, intravitreal, and suprachoroidal delivery, in the management of AMD.
Suprachoroidal delivery of an AAV vector carrying an anti-vascular endothelial growth factor (anti-VEGF) fab segment is being evaluated for diabetic retinopathy without central involving macular edema in a phase I clinical trial.58 A clinical trial is also evaluating an intravitreally delivered AAV vector coding for aflibercept for diabetic macular edema.59
Leber hereditary optic neuropathy (LHON), an inherited mitochondrial optic neuropathy related to retinal ganglion cell death, is most commonly linked to ND1 (G3460A), ND4 (G11778A), and ND6 (T14484C) gene mutations.60 As delivering genes into the ganglion cell mitochondria is difficult, allotopic expression strategy (mitochondrial gene expression in nucleus) has been developed.61 Different trials have demonstrated the safety and efficacy of gene therapy using an AAV vector, delivered through an intravitreal route, for LHON.6264
Gene therapy can be administered into the eye via different ways such as intravitreal, subretinal, and suprachoroidal routes. Each mode of delivery has its own advantages and unique effects on how the immune system reacts to the vector, which in turn affects the phenotype of ocular inflammation. Different types of intraocular gene delivery are illustrated in Figure 1.
Figure 1 Images showing different methods of intraocular gene delivery: (A) intravitreal, (B) suprachoroidal, and (C) subretinal.
The intravitreal route is the traditional route used by ophthalmologists to deliver most intraocular medications into the eye, such as anti-vascular endothelial growth factors (anti-VEGFs), antibiotics, and steroids. The intravitreal route is a convenient choice; it can be administered in office settings and requires fewer instruments and equipment than the subretinal route. In addition, it is surgically simpler, less invasive, and generally safe. Also, this method is more logistically plausible due to its relative ease in delivery. Another advantage of intravitreal gene delivery is its theoretic ability to transduce the whole retinal surface, in contrast to the localized transduction induced by subretinal delivery. Such approach may be beneficial in cases where the targeted cells are not limited only to the macula.65,66
There are two main limitations of the intravitreal route: the inability to transduce outer retina layers and possible immune and inflammatory reaction. The outer retina is the main target of gene therapy for most retinal diseases. Most of the retinal genetic diseases are due to defects in the RPE or photoreceptor cells.67 Vectors delivered via the intravitreal route have limited ability to transduce the outer retina possibly due to the internal limiting membrane (ILM), evidenced by the improvement of outer retinal transduction after removing or degrading the ILM.68,69 However, other studies showed that some specially engineered vectors, via directed evolution, can transduce the outer retina after being injected intravitreally.65,70 If this result can be reproduced, it may revolutionize gene therapy.
Several reports showed that the vitreous cavity may be considered an immune-privileged space.7173 Yet, the intravitreal vector approach has still shown a different and distinct immune response from subretinal vector delivery.74 Studies on humans and NHPs have demonstrated consistently that intravitreal delivery of vectors induces a significant humoral immune response.13,21,75,76 The response is marked by the production of Abs, which may not lead to inflammation, but can significantly reduce the efficacy of treatment by attacking and eliminating transduced cells through the neutralizing antibodies. Intravitreal injection of one eye has also been shown to block vector expression in the contralateral eye when injected intravitreally with the same vector, due to the production of neutralizing Abs.75
Reichel et al directly compared the degree of inflammation between intravitreal and subretinal gene therapy.13 In their study, they found that the subretinal route caused more anterior and posterior segment inflammation than the intravitreal route, although the intravitreal route caused a stronger humoral response. The finding suggests that there might not be a clear association between intraocular inflammation and humoral response,77,78 which is further supported by the work of Bouquet et al79 who showed that neither baseline Abs nor the degree of immune response, defined by increased Ab titers, correlated with the degree of intraocular inflammation.
However, Cukras et al showed that antibody titers were correlated with the degree of inflammation.41 In this phase I/II clinical trial, patients were divided into low dose, intermediate dose, and high-dose groups. No patient in the low-dose group had a significant increase in their neutralizing Ab titers. Ab titers increased significantly in both intermediate and high-dose groups. In this study, anterior chamber inflammation correlated significantly with higher Ab levels. All patients of the high-dose group had high Abs titers for 18 months. It should be noted that, in this study, inflammation in all cases in this study was controlled by topical and oral steroids.
In the relatively recent INFINITY clinical trial that evaluated intravitreal AAV for diabetic macular edema (DME), late onset severe intraocular inflammation was observed. In this trial, patients were randomized to three groups: high virus dose (N=12), lower virus dose (N=13) and aflibercept (N=9) groups. Three patients in the high-dose group developed late onset significant inflammation including panuveitis, which resulted in hypotony. All three were treated with pars plana vitrectomy (PPV), silicone oil (SO) and Retisert implantation. None of the patients in the low dose or aflibercept groups developed hypotony. Most patients in both virus treatment groups developed some sort of intraocular inflammation that required difluprednate eye drops beyond a prophylactic post injection 10 weeks period. Most of the high-dose group required additional medications including steroids administered through multiple routes including oral, periocular, and intraocular. Two patients in the high-dose groups required mycophenolate therapy to further suppress intraocular inflammation. Around 50% of the low dose group required additional periocular or intravitreal steroid therapy.80
Interestingly, the same viral concentrations were administered in the Optic trial for AMD, but no hypotony developed and the reported intraocular inflammation was less frequent and less severe, and all incidences were successfully treated with topical steroids only.81 This clearly suggests a role of the underlying disease in the development of inflammation in addition to the route and dose. Inflammatory processes are known to be integral in the pathogenesis of diabetic retinopathy,82 and this might explain the difference in rates of intraocular inflammation between eyes with diabetic retinopathy and those with AMD, despite being treated with the same vector and concentration.
Subretinal vector delivery requires pars plana vitrectomy. After completion of the vitrectomy, a macular retinotomy is done via a small gauge cannula. Detachment of the macula is achieved by injecting balanced saline solution followed by vector injection in the preformed bleb.14,83
Using the subretinal approach to deliver vector therapy is well established as it has many advantages. It ensures transduction of outer retinal layers through direct vector delivery. The efficacy of transducing the outer retina by injecting vectors through this route has been reported extensively and consistently.4,14,29,8486 The subretinal space itself has a special immunological response, which will be discussed below. As mentioned previously, voretigene neparvovec, the only FDA approved ocular gene therapy, is delivered through this approach.
The main disadvantage of this approach is the surgery itself. Traditional vitrectomy complications such as cataract, IOP rise and retinal tears, as well as subretinal injection-related complications such as a macular hole.4,87,88 The technique itself requires significant surgical experience. Ochacovski et al89 have shown that subretinal injection, in NHPs, can cause mild thinning of the outer layers of the fovea in comparison with an intravitreal injection of the same vector.89,90 However, the difference was not clinically significant. Photoreceptor damage was also reported in the phase I trial for the same gene therapy.
The subretinal space is immune privileged and has a deviant immune response. Immune responses to antigens in this space can be similar to anterior chamber associated immune deviation (ACAID); immune responses are suppressed by activating T helper 2 cells.19,91,92 Many studies have shown minimal to absent humoral response to antigens delivered to this space.13,74,75 Furthermore, Anand et al reported suppression of pre-existing cellular immune response to certain antigens after injecting them into the subretinal space.19 Other studies also found that gene transduction was achievable if injected in the subretinal space even if the subjects have neutralizing antibodies.74,92 This beneficial immune response has raised the question of whether it is better not to use steroids with a subretinal injection, as this would theoretically negate the good suppressive nature of that deviant immune response.13,19
As mentioned above, few studies found that subretinal route can induce more inflammation compared to the intravitreal route.13,77,78 One may consider this secondary to the surgical technique itself rather than the immune response to the vector; however, Reichel et al showed that subretinal delivery of a vector caused more inflammation than just performing the same surgical procedure without injecting a vector.13 Nevertheless, to our knowledge, none of the studies that evaluated the subretinal gene delivery have reported devastating panuveitis with loss of vision similar to the above mentioned case that was associated with intravitreal delivery.
Another infrequent but potentially severe immune/inflammatory response to subretinal injection is the poorly understood phenomenon of intraretinal hyperreflective foci, found on optical coherence tomography, following subretinal injection which has been reported in several studies. It was reported at least in two human subjects in two different studies: one study had a subject who suffered from irreversible photoreceptor and vision loss despite steroid use, and another study demonstrated the adverse event in one subject but fortunately resolved following oral steroid treatment.14,93 It was also reported in NHPs, but resolved and the retina returned to baseline.13 To our knowledge, it has not been reported with voretigene neparvovec. It is possible that this reaction represents a unique side effect of a special type of vector, but it was reported with the use of both AAV2 and AAV8 subtypes, suggesting it may not be vector specific.
With both intravitreal and subretinal routes having their disadvantages, suprachoroidal route was studied to overcome these challenges. The suprachoroidal route is less invasive than the subretinal route. It also has the potential of a weaker immune response than the intravitreal route, leading to lower levels of produced antibodies.78 It can also deliver the vectors to the outer retina, which is a main limitation of the intravitreal route.78 This route is also being investigated for delivering non-viral vectors with promising results in animals.94
Different techniques are being used for suprachoroidal drug delivery. It can be done via a microcatheter,9597 hypodermic needle,98 or microneedles.99,100 Microcatheters require a sclerotomy that requires visualization with a surgical microscope. Cautious dissection of the sclera is done until the scleral-choroidal junction has been reached. The blunt-tipped catheter is then inserted and directed toward the posterior pole, using a light pulp at the tip of the catheter to aid in visualizing its position. The hypodermic needle technique requires merely inserting the needle at an oblique angle through the sclera until a release sensation is just felt. Because it is a somewhat blind procedure, it may lead to choroidal or retinal penetration. Another technique utilizes the microneedle which is a very short needle that is applied perpendicularly into the sclera. A large clinical trial employed this method with no serious side effects.99
Yiu et al have shown that humoral response to suprachoroidal gene therapy was weaker than the response to the intravitreal route, with levels of neutralizing Abs being significantly lower.78 To our knowledge, this is the only published study that compared antibody production between the two routes. Although the sample size was small, and the study was on NHPs, it is very encouraging. This study has also shown that suprachoroidal delivery was associated with widespread transduction of RPE cells, in contrast to the subretinal delivery in which the transduction is localized to the macular bleb.
However, there are issues with the suprachoroidal route as well. There are inconsistent reports about its efficacy in infecting photoreceptors. Two studies involving NHPs showed conflicting results in the efficacy of photoreceptor cell uptake.78,101 This may be due to the difference in AAVs capsid or promoter sequence, but further studies are needed. Studies on animals other than NHPs showed that the suprachoroidal route can be used effectively to infect photoreceptors.95,101 Another issue is the non-sustainability of gene expression via this route, which can be gradually diminished over 3 months.78 Such non-sustainability may be due to the high flow of the choroidal circulation, with a stronger immune response.
Safety of the suprachoroidal route is also an issue. Yiu et al had inadvertent subretinal injection twice by a microneedle when they changed the site of injection from 4 to 10 mm posterior to the limbus.78 Other human clinical trials did not report this adverse event.99,100
Inflammation can also occur secondary to the suprachoroidal route. Different degrees of posterior segment inflammation following delivery of the same antigen via intravitreal, subretinal, and suprachoroidal routes have been reported. While the intravitreal route did not cause significant posterior segment inflammation in the form of chorioretinitis, both suprachoroidal and subretinal routes elicited it.78 There has been no evidence of a deviant immune response in the suprachoroidal space.
The key differences between intravitreal, subretinal and suprachoroidal modes of delivery are listed in Table 2.
Table 2 Key Differences Between Different Types of Modes of Delivery of Gene Therapy
Electrotransfection is a non-viral gene therapy modality that uses high voltage short electrical pulses that increases cell membrane permeability to naked genetic material. To our knowledge, there are no published data regarding safety of electrotransfection in human eyes. In different studies performed on rabbits and rodents, there were no reported safety issues.33,102104 There were no histological or functional (electroretinogram) toxicities following electrotransfection. Postoperative inflammation could not be accurately assessed as the studies were done on animal models of intraocular inflammation. However, the studies demonstrated that electrotransfection was effective in decreasing ocular inflammation in these models.33,102104
Timmers et al have shown that the site of ocular inflammation following intravitreal injection varies according to the presence of the viral genome and/or capsid.16 They demonstrated that inflammation in the anterior segment is dependent on the presence of the genome while viral particles with no genome (empty capsids) did not induce an anterior segment reaction. Contrarily, both full viral particles and empty capsids induced vitreal inflammation. Empty capsids induced vitreal inflammation at a lower level than the full particles, implying that capsids induced vitreal inflammation only, while the genetic material induced inflammation in both anterior and posterior segments. The investigators also found that Abs were generated regardless of the presence of the genome, meaning that it is mainly generated by the capsid.
Pre-clinical and clinical studies have indicated that gene therapy with AAV can induce dose-dependent innate and adaptive immune responses. This was true in both subretinal and intravitreal deliveries, although the same viral dose induced lower immune responses when delivered via the subretinal route.91,105107 For example, Cukras et al found a dose-dependent response of ocular inflammation.41 They evaluated the safety of AAV8 as the vector for delivery of RS1 gene in patients with XLRS caused by RS1 gene mutations in a phase I/II an open-label clinical trial. They administered three increasing doses of 1109, 11010, and 11011 viral particle/eye of AAV8 to nine patients through intravitreal injections. The authors found that ocular inflammation was dose-dependent, but it resolved with administration of oral and topical corticosteroids. There was also a dose-dependent increase in the serum level of systemic antibodies against AAV8.
Another clinical trial on the safety and efficacy of subretinal AAV2 injection in patients with LCA with RPE65 gene deficiency showed comparable findings. Le Meur et al administered low (1.222 1010) or high (3.274.8 1010) viral genomes of AAV2 to nine patients.108 Although no clinical abnormality was observed, a mild increase in anterior chamber protein flare was seen, indicating ocular inflammation, in only three patients who received the highest dose. The inflammation was minimal and resolved with no consequences after 14 days with local and systemic steroids. In the aforementioned INFINITY trial, rates and severity of ocular inflammation were higher in the high-dose group. Three patients developed severe hypotony in the high dose (6 1011) group while none of the low dose (2 1011) group showed such complication. The OPTIC trial, which used the same vector type in neovascular AMD patients, did also show a dose dependent inflammatory response but much less in severity when compared with INFINITY trial, implying that the underlying disease should also be considered a factor when assessing the risk of inflammation.80,81,109
Few studies did not show this association between the inflammatory responses and the viral doses. In an open-label phase I/II randomized clinical trial, Bouquet et al79 assessed the link between immune response and intraocular inflammation in 15 patients diagnosed with ND4 LHON undergoing ocular gene therapy with rAAV2 vectors. The authors introduced four increasing doses of 9109, 31010, 91010, and 1.81011 viral genomes per eye through intravitreal injections. Following the injections, mild inflammatory reactions were noted in nearly all patients, regardless of the administered dose. Intensity of inflammation showed no correlation with dosage, and it was also not associated with baseline immune responses and antibody titers. Similarly, Guy et al evaluated the efficacy of AAV2 at two escalating doses of 5109and 2.461010 vector genomes in LHON patients.64 Their results indicated that only 14% of the eyes showed ocular inflammation over a one-year follow-up, which was not associated with vector dose. One can explain the absence of the dose dependent ocular inflammation in these studies by the small number of patients, which might not have been enough to detect the relationship.
As mentioned, Timmers et al16 found that the relationship between the dose and the inflammation may be dependent on the site of intraocular inflammation.16 No or weak correlation was found between the dose and degree of anterior segment inflammation (which was incited by the capsids only), while a strong correlation was noticed with vitreal inflammation (incited by both the genome and capsid).
Steroid administration through different routes has been shown control ocular inflammation following viral vector delivery in most cases. Many studies reported that the resultant ocular inflammation was mild, transient, and controlled by systemic or even topical steroid therapy.4,13,14,29,41,79,87 Such control was reported regardless of vector type/subtype or mode of delivery.
Russel et al used perioperative oral steroids at the dose of 1 mg/kg/day, up to 40 mg/day, as a prophylactic method against postoperative inflammation after subretinal delivery of AAV vector.4 In their study, only 10% of the patients developed mild transient inflammation, which resolved in all patients. Bouquet et al have not used perioperative steroids in their trial which involved an intravitreal injection of AAV vector.79 Most patients who developed postoperative vitreal inflammation were controlled by topical steroids. Oral steroids were used effectively in 2/11 patients who did not respond to topical therapy.
On the other hand, the results of the INFINITY trial clearly show that ocular inflammation following gene therapy does not always respond well to steroids. As mentioned before, some patients responded poorly to intravitreal steroids and required surgery as well as mycophenolate therapy to ameliorate the inflammation.
In such cases where ocular inflammation is significant and can lead to permanent visual loss, aggressive management with zero-tolerance to inflammation should be a rule of thumb to avoid vision threatening complications. It should be noted that the inflammation can develop lately up to 20 weeks following an initial inflammation-free period. Follow-up should be done with due diligence to avoid such late onset, devastating complication.
Gene therapy can be delivered via viral or non-viral vectors. The mode of delivery of gene therapy as well as the underlying ocular pathology influence the postoperative inflammatory and immune responses. While there is no clear evidence of weaker or less inflammatory reactions of the subretinal route when compared with the intravitreal one, immune responses with antibody formations are clearly stronger in the latter. The dose of delivered viral vectors plays a factor in the development of immune and inflammatory responses, and high dose viral vectors were associated with sight threatening ocular inflammation. In general, although the inflammation associated with gene therapy of all routes of delivery has proven to be usually mild and often controlled with steroid therapy, intravitreal route may be associated with late onset sight threatening inflammation.
Suprachoroidal delivery is a potentially simpler and safer approach to deliver gene therapy, but further studies need to determine how unique it is regarding the immune and inflammatory responses. Non-viral gene therapy is also potentially a safe alternative, but its use for inherited diseases can be limited by the short-term expression of transduced genetic materials.
AAV, adeno-associated virus; Ab, antibody; ACAID, anterior chamber associated immune deviation; AMD, age-related macular degeneration; Anti-VEGF, anti-vascular endothelial growth factor; AR, autosomal recessive; AV, adenovirus; DME, diabetic macular edema; DNA, double-stranded deoxyribonucleic acid; EEC, ectrodactyly-ectodermal dysplasia-clefting; EIAV, equine infectious anemia virus; FDA, Food and Drug Administration; HIV, human immunodeficiency virus; IOP, intraocular pressure; LCA, Leber congenital amaurosis; LHON, Leber hereditary optic neuropathy; MPS, mucopolysaccharidosis; NHP, non-human primates; PPV, pars plana vitrectomy; RHO, rhodopsin; RNA, ribonucleic acid; RP, retinitis pigmentosa; RPE, retinal pigment epithelium; RPGR, retinitis pigmentosa GTPase regulator; siRNA, small interference RNA; SO, silicone oil; SS, Sjogrens syndrome; USH2A, Usherin2A; XLRS, X-linked retinoschisis.
There is no funding to report.
Diana Do reports grants from and consultancy for Regeneron during the conduct of the study and grants from and advisory board for Genentech outside the submitted work. Quan Dong Nguyen reports grants and personal fees from Genentech, Novartis, and Regeneron, and personal fees from Rezolute, outside the submitted work. The authors report no other potential conflicts of interest in relation to this work.
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23. Balaggan KS, Ali RR. Ocular gene delivery using lentiviral vectors. Gene Ther. 2012;19(2):145153. doi:10.1038/gt.2011.153
24. Philippe S, Sarkis C, Barkats M, et al. Lentiviral vectors with a defective integrase allow efficient and sustained transgene expression in vitro and in vivo. Proc Natl Acad Sci U S A. 2006;103(47):1768417689. doi:10.1073/pnas.0606197103
25. Nuzbrokh Y, Kassotis AS, Ragi SD, Jauregui R, Tsang SH. Treatment-emergent adverse events in gene therapy trials for inherited retinal diseases: a narrative review. Ophthalmol Ther. 2020;9(4):709724. doi:10.1007/s40123-020-00287-1
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Ocular Gene Therapy: Immune and Inflammatory Responses | OPTH - Dove Medical Press
The Personalized Medicine Coalition, representing innovators, scientists, patients, providers and payers, promotes the understanding and adoption of personalized medicine concepts, services, and products to benefit patients and health systems.
Personalized medicine is an evolving field in which physicians use diagnostic tests to determine which medical treatments will work best for each patient or use medical interventions to alter molecular mechanisms that impact health. By combining data from diagnostic tests with an individuals medical history, circumstances and values, health care providers can develop targeted treatment and prevention plans with their patients.
To understand how quickly personalized treatments and diagnostic tools are reaching the United States market, PMC recently conducted its seventh annual analysis of the Food and Drug Administration's activities in personalized medicine. With personalized medicines accounting for more than 25 percent of newly approved drugs for each of the last seven years and topping one-third of new drug approvals for four of the last five, the findings leave no question that the era of personalized medicine is upon us, presenting both opportunities and challenges for patients and health systems.
Use the link provided below to access a PDF version of the report. Personalized Medicine at FDA: The Scope & Significance of Progress in 2021
Excerpt from:
Personalized Medicine Coalition - Precision Medicine Advocacy and ...
Most medical treatments are designed for the "average patient" as a one-size-fits-all-approach, which may be successful for some patients but not for others. Precision medicine, sometimes known as "personalized medicine" is an innovative approach to tailoring disease prevention and treatment that takes into account differences in people's genes, environments, and lifestyles. The goal of precision medicine is to target the right treatments to the right patients at the right time.
Advances in precision medicine have already led to powerful new discoveries and FDA-approved treatments that are tailored to specific characteristics of individuals, such as a person's genetic makeup, or the genetic profile of an individual's tumor. Patients with a variety of cancers routinely undergo molecular testing as part of patient care, enabling physicians to select treatments that improve chances of survival and reduce exposure to adverse effects.
Precision care will only be as good as the tests that guide diagnosis and treatment. Next Generation Sequencing (NGS) tests are capable of rapidly identifying or 'sequencing' large sections of a person's genome and are important advances in the clinical applications of precision medicine.Patients, physicians and researchers can use these tests to find genetic variants that help them diagnose, treat, and understand more about human disease.
The FDA is working to ensure the accuracy of NGS tests, so that patients and clinicians can receive accurate and clinically meaningful test results.
The vast amount of information generated through NGS poses novel regulatory issues for the FDA. While current regulatory approaches are appropriate for conventional diagnostics that detect a single disease or condition (such as blood glucose or cholesterol levels), these new sequencing techniques contain the equivalent of millions of tests in one. Because of this, the FDA has worked with stakeholders in industry, laboratories, academia, and patient and professional societies to develop a flexible regulatory approach to accommodate this rapidly evolving technology that leverages consensus standards, crowd-sourced data, and state-of-the-art open-source computing technology to support NGS test development. This approach will enable innovation in testing and research, and will speed access to accurate, reliable genetic tests.
InApril 2018, the FDA issued two final guidances that recommend approaches to streamline the submission and review of data supporting the clinical and analytical validity of NGS-based tests. These recommendations are intended to provide an efficient and flexible regulatory oversight approach: as technology advances, standards can rapidly evolve and be used to set appropriate metrics for fast growing fields such as NGS. Similarly, as clinical evidence improves, new assertions could be supported. This adaptive approach would ultimately foster innovation among test developers and improve patients' access to these new technologies.
Thefinal guidance "Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics" allows developers to use data from FDA-recognized public databases of genetic variants to help support a test's clinical validity and outlines how database administrators can seek recognition for their databases if they meet certain quality recommendations. This approach incentivizes data sharing and provides a more efficient path to market.
More information about database recognition is available on the FDAs Recognition of Public Human Genetic Variants Databases webpage.
The final guidance "Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS) Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases" offers recommendations for designing, developing and validating NGS tests. The guidance also encourages community engagement in developing NGS-related standards by standards developing organizations (SDOs) since standards can more rapidly evolve with changes in technology and knowledge and can therefore be used to set appropriate metrics such as specific performance thresholds for fast growing fields such as NGS.
The FDA created precisionFDA, a cloud-based community research and development portal that engages users across the world to share data and tools to test, pilot, and validate existing and new bioinformatics approaches to NGS processing. Individuals and organizations in the genomics community can find more information and sign up to participate at http://precision.fda.gov.
Please contact us with any questions about the FDA's precision medicine efforts at OIRPMgroup@fda.hhs.gov.
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Precision Medicine | FDA
Brussels, Belgium, June 06, 2022 (GLOBE NEWSWIRE) --
Description:
Precision medicine, sometimes known as "personalized medicine" is an innovative approach to tailoring disease prevention and treatment based on the individuals unique characteristics and genetic make-up. Precision medicine software (platforms, data-sharing networks, clinical decision support software, AI-enabled, etc.) provides the healthcare/life sciences community with integrated data and data-driven insights to strengthen their precision medicine program.
The Shift from the Dominant One-Size-Fits-All Approach to Personalized Care
The precision medicine approach promises better clinical outcomes, safer medicines, and less wastage/cost savings. With the increasing demand to provide value to healthcare systems, drug developers have started to move away from the traditional one-size-fits-all approach to the personalized care approach.
In 2020, the FDA approved 20 personalized drugs and biologics (39% of the new approvals). Precision medicines accounted for a quarter or more of all new drugs approved by the FDA each year in the past five years. With the growing interest and increasing opportunities in precision medicine, the demand for precision medicine software is also anticipated to grow.
Favorable Government Initiatives
Realizing the long-term benefits of personalized care in improving population health and reducing healthcare costs, governments across the globe are supporting advanced treatments like precision medicine through initiatives, regulatory changes, and/or funding research. For instance, in the US, The Oncology Care Model, a specialty payment and delivery model developed by the CMS Innovation Center is providing incentives that have led to a surge of large community provider networks implementing precision medicine initiatives. Some of the other programs to advance the research/use of precision medicine include The Precision Medicine Initiative (PMI), All of Us Research Program, precision FDA, and Million Veteran Program. In addition, FDA issued seven guidance documents in 2020 related to precision medicine. All these efforts would eventually boost the demand for precision medicine software.
Vast Growth Opportunities in Oncology
Precision medicine holds great promise for reshaping the way cancer is treated. The increasing prevalence of cancer and growing funding for cancer research would propel the adoption of precision medicine in oncology. High-quality patient datasets are the foundation to bring precision oncology into clinical practice. Thus, providing great opportunities for precision oncology software providers. Some of the recent activities in this space include:
Key Challenges: Precision Medicine Software Market
For the emergence of precision medicine in every disease area, the industry needs to know how to optimize the use of big data with the increase in the amount of genomics, health, and lifestyle information.
Further, the high cost of deployment, issues related to the secure storage of large volumes of sequenced data, lack of reimbursement for precision medicine-based treatments, and the shortage of expert technicians/bioinformaticians are some of the key challenges faced by this industry.
Competitive Landscape Analysis: Precision Medicine Software Market
The global precision medicine software market is highly competitive and fragmented. Some of the key/promising players operating in the precision medicine software market are Syapse, Fabric Genomics, Sophia Genetics, 2bprecise, PierianDx, Inc., PhenoTips, Foundation Medicine, Inc., GenomOncology, LLC, Translational Software, Inc., LifeOmic Health, LLC, Sunquest Information Systems, Inc., Tempus, Human Longevity, Inc., and N-of-One Inc.
Explore Detailed Insights on Precision Medicine Software Market @ https://meditechinsights.com/precision-medicine-software-market/
About Medi-Tech Insights:
Medi-Tech Insights is a healthcare-focused business research & insights firm. Our clients include Fortune 500 companies, blue-chip investors & hyper-growth start-ups. We have successfully completed 100+ projects in Healthcare IT, Medical Technology, Medical Devices & Pharma Services.
Contact Us:
Ruta HaldeAssociate, Medi-Tech Insights+32 498 86 80 79info@meditechinsights.com
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Global Precision Medicine Software Market is anticipated to witness a lucrative CAGR of 10% - GlobeNewswire
DUBLIN, June 7, 2022 /PRNewswire/ -- The "Biomarkers Market - Global Outlook & Forecast 2022-2027" report has been added to ResearchAndMarkets.com's offering.
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The global biomarkers market is expected to grow at a CAGR of 11.44%.
In-depth Analysis and Data-driven Insights on the Vendor Landscape, Competitive Analysis, and Critical Market Strategies are Included in this Global Biomarkers Market Report
Biomarkers are increasingly useful tools to predict prognosis and response to therapy in cancer patients. Furthermore, it allows to improve understanding of mechanisms of action and resistance to treatment.
GLOBAL BIOMARKERS MARKET SEGMENTATION
Oncology dominated the indication segment because biomarkers are being largely used for cancer research and diagnostics due to its high prevalence worldwide. Biomarkers in the field of oncology has revolutionized the diagnostics and treatment pathways.
Diagnostics dominated the application segment. However, the application of biomarkers in drug discovery & development is expected to grow significantly during the forecast period because biomarkers studies is expected to become an integral part of the drug development process with the aim of developing more effective drugs at a lower cost
Diagnostic biomarker dominated the type of segment as diagnostic biomarker studies have entered a new era where it holds promise for early diagnosis and effective treatment of many diseases.
GEOGRAPHICAL ANALYSIS
North America dominated the geography because biomarkers have been in use highly for diagnostic purposes, drug discovery & development, and precision medicine. The increase in R&D expenditures and fundings for biomarker-driven drug discovery & development and precision medicine is one of the major driving factors in all the regions.
APAC is anticipated to exhibit the highest CAGR of 13.96% during the forecast period. Increasing developments and incorporation of advanced technologies to enhance the biomarker-based testing and increasing demand for biomarkers in drug development and personalized medicine are one of the primary factors in the region.
Story continues
KEY HIGHLIGHTS
Increased Adoption of Biomarkers in Personalized Medicine is driving the global biomarkers market growth. As many healthcare settings have gained interest in personalized/precision medicine, many vendors have increased the studies focusing on identifying biomarkers to provide healthcare system solutions to them.
Increasing focus on digital biomarkers will also drive the global Currently, several digital biomarkers are being tested for feasibility and reliability in Parkinson's and Alzheimer's disease and clinical outcome assessments.
Increasing discovery of epigenetic biomarkers for oncology is also driving the biomarker technologies market. There are more emerging companies increasing their research & development focus on discovering more epigenetics to diagnose various types of cancers.
Technological Advancements in Biomarker Discovery are also positively impacting the biomarkers diagnostics industry. For instance, a recent development in portable biosensors allows rapid, accurate, and on-site detection of biomarkers, which helps prevent disease spread by controlling sources.
VENDOR ANALYSIS
Multiple companies partnering and investing in biomarkers research and development will help the companies to innovate new drugs and reduce the economic burden.
Key Vendors
Other Prominent Vendors
Key Topics Covered:
1 Research Methodology
2 Research Objectives
3 Research Process
4 Scope & Coverage4.1 Market Definition4.1.1 Inclusions4.1.2 Exclusions4.1.3 Market Estimation Caveats4.2 Base Year4.3 Scope of the Study4.4 Market Segments4.4.1 Market Segmentation by Indication4.4.2 Market Segmentation by Application4.4.3 Market Segmentation by Type4.4.5 Market Segmentation by Geography
5 Report Assumptions & Caveats5.1 Key Caveats5.2 Currency Conversion5.3 Market Derivation
6 Market at a Glance
7 Introduction7.1 Overview
8 Market Opportunities & Trends8.1 Increased Adoption of Biomarkers in Personalized Medicine8.2 Increasing Focus on Digital Biomarkers8.3 Increased Discovery of Epigenetic Biomarkers in Oncology
9 Market Growth Enablers9.1 Increase in the Number of Pipeline Biomarkers9.2 Rising Adoption of Biomarkers in Disease Diagnostics9.3 Technological Advancements in Biomarker Discovery
10 Market Restraints10.1 High Cost and Time-Consuming Development10.2 High Number of False Discoveries10.3 Strict Regulations and Ethics for Biomarker Validation & Qualification
11 Market Landscape11.1 Market Overview11.2 Market Size & Forecast11.2.1 Insights by Indication11.2.2 Insights by Application11.2.3 Insights by Type11.2.4 Insights by Geography11.3 Five Forces Analysis
12 Indication12.1 Market Snapshot & Growth Engine12.2 Market Overview12.3 Oncology12.4 Cardiology12.5 Neurology12.6 Immunology12.7 Others
13 Application13.1 Market Snapshot & Growth Engine13.2 Market Overview13.3 Diagnostics13.4 Drug Discovery & Development13.5 Personalized Medicine13.6 Others
14 Type14.1 Market Snapshot & Growth Engine14.2 Market Overview14.3 Diagnostic Biomarkers14.4 Monitoring Biomarkers14.5 Prognostic Biomarkers14.6 Predictive Biomarkers14.7 Susceptibility Biomarkers14.8 Other Biomarkers
15 Geography15.1 Market Snapshot & Growth Engine15.2 Geographic Overview
For more information about this report visit https://www.researchandmarkets.com/r/vnt809
Media Contact:Research and MarketsLaura Wood, Senior Managerpress@researchandmarkets.comFor E.S.T Office Hours Call +1-917-300-0470For U.S./CAN Toll Free Call +1-800-526-8630For GMT Office Hours Call +353-1-416-8900U.S. Fax: 646-607-1907Fax (outside U.S.): +353-1-481-1716
Cision
SOURCE Research and Markets
A small clinical trial conducted by Memorial Sloan Kettering Cancer Center found that every single rectal cancer patient who received an experimental immunotherapy treatment had their cancer go into remission.
One participant, Sascha Roth, was preparing to travel to Manhattan for weeks of radiation therapy when the results came in,Memorial Sloan Ketteringsaid. That's when doctors gave her the good news: She was now cancer-free.
"I told my family," Roth told The New York Times. "They didn't believe me."
These same remarkable results would be seen in14 patientsto date. The study was published Sundayin the New England Journal of Medicine. All of the patients had rectal cancer in a locally advanced stage, with a rare mutation calledmismatch repair deficiency(MMRd).
They were given six months of treatment with an immunotherapy drug called dostarlimab, from the pharmaceutical company GlaxoSmithKline, which helped fund the research. The cancer vanished in every single one of them undetectable by physical exam, endoscopy, PET scans or MRI scans, the researchers said.
The drug costs about $11,000 per dose, The Times reports. It was administered to each patient every three weeks for six months, and it works by exposing cancer cells so the immune system can identify and destroy them.
"This new treatment is a type of immunotherapy, a treatment that blocks the 'don't eat me' signal on cancer cells enabling the immune system to eliminate them," CBS News medical contributor Dr. David Agus explains.
"The treatment targets a subtype of rectal cancer that has the DNA repair system not working. When this system isn't working there are more errors in proteins and the immune system recognizes these and kills the cancer cells."
After six months or more of follow-up, the patients continued to show no signs of cancer without the need for the standard treatments of surgery, radiation and chemotherapy and the cancer has not returned in any of the patients, who have now been cancer-free for a range of six to 25 months after the trial ended.
"Amazing to have every patient in a clinical trial respond to a drug, almost unheard of," Agus said, adding that it "speaks to the role of personalized medicine that is identifying a subtype of cancer for a particular treatment, rather than treating all cancers the same."
Another surprise from the study was that none of the patients suffered serious side effects.
"Surgery and radiation have permanent effects on fertility, sexual health, bowel and bladder function," Dr. Andrea Cercek, a medical oncologist and principal investigator in the study, said in an MSKnews release. "The implications for quality of life are substantial, especially in those where standard treatment would impact childbearing potential. As the incidence of rectal cancer is rising in young adults, this approach can have a major impact."
"It's incredibly rewarding," Cercek said, "to get these happy tears and happy emails from the patients in this study who finish treatment and realize, 'Oh my God, I get to keep all my normal body functions that I feared I might lose to radiation or surgery.'"
Researchers agree the trial needs to now be replicated in a much bigger study, and noted that the small study focused only on patients who had a rare genetic signature in their tumors. But they say that seeing complete remission in 100% of patients tested is a very promising early signal.
Dr. Hanna K. Sanoff of the University of North Carolina's Lineberger Comprehensive Cancer Center, who was not involved in the study, said it is not yet clear if the patients are cured.
"Very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure," Dr. Sanoff wrote in an editorial accompanying the paper.
But she noted, "These results are cause for great optimism."
The trial is expected to include about 30 patients, which will give a fuller picture of how safe and effective dostarlimab is in this group.
"While longer follow-up is needed to assess response duration, this is practice-changing for patients with MMRd locally advanced rectal cancer," said study co-leader Dr. Luis Diaz Jr., head of the division of solid tumor oncology at MSK.
Natacha Larnaud is a social TV producer for CBS News.
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Every patient in this experimental drug trial saw their cancer disappear, researchers say - CBS News