Research sheds new light on the behavior of KRAS gene in pancreatic and colorectal cancer News-Medical.Net
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Research sheds new light on the behavior of KRAS gene in pancreatic and colorectal cancer - News-Medical.Net
Clemson professor Trudy Mackay elected to the National Academy of Medicine Clemson News
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Clemson professor Trudy Mackay elected to the National Academy of Medicine - Clemson News
Pushing the boundaries of rare disease diagnostics with the help of the first Undiagnosed Hackathon Nature.com
Tailored Genetic Medicine: AAV Gene Therapy and mRNA Vaccines Redefine Healthcare's Future Intelligent Living
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Tailored Genetic Medicine: AAV Gene Therapy and mRNA Vaccines Redefine Healthcare's Future - Intelligent Living
If you have family members with Parkinsons disease, or if you yourself have the disease and are concerned about your childrens chances of developing it, youve probably already wondered: Is there a gene that causes Parkinsons disease? How direct is the link?
About 15 percent of people with Parkinsons disease have a family history of the condition, and family-linked cases can result from genetic mutations in a group of genes LRRK2, PARK2, PARK7, PINK1 or the SNCA gene (see below). However, the interaction between genetic changes, or mutations, and an individuals risk of developing the disease is not fully understood, says Ted Dawson, M.D., Ph.D., director of the Institute for Cell Engineering at Johns Hopkins.
Heres what you need to know:
Theres a long list of genes known to contribute to Parkinsons, and there may be many more yet to be discovered. Here are some of the main players:
SNCA: SNCA makes the protein alpha-synuclein. In brain cells of individuals with Parkinsons disease, this protein gathers in clumps called Lewy bodies. Mutations in the SNCA gene occur in early-onset Parkinsons disease.
PARK2: The PARK2 gene makes the protein parkin, which normally helps cells break down and recycle proteins.
PARK7: Mutations in this gene cause a rare form of early-onset Parkinsons disease. The PARK7 gene makes the protein DJ-1, which protects against mitochondrial stress.
PINK1: The protein made by PINK1 is a protein kinase that protects mitochondria (structures inside cells) from stress. PINK1 mutations occur in early-onset Parkinsons disease.
LRRK2: The protein made by LRRK2 is also a protein kinase. Mutations in the LRRK2 gene have been linked to late-onset Parkinsons disease.
Among inherited cases of Parkinsons, the inheritance patterns differ depending on the genes involved. If the LRRK2 or SNCA genes are involved, Parkinsons is likely inherited from just one parent. Thats called an autosomal dominant pattern, which is when you only need one copy of a gene to be altered for the disorder to happen.
If the PARK2, PARK7 or PINK1 gene is involved, its typically in an autosomal recessive pattern, which is when you need two copies of the gene altered for the disorder to happen. That means that two copies of the gene in each cell have been altered. Both parents passed on the altered gene but may not have had any signs of Parkinsons disease themselves.
Our major effort now is understanding how mutations in these genes cause Parkinsons disease, says Dawson. SNCA, the gene responsible for making the protein that clumps in the brain and triggers symptoms, is particularly interesting.
Our research is trying to understand how alpha-synuclein works, how it travels through the brain, says Dawson. The latest theory is that it transfers from cell to cell, and our work supports that idea. Weve identified a protein that lets clumps of alpha-synuclein into cells, and we hope a therapy can be developed that interferes with that process.
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The Genetic Link to Parkinson's Disease - Hopkins Medicine
CRISPR-Cas9 genome editing has changed the game for gene therapy, but carries safety risks when cutting DNA. The new U.S. firm Epic Bio aims to reduce these risks by targeting epigenetic controls on gene expression.
The development of the genome-editing tool CRISPR-Cas9 caused a paradigm shift in the biotech industry because it made it easier than ever to make small edits to the genetic code. The tool is also being tested in clinical trials to see if it can form the basis of gene and cell therapies for conditions including genetic blindness, cancer and blood disorders.
However, CRISPR-Cas9 gene editing also has its limitations. One is that the Cas9 protein used to cut DNA molecules can also make permanent cuts in unexpected parts of the genome, which could be dangerous for the cell. Another is that the CRISPR-Cas9 machinery is too large to deliver into the patients body using adeno-associated viral (AAV) vectors, the most common delivery method for gene therapies.
To overcome the obstacles for CRISPR-Cas9 gene editing, the startup Epic Bio was launched in July 2022 with an impressive Series A round worth $55 million. The firm, based in San Francisco, U.S., is developing gene therapies based on editing the epigenome, a biological system that cells use to control which genes become proteins.
Epic Bios therapies involve fusing together a protein that binds to DNA with a so-called modulator protein that can make epigenetic changes to the DNA molecule. This construct is directed to a target site in the genome using a customized guide RNA molecule. Epic Bios technology is dubbed Gene Expression Modulation System, or GEMS for short.
CRISPR-Cas9 binds and cuts the DNA whereas GEMS binds and modifies the chemistry of DNA without changing the genetic code, explained Amber Salzman, CEO of Epic Bio. This allows fine-tuning gene expression and avoids the risks of cutting DNA.
Epic Bio is deploying its epigenome-editing therapies in a range of rare diseases such as facioscapulohumeral muscular dystrophy, heterozygous familial hypercholesterolemia, and forms of retinitis pigmentosa. In each case, the therapy is designed to correct harmful epigenetic changes to genes that are linked to the disease.
Epic Bio aims to prepare for clinical testing by the end of 2023. According to Salzman, earlier generations of gene therapy technology have struggled to treat these diseases as they arent precise enough to hit the target site in the genome.
By leveraging CRISPR and sequence-specific guide RNAs to home to target sequences, Epic Bio can address limitations of specificity, said Salzman. Similarly, robust and durable activators and suppressors are needed to drive desired target gene behaviors. Epic Bio has the largest library of such precise epigenetic modulators to address this challenge.
Another problem with gene editing therapies is that its tough to deliver them to the patient in vivo because AAV vectors can only carry a small amount of genetic cargo. To get around this problem, Epic Bio licensed a tiny DNA-binding protein called CasMINI from Stanford University, which allows the companys gene therapies to fit on a single AAV vector.
Today, AAV is the most validated vector to deliver genetic medicine in vivo, and our therapies can fit in an AAV, explained Salzman. She added that the main alternative delivery method, via lipid nanoparticles, is currently limited to targeting the liver.
Because of the small size of CasMINI, that leaves more room for guide RNAs and multiple modulators that could perhaps regulate multiple genes at a time.
Epic Bio is one of several biotech players that have kicked off in the epigenome editing space. Chroma Medicine launched in late 2021 with a neat $125 million investment. This was swiftly followed by Tune Therapeutics, which debuted with $40 million. As it launched, Chroma Medicine also acquired another epigenome editing specialist, the Italian firm Epsilen Bio.
Epigenome editing remains an emerging therapeutic field with a lot of challenges. For example, its crucial to make sure the target sequence is verified when making epigenetic changes, and companies need to avoid the bodys own DNA repair systems reversing the edits. Nonetheless, the technology has a lot of potential to treat conditions that have been out of reach of traditional gene therapies.
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Epic Bio makes gene therapies by editing the epigenome - Labiotech.eu
Ovid Therapeutics has struck a deal with young biotechnology company Gensaic, hoping the startups method of delivering genetic medicines can yield new brain drugs.
Under the deal, the partners will develop up to three gene-based treatments for neurological conditions Ovid is targeting. The New York biotech will get rights to license any gene therapies that emerge from the deal, so long as the two can agree on terms. Ovid also invested $5 million in the startup and committed to participate in future financing rounds.
The deal is the latest step in a rebuilding plan for Ovid, a biotech former Teva and Bristol Myers Squibb executive Jeremy Levin formed seven years ago.
Levins plan in starting Ovid was to grab medicines overlooked elsewhere, license them and develop them for rare brain diseases. That strategy led Ovid to two medicines the company developed for Angelmans syndrome and rare forms of epilepsy, and helped the biotech to go public in 2017.
Ovid hasnt been successful, however. The Angelmans drug failed a Phase 3 trial in 2020, erasing more than half of the companys value. One year later, Ovid, aiming to bolster its dwindling cash reserves, sold rights to the epilepsy drug back to Takeda. Though Ovid can still receive milestone payments and royalties from the drug, which is now in late-stage testing, its only remaining in-house programs are in preclinical testing. At just over $2 apiece, shares trade near all-time lows.
Recently, Ovid has taken steps to restock its pipeline. One experimental medicine for treatment-resistant epileptic seizures could start human trials later this year, while a licensing deal with AstraZeneca and a related partnership with Tufts University could yield other drug candidates that might follow in 2024.
The alliance with Gensaic adds up to three more prospects, while pushing Ovid into the field of gene therapy.
Gensaic was seeded in 2021 as M13 Therapeutics and is currently housed in Cambridge, Massachusetts biotech startup incubator LabCentral. Over the past two years, the company has won awards in multiple startup competitions for its research into a method of gene therapy delivery designed to overcome the limitations of standard approaches.
Many gene therapies rely on modified viruses to send genetic instructions into the bodys cells. Those delivery vehicles are used in multiple products approved for rare inherited diseases, but they also come with weaknesses, too. One commonly used tool, the adeno-associated virus, can only carry a relatively small amount of genetic cargo and is sometimes shut down by the body. Another, the lentivirus, also has limited packaging capacity and has been linked in rare cases to the development of cancers.
Gensaic instead aims to use tiny particles derived from phages, the viruses that infect bacteria, to deliver genetic material. Gensaic claims these particles can be engineered to target multiple tissue types among them the lung and brain and can carry much larger genes. Gensaic believes they may have the potential to be administered more than once, too, though that hasnt yet been proven.
In a statement, Levin said the approach appears to be optimal for carrying substantial genetic cargo across the blood-brain barrier, a filtering mechanism the body uses to keep foreign substances out of the brain.
We believe it may hold the potential to treat a broad continuum of diseases in the brain, Levin said.
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Ovid turns to gene therapy startup to restock drug pipeline - BioPharma Dive
Clinical features of patients
Between 2015 and 2017, a total of 177 patients (81 males; median [range] age, 4 [030] years) from 169 families were referred to the TOKAI-IRUD program. All patients registered in this study were new patients, i.e., those who had not been previously analyzed for comprehensive genomic variants; however, several patients have been included in a few subsequent investigations19,20,21,22.
The TOKAI-IRUD program is open to the possibility of accepting any patient. The clinical symptoms of the applicants were global developmental delay (HP: 0001263; n=95, 54%), seizures (HP: 0001250; n=40, 23%), intellectual disability (HP: 0001249; n=29, 16%), muscular hypotonia (HP: 0001252; n=24, 14%), dysmorphic facial features (HP: 0001999; n=17, 9.6%), short stature (HP: 0004322; n=14, 7.9%), microcephaly (HP: 0000252; n=11, 6.2%), and others (n=38, 21%) (Table 1, Supplementary Table S2, and Supplementary Table S3).
In accordance with ACMG guidelines, pathogenic SNVs were identified in 36 (20%) patients. Furthermore, 30 (17%) patients carried SNVs classified as likely pathogenic based on clinical validity assessment and consistency in clinical information and phenotypes with applicable diseases. Among 66 patients with pathogenic or likely pathogenic SNVs, 47 had autosomal dominant genetic disorders, seven had autosomal recessive genetic disorders, eight had X-linked dominant genetic disorders, and four had X-linked recessive genetic disorders (Fig.1).
Patient characteristics and information on detected variants. Each column indicates one patient. SNV single-nucleotide variant, CNV copy number variant, UPD uniparental disomy, AD autosomal dominant, AR autosomal recessive, XLD X-linked dominant, XLR X-linked recessive.
Copy number analysis identified diagnostic duplication/deletion in 11 (6.2%) patients, and these included a 10q26.3 deletion (TOKAI-IRUD-1135 and TOKAI-IRUD-1273), 22q11.2 duplication (TOKAI-IRUD-1236), 5q14.3 deletion (TOKAI-IRUD-1252), 47,XXY (TOKAI-IRUD-1297), 1p36 deletion (TOKAI-IRUD-1301), 7q11.23 duplication (TOKAI-IRUD-1321), 19p13.13 deletion (TOKAI-IRUD-1335), 16p13.3 duplication (TOKAI-IRUD-1337), 17p11.2 duplication (TOKAI-IRUD-1343), and 4p16.3 deletion (TOKAI-IRUD-1475).
ROH analysis identified homozygous regions larger than 10Mb in 105 cases; this included a diagnostic upd(15)pat in 1 patient (0.6%) who was diagnosed with Angelman syndrome (TOKAI-IRUD-1290, OMIM #105830). Furthermore, UPD of a whole chromosome was identified in 2 (1.1%) patients [upd(2)pat; TOKAI-IRUD-1249 and upd(3)pat; TOKAI-IRUD-1180] with no diagnostic SNVs or CNVs. Thus, genetic diagnoses were obtained for 78 of 177 (44%) patients, and of these, 10 (13%) cases were diagnosed with diseases recognized after 2015, i.e., when this project was initiated. A considerable number of patients showed a milder phenotype (26 [33%]), a more severe phenotype (9 [12%]), or an atypical complex phenotype (17 [22%]) compared to conventional clinical presentation of the respective disease.
TOKAI-IRUD-1290 with upd(15)pat: The patient, a 2-year-old boy at the time of sample submission, was the third of three children of healthy non-consanguineous parents (Fig.2b). Gyrus dysplasia, suspected since the fetal period, was confirmed by magnetic resonance imaging (MRI) after birth (Fig.2a). He was tube fed due to difficulties with oral intake and a tracheostomy was performed after repeated aspiration pneumonia. He also had congenital hydronephrosis, congenital hypothyroidism, gastroesophageal reflux disease, developmental delay, epilepsy, deafness, and laryngotracheomalacia. ROH analysis identified a paternal UPD region over the entire length of the long arm of chromosome 15 [upd(15)pat], covering the region of the UBE3A gene, which led to a diagnosis of Angelman syndrome (OMIM#105830) (Fig.2b). Additionally, 11 homozygous rare variants were identified in a paternally derived UPD region, which included a DUOX2 (c.G1560C, p.E520D) variant. DUOX2 is a known causative gene for congenital hypothyroidism, but this particular variant has not been previously reported.
Clinical features and results of UPD analysis of TOKAI-IRUD-1290. (a) Brain MRI at the age of 2years showing cortical dysplasia of the temporal lobes (arrowheads) and corpus callosum dysgenesis (arrow). (b) Results of UPD analysis. A paternally inherited UPD region over the entire length of the long arm of chromosome 15 [upd(15)pat] was identified, which covers the region of the UBE3A gene. (c) H2O2-producing capacity of the DUOX2 proteins was measured with Amplex Red reagent in the presence of co-expressed DUOXA2-FLAG. The activity of the mutants were standardized based on those of the WT (100%) and mock-transfected control (0%). Data are representative of three independent experiments (each performed in triplicate) with similar results. T-bars indicate standard errors of the mean.*p<0 05 vs. WT (Welchs t-test). (d) Subcellular localization analysis using HA-tagged DUOX2 constructs (WT or E520D; green fluorescence). (e) Fluorescence immunostaining under permeabilized conditions revealed that the localization of E520D-DUOX2 was consistent with DUOXA2.
To verify the pathogenicity of the DUOX2 p.E520D missense substitution detected in this case, expression experiments were conducted using HEK293 cells wherein the H2O2-producing capacity of the E520D mutant in the presence of co-expressed DUOXA2-FLAG was evaluated. We show that the E520D mutant showed complete loss of H2O2-producing activity (Fig.2c). Visualization of subcellular localization using immunofluorescence revealed substantial differences in membrane expression levels between the WT and E520D mutant (Fig.2d,e), indicating that protein localization was affected by the missense substitution.
TOKAI-IRUD-1180 with upd(3)pat: This patient, a 3-year-old girl at the time of sample submission, was the only child of healthy non-consanguineous parents. She suffered seizures beginning on day 1 after birth and symptomatic epilepsy was suspected based on abnormalities detected on an electroencephalogram. However, the seizures ceased from day 14, when oral administration of phenobarbital was initiated. She was unable to sit and had poor language understanding at the time of sample submission. ROH analysis revealed a full-length UPD of chromosome 3 [upd(3)pat], and although 40 homozygous rare missense variants were identified on chromosome 3, it was not possible to arrive at a genetic diagnosis by WES analysis.
TOKAI-IRUD-1249 with upd(2)pat: The patient, a 4-month-old girl at the time of sample submission, was the only child of healthy non-consanguineous parents. A prenatal MRI confirmed hydrocephalus. She was born by scheduled cesarean section at gestational week 34 and suffered from deafness, bilateral club feet, bilateral hip dislocation, multiple joint contractures, congenital hydrocephalus, ventricular septal defect, developmental delay, short and mildly curved femurs, a bell-shaped rib cage, and a vagina without an external opening. ROH analysis revealed a full-length UPD of chromosome 2 [upd(2)pat]. She died of aspiration pneumonia at the age of 10months, and although 34 rare homozygous missense variants and one nonsense variant were identified on chromosome 2, WES analysis did not lead to a genetic diagnosis.
One pathogenic variant of a gene included in the ACMG recommendations for reporting incidental findings was detected in one patient (TOKAI-IRUD-1150), viz, c.C6952T in BRCA2. Additionally, discordant parentchild relationships were identified in three families.
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Whole-exome analysis of 177 pediatric patients with undiagnosed diseases | Scientific Reports - Nature.com
First Gene Therapy for Adults with Severe Hemophilia A, BioMarin's ROCTAVIAN (valoctocogene roxaparvovec), Approved by European Commission (EC)
Maintains Orphan Drug Designation (ODD) in the EU Providing 10-years of Market Exclusivity
Significant BenefitOver Existing Therapies for Patients with Severe Hemophilia A in EU Based on EMA Determination of ODD
Conference Call and Webcast to be Held Wed., Aug. 24th at 8:00 pm Eastern
SAN RAFAEL, Calif., Aug. 24, 2022 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) today announced that the European Commission (EC) has granted conditional marketing authorization (CMA) to ROCTAVIAN (valoctocogene roxaparvovec) gene therapy for the treatment of severe hemophilia A (congenital Factor VIII deficiency) in adult patients without a history of Factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5 (AAV5). The EC also endorsed EMA's recommendation for Roctavian to maintain orphan drug designation, thereby granting a 10-year period of market exclusivity. The EMA recommendation noted that, even in light of existing treatments, Roctavian may potentially offer a significant benefit to those affected with severe Hemophilia A. The one-time infusion is the first approved gene therapy for hemophilia A and works by delivering a functional gene that is designed to enable the body to produce Factor VIII on its own without the need for continued hemophilia prophylaxis, thus relieving patients of their treatment burden relative to currently available therapies. People with hemophilia A have a mutation in the gene responsible for producing Factor VIII, a protein necessary for blood clotting.
It is estimated that more than 20,000 adults are affected by severe hemophilia A across more than 70 countries in Europe, the Middle East, and Africa. Of the 8,000 adults with severe hemophilia A in the 24 countries within BioMarin's footprint covered by today's EMA approval, there are an estimated 3,200 patients who will be indicated for Roctavian. BioMarin anticipates additional access to ROCTAVIAN for patients outside of the EU through named patient sales based on the European Medicines Agency (EMA) approval in countries in the Middle East, Africa and Latin America and expects additional market registrations to be facilitated by the EMA license.
"This approval in the EU represents a medical breakthrough in the treatment of patients with severe hemophilia A that expands the conversation between a patient and physician on treatment choices to now include a one-time infusion that protects from bleeds for several years," said Professor Johannes Oldenburg, Director of the Institute of Experimental Haematology and Transfusion Medicine and the Haemophilia Centre at the University Clinic in Bonn, Germany. "It is exciting to imagine the possibilities of this approved gene therapy, which has demonstrated a substantial and sustained reduction in bleeding for patients, who potentially could be freed from the burden of regular infusions."
"Roctavian approval in Europe is a historic milestone in medicine and is built upon almost four decades of scientific discovery, innovation, and perseverance. We thank the European Commission for recognizing Roctavian's value as the first gene therapy for hemophilia A, a feat that we believe will transform how healthcare professionals and the patient community think about caring for bleeding disorders," said Jean-Jacques Bienaim, Chairman and Chief Executive Officer of BioMarin. "We are grateful to the patients, investigators and community, who dedicated their time and effort to this achievement and whose aspirations provided the driving force behind making this one-time therapy a reality."
The EC based its decision on a significant body of data from the Roctavian clinical development program, the most extensively studied gene therapy for hemophilia A, including two-year outcomes from the global GENEr8-1 Phase 3 study. The GENEr8-1 Phase 3 study demonstrated stable and durable bleed control, including a reduction in the mean annualized bleeding rate (ABR) and the mean annualized Factor VIII infusion rate. In addition, the data included five and four years of follow-up from the 6e13 vg/kg and 4e13 vg/kg dose cohorts, respectively, in the ongoing Phase 1/2 dose escalation study. BioMarin has committed to continue working with the broader community and the EMA to monitor the long-term effects of treatment. The Product Information will be available shortly on the EMA website under the Medicines tab. Search for "ROCTAVIAN" and select "Human medicine European public assessment report (EPAR): Roctavian. Then select "Product Information" in the Table of Contents and then select "Roctavian: EPAR Product Information."
A Conditional Marketing Authorization (CMA) recognizes that the medicine fulfils an unmet medical need based on a positive benefit-risk assessment, and that the benefit to public health of the immediate availability on the market outweighs the uncertainties inherent to the fact that additional data are still required. BioMarin will provide further data from ongoing studies within defined timelines to confirm that the benefits continue to outweigh the risks, building on what already constitutes the largest clinical data package for gene therapy in hemophilia A. Conversion to a standard marketing authorization will be contingent on the provision of additional data from currently ongoing Roctavian clinical studies, including longer-term follow up of patients enrolled in the pivotal trial GENEr8-1, as well as a study investigating efficacy and safety of ROCTAVIAN with prophylactic use of corticosteroids (Study 270-303), for which enrollment is now complete.
Orphan drug designation is reserved for medicines treating rare (affecting not more than five in 10,000 people in the EU), life-threatening or chronically debilitating diseases. Authorized orphan medicines benefit from ten years of market exclusivity, protecting them from competition with similar medicines with the same therapeutic indication, which cannot be marketed during the exclusivity period.
BioMarin remains committed to bringing Roctavian to eligible patients with severe hemophilia A in the United States and is targeting a Biologics License Application (BLA) resubmission for Roctavian by the end of September 2022. Typically, BLA resubmissions are followed by a six-month review procedure. However, the Company anticipates three additional months of review may be necessary based on the number of data read-outs that will emerge during the procedure.
Robust Clinical Program
BioMarin has multiple clinical studies underway in its comprehensive gene therapy program for the treatment of hemophilia A. In addition to the global Phase 3 study GENEr8-1 and the ongoing Phase 1/2 dose escalation study, the Company is also conducting a Phase 3B, single arm, open-label study to evaluate the efficacy and safety of Roctavian at a dose of 6e13 vg/kg with prophylactic corticosteroids in people with hemophilia A (Study 270-303). Also ongoing are a Phase 1/2 Study with the 6e13 vg/kg dose of Roctavian in people with hemophilia A with pre-existing AAV5 antibodies (Study 270-203) and aa Phase 1/2 Study with the 6e13 vg/kg dose of Roctavian in people with hemophilia A with active or prior Factor VIII inhibitors (Study 270-205).
Safety Summary
Overall, single 6e13 vg/kg dose of Roctavian has been well tolerated with no delayed-onset treatment related adverse events. The most common adverse events (AE) associated with Roctavian occurred early and included transient infusion associated reactions and mild to moderate rise in liver enzymes with no long-lasting clinical sequelae. Alanine aminotransferase (ALT) elevation (113 participants, 80%), a laboratory test of liver function, remained the most common adverse drug reaction. Other adverse reactions included aspartate aminotransferase (AST) elevation (95 participants, 67%), nausea (52 participants, 37%), headache (50 participants, 35%), and fatigue (42 participants, 30%). No participants developed inhibitors to Factor VIII, thromboembolic events or malignancy associated with Roctavian.
About Hemophilia A
People living with hemophilia A lack sufficient functioning Factor VIII protein to help their blood clot and are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. Additionally, people with the most severe form of hemophilia A (Factor VIII levels <1%) often experience painful, spontaneous bleeds into their muscles or joints. Individuals with the most severe form of hemophilia A make up approximately 50 percent of the hemophilia A population. People with hemophilia A with moderate (Factor VIII 1-5%) or mild (Factor VIII 5-40%) disease show a much-reduced propensity to bleed. Individuals with severe hemophilia A are treated with a prophylactic regimen of intravenous Factor VIII infusions administered 2-3 times per week (100-150 infusions per year) or a bispecific monoclonal antibody that mimics the activity of Factor VIII administered 1-4 times per month (12-48 infusions per year). Despite these regimens, many people continue to experience breakthrough bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.
Hemophilia A, also called Factor VIII deficiency or classic hemophilia, is an X-linked genetic disorder caused by missing or defective Factor VIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a new mutation that was not inherited. Approximately 1 in 10,000 people have hemophilia A.
Conference Call and Webcast to be Held Wed., Aug. 24th at 8:00 pm Eastern
BioMarin will host a conference call and webcast to discuss the EC approval today, Wed., Aug. 24th at 8:00 pm Eastern. This event can be accessed in the investor section of the BioMarin website at https://investors.biomarin.com/events-presentations.
U.S./Canada Dial-in Number: 800-831-4163
Replay Dial-in Number: 800-645-7964
International Dial-in Number: 213-992-4616
Replay International Dial-in Number: 757-849-6722
(No ID required for live call)
Playback ID: 9184
About BioMarin
BioMarin is a global biotechnology company that develops and commercializes innovative therapies for people with serious and life-threatening genetic diseases and medical conditions. The Company selects product candidates for diseases and conditions that represent a significant unmet medical need, have well-understood biology and provide an opportunity to be first-to-market or offer a significant benefit over existing products. The Company's portfolio consists of eight commercial products and multiple clinical and preclinical product candidates for the treatment of various diseases. For additional information, please visit http://www.biomarin.com.
Forward-Looking Statements
This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc. (BioMarin), including without limitation, statements about: the number of adults across Europe, the Middle East, and Africa who are affected by severe hemophilia A; the number of adults in the countries within BioMarin's footprint covered by the EMA approval who have severe hemophilia A and are indicated for Roctavian; BioMarin anticipating additional access to Roctavian for patients outside of the EU through named patient sales based on the EMA approval in countries in the Middle East, Africa and Latin America and the expectation that additional market registrations will be facilitated by the EMA license; the potential for Roctavian to be a one-time infusion protecting patients from bleeds for several years and freeing them from the burden of regular infusions; Roctavian potentially offering a significant benefit to those affected with severe hemophilia A; Roctavian potentially transforming how healthcare professionals and the patient community think about caring for bleeding disorders; BioMarin's plans to provide further data from ongoing studies within defined timelines to confirm that the benefits of Roctavian continue to outweigh the risks; conversion of Roctavian's CMA to a standard marketing authorization; BioMarin's plans to re-submit a BLA for Roctavian to the FDA by the end of September 2022; and the duration of the FDA's review procedure of BioMarin's BLA resubmission for Roctavian. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: the results and timing of current and planned preclinical studies and clinical trials of Roctavian; additional data from the continuation of the clinical trials of Roctavian, any potential adverse events observed in the continuing monitoring of the participants in the clinical trials; the content and timing of decisions by the FDA, the EC and other regulatory authorities, including decisions to grant additional marketing registrations based on an EMA license; the content and timing of decisions by local and central ethics committees regarding the clinical trials; our ability to successfully manufacture Roctavian for the clinical trials and commercially; our ability to provide the additional data from currently ongoing Roctavian clinical studies to support the conversion from a CMA to a standard marketing authorization; and those and those factors detailed in BioMarin's filings with the Securities and Exchange Commission (SEC), including, without limitation, the factors contained under the caption "Risk Factors" in BioMarin's Quarterly Report on Form 10-Q for the quarter ended June 30, 2022 as such factors may be updated by any subsequent reports. Stockholders are urged not to place undue reliance on forward-looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation to update or alter any forward-looking statement, whether as a result of new information, future events or otherwise.
BioMarin is a registered trademark of BioMarin Pharmaceutical Inc and ROCTAVIAN is a trademark of BioMarin Pharmaceutical Inc.
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First Gene Therapy for Adults with Severe Hemophilia A, BioMarin's ROCTAVIAN (valoctocogene roxaparvovec), Approved by European Commission (EC) -...
CAMBRIDGE, Mass., Aug. 25, 2022 (GLOBE NEWSWIRE) --Arbor Biotechnologies, Inc. a biotechnology company discovering and developing the next generation of genetic medicines, today announced that it has entered into an agreement with Acuitas Therapeutics, a leader in the development of lipid nanoparticles (LNP).
As part of the agreement, the companies will combine the optimized delivery of Acuitas' highly validated LNP technology with Arbors differentiated, proprietary CRISPR gene editing technology designed for use in vivo in patients with rare liver diseases.
We are building a robust, proprietary portfolio of genomic medicines, beginning with severe liver diseases, for which LNPs are known to provide an optimal delivery approach with their ability to efficiently target hepatocytes, limit off target toxicity and have minimal immunogenicity. We are looking forward to working with Acuitas, a leading global developer of clinically-validated LNP technology, said Devyn Smith, Ph.D., CEO, Arbor Biotechnologies. Importantly, we believe this partnership accelerates our path to the clinic, with an ability to leverage established and scalable manufacturing.
Commented Dr. Thomas Madden, President & CEO of Acuitas Therapeutics: We are excited to collaborate with Arbor on the development of novel genomic medicines for patients who currently have few, if any, therapeutic options. Arbors commitment to addressing this unmet clinical need resonates with Acuitas. We look forward to supporting their advance into the clinic.
About Arbor BiotechnologiesArbor Biotechnologies is a next-generation gene editing company focused on discovering and developing potentially curative genomic medicines. Founded by Feng Zhang, David Walt, David Scott, and Winston Yan, our proprietary discovery engine is focused on discovering genetic editing capabilities spanning knockdowns to whole gene insertions, which has enabled us to generate the most extensive toolbox of proprietary genomic editors in the industry to date. Leveraging our wholly-owned nucleases as the chassis for genetic modification, we can work backward from disease pathology to choose the optimal editing approach that specifically addresses the underlying cause of disease, resulting in a potentially curative medicine for a wider range of genetic disorders. As Arbor continues to advance its pipeline toward the clinic with an initial focus in liver and CNS disease, the Company has also secured several partnerships around gene editing and ex vivo cell therapy programs to broaden the reach of its novel nuclease technology. For more information, visit arbor.bio.
About Acuitas TherapeuticsFounded in February 2009, Vancouver-based Acuitas Therapeutics (www.acuitastx.com) is a private biotechnology company that specializes in the development of delivery systems for nucleic acid therapeutics based on lipid nanoparticles. The company partners with pharmaceutical and biotechnology companies, as well as non-governmental organizations and academic institutes to advance nucleic acid therapeutics into clinical trials and to the marketplace. The team works with partners to develop new therapies to address unmet clinical needs based on its internationally recognized capabilities in delivery technology. Acuitas Therapeutics has agreements in place with several partners to use its proprietary lipid nanotechnology in the development of COVID-19 vaccines. These include Pfizer/BioNTech for COMIRNATY, which has received full approval in the U.S. and Canada and is authorized for Emergency Use in Europe, the UK and many other countries. The Acuitas team is currently working on therapeutics focused on addressing cancer, HIV/AIDS, tuberculosis, malaria, rabies, and other serious diseases.
Contacts
MediaAmy Bonanno, Solebury Troutabonanno@soleburytrout.com914-450-0349
Investor RelationsAlexandra Roy, Solebury Troutaroy@soleburytrout.com617-221-9197
WALTHAM, Mass.--(BUSINESS WIRE)--ElevateBio, LLC (ElevateBio), a technology-driven company focused on powering transformative cell and gene therapies, today announced that it has partnered with the California Institute for Regenerative Medicine (CIRM) to advance the discovery and development of regenerative medicine as part of CIRMs Industry Alliance Program. Through the partnership, ElevateBio will provide access to high quality, well-characterized iPSC lines to academic institutions and biopharmaceutical companies that are awarded CIRM Discovery and Translational Grants. ElevateBio will also offer access to its viral vector technology, process development, analytical development, and Good Manufacturing Practice (GMP) manufacturing capabilities that are part of its integrated ecosystem built to power the cell and gene therapy industry.
This exciting partnership with CIRM reflects the novelty of our iPSC platform and recognition of our next-generation cell lines that address industry challenges and could potentially save time and costs for partners developing iPSC-derived therapeutics, said David Hallal, Chairman and Chief Executive Officer of ElevateBio. We are setting a new standard with iPSCs that can streamline the transition from research to clinical development and commercialization and leveraging our unique ecosystem of enabling technologies and expertise to help strategic partners harness the power of regenerative medicines.
With $5.5 billion in funding from the state of California, CIRM has funded 81 clinical trials and currently supports over 161 active regenerative medicine research projects spanning candidate discovery through phase III clinical trials. As part of CIRMs expansion of its Industry Alliance Program to incorporate Industry Resource Partners, this partnership will provide CIRM Awardees the option to license ElevateBios iPSC lines produced in xeno-free, feeder-free conditions using non-integrating technologies and have the ability to gain access to other enabling technologies, including gene editing, cell and vector engineering, and end-to-end services within ElevateBios integrated ecosystem, which are essential for driving the development of regenerative medicines.
About ElevateBio:
ElevateBio is a technology-driven company built to power the development of transformative cell and gene therapies today and for many decades to come. The company has assembled industry-leading talent, built state-of-the-art facilities, and integrated diverse technology platforms, including gene editing, induced pluripotent stem cells (iPSCs), and protein, vector, and cellular engineering, necessary to drive innovation and commercialization of cellular and genetic medicines. In addition, BaseCamp is a purpose-built facility offering process innovation, process sciences, and current Good Manufacturing Practice (cGMP) manufacturing capabilities. Through BaseCamp and its enabling technologies, ElevateBio is focused on growing its collaborations with industry partners while also developing its own portfolio of cellular and genetic medicines. ElevateBio's team of scientists, drug developers, and company builders are redefining what it means to be a technology company in the world of drug development, blurring the line between technology and healthcare.
ElevateBio is located in Waltham, Mass. For more information, visit us at http://www.elevate.bio, or follow Elevate on LinkedIn, Twitter, or Instagram.
The rest is here:
ElevateBio Partners with the California Institute for Regenerative Medicine to Accelerate the Development of Regenerative Medicines - Business Wire
PITTSBURGH--(BUSINESS WIRE)--ElevateBio, LLC (ElevateBio) and the University of Pittsburgh today announced that they have entered into a long-term strategic partnership to accelerate the development of highly innovative cell and gene therapies. Through this agreement, ElevateBio will locate one of its next BaseCamp process development and Good Manufacturing Practice (GMP) manufacturing facilities in Pittsburgh, fully equipped with its enabling technologies, including gene editing, induced pluripotent stem cell (iPSC) and cell, vector, and protein engineering capabilities. The University of Pittsburgh has long been a research powerhouse and is consistently among the top U.S. institutions in National Institutes of Health research funding.
The Richard King Mellon Foundation announced a $100 million grant to the University of Pittsburgh in November 2021 to create the Pitt BioForge BioManufacturing Center at Hazelwood Green. The grant was the largest single-project grant in the Foundation's 75-year history. The University of Pittsburgh and ElevateBio BaseCamp intend to locate the new technology-enabled process development and GMP manufacturing facility at Pitt BioForge at Hazelwood Green to further innovation in the Pittsburgh region. The new facility is expected to generate more than 170 permanent full-time jobs, 900 construction jobs, and 360 off-site support jobs.
This announcement supports the region's rise as a leader in cell and gene therapy and advances our vision of bringing an entirely new commercial manufacturing sector to the area," says Patrick Gallagher, Chancellor of the University of Pittsburgh. "The University of Pittsburgh is proud to partner with ElevateBio in this work, which will see us leveraging lessons from the labin new and exciting waysfor the benefit of human health.
To realize our vision of transforming the cell and gene therapy field for decades to come, broadening our footprint across metropolitan areas is a key priority for us, and we are thrilled that the University of Pittsburgh will be home to one of our BaseCamp facilities, said David Hallal, Chairman and Chief Executive Officer of ElevateBio. Weve identified Pittsburgh as an ideal location to extend our BaseCamp presence as it sits at the intersection of science, technology, and talent. We are grateful for the support of the Governor and County Executive as we bring the first-of-its-kind offering we have built at ElevateBio BaseCamp to advance the work of the entire biopharmaceutical industry.
Pitt Senior Vice Chancellor for the Health Sciences, Dr. Anantha Shekhar, continued by saying, We have some exceptional emerging research coming out of the University of Pittsburgh. However, the missing ingredient has been access to high-quality process science and manufacturing capabilities. As we position ourselves to become the next global hub for life sciences and biotech, we were in search of the right partner to help us realize our vision, and ElevateBios expertise and reputation in cell and gene therapy made them the perfect partner to accelerate our ability to build our biomanufacturing center of excellence.
This partnership between two national life-science powerhouses the University of Pittsburgh and ElevateBio - is a consequential step forward in realizing our shared vision to make Pittsburgh a national and international biomanufacturing destination, said Sam Reiman, Director of the Richard King Mellon Foundation. Pitt BioForge is a generational opportunity to bring extraordinary economic-development benefits to our region, and life-changing cell and gene therapies to patients - distribution that will be accelerated and enhanced by Pitts partnership with UPMC. ElevateBio could have chosen to locate its next biomanufacturing hub anywhere in the world; the fact they are choosing to come to Pittsburgh is another powerful validation of our region, and the Pitt BioForge project at Hazelwood Green.
We are excited that Pitt, working with UPMC Enterprises, has attracted ElevateBio to this region, said Leslie Davis, President and Chief Executive Officer of UPMC (University of Pittsburgh Medical Center). The companys expertise and manufacturing capabilities, combined with Pitt research and UPMCs clinical excellence, are essential to delivering the life-changing therapies that people depend on UPMC to deliver.
In addition, the Commonwealth of Pennsylvania and the County of Allegheny have provided incentive grants to ElevateBio in support of this partnership to build a biomanufacturing center and establish Pittsburgh as a premier biomanufacturing destination.
This announcement is continued verification of Pittsburgh's ability to attract new and emerging companies that provide economic opportunities in the life sciences field. The University of Pittsburgh and its medical school are a magnet for that ecosystem and along with this region's quality of life and investment in innovation, we continue to see businesses choosing Pittsburgh, said County Executive Rich Fitzgerald. The creation of the Innovation District, and the many companies that call it home, continue to provide great opportunities for talent to fill jobs across the ecosystem's pipeline. We welcome ElevateBio to our region and look forward to all that you will do here as part of this great ecosystem.
About ElevateBio:
ElevateBio is a technology-driven company built to power the development of transformative cell and gene therapies today and for many decades to come. The company has assembled industry-leading talent, built state-of-the-art facilities, and integrated diverse technology platforms, including gene editing, induced pluripotent stem cells (iPSCs), and protein, vector, and cellular engineering, necessary to drive innovation and commercialization of cellular and genetic medicines. In addition, BaseCamp in Waltham, MA, is a purpose-built facility offering process innovation, process sciences, and current Good Manufacturing Practice (cGMP) manufacturing capabilities. It was designed to support diverse cell and gene therapy products, including autologous, allogeneic, and regenerative medicine cell products such as induced pluripotent stem cells, or iPSC, and viral vector manufacturing capabilities.
Through BaseCamp and its enabling technologies, ElevateBio is focused on growing its collaborations with industry partners while also developing its own portfolio of cellular and genetic medicines. ElevateBio's team of scientists, drug developers, and company builders are redefining what it means to be a technology company in the world of drug development, blurring the line between technology and healthcare.
For more information, visit us at http://www.elevate.bio, or follow ElevateBio on LinkedIn, Twitter, or Instagram.
About the University of Pittsburgh:
Founded in 1787, the University of Pittsburgh is an internationally renowned leader in health sciences learning and research. A top 10 recipient of NIH funding since 1998, Pitt has repeatedly been ranked as the best public university in the Northeast, per The Wall Street Journal/Times Higher Education. Pitt consists of a campus in Pittsburghhome to 16 undergraduate, graduate and professional schools and four regional campuses located throughout Western Pennsylvania. Pitt offers nearly 500 distinct degree programs, serves more than 33,000 students, employs more than 14,000 faculty and staff, and awards 9,000 degrees systemwide.
For more information, please visit http://www.pitt.edu and http://www.health.pitt.edu.
About the Richard King Mellon Foundation:
Founded in 1947, the Richard King Mellon Foundation is the largest foundation in Southwestern Pennsylvania, and one of the 50 largest in the world. The Foundations 2021 year-end net assets were $3.4 billion, and its Trustees in 2021 disbursed $152 million in grants and Program-Related Investments. The Foundation focuses its funding on six primary program areas, delineated in its 2021-2030 Strategic Plan.
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ElevateBio and the University of Pittsburgh Announce Creation of Pitt BioForge BioManufacturing Center at Hazelwood Green to Accelerate Cell and Gene...
When all else fails, some patients trying to overcome alcoholism, severe depression or anxiety, and even cluster headaches, turn to psychedelic drugs, which clinical research has shown can help treat individuals with these conditions, sometimes with dramatically positive results.
But sometimes, as with any therapy, the psychedelic treatment does not work. It just takes a patient on a long strange trip.
Now, UNC School of Medicine researchers led by Dr. Bryan Roth, the Michael Hooker Distinguished Professor of Pharmacology, report that one reason for treatment disparity could be common genetic variations in one serotonin receptor.
Dr. Bryan L. Roth
Published in the journal ACS Chemical Neuroscience, the lab research in cells shows that seven variants uniquely and differentially impact the receptors response to four psychedelic drugs psilocin, LSD, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and mescaline.
Based on our study, we expect that patients with different genetic variations will react differently to psychedelic-assisted treatments, said Roth, who leads the NIH Psychotropic Drug Screening Program. We think physicians should consider the genetics of a patients serotonin receptors to identify which psychedelic compound is likely to be the most effective treatment in future clinical trials.
After decades of taboo regarding potential therapeutic benefit of psychotropic drugs, there has been renewed interest and research in using such compounds to treat neuropsychiatric disorders, such as major depression disorder, because the drugs stimulate serotonin receptors in the brain. These receptors bind the neurotransmitter serotonin and other similar amine-containing molecules, helping regulate peoples mood and emotions, as well as their appetite. In particular, the 5-hydroxytryptamine receptor known as 5-HT2A is responsible for mediating how a person reacts to psychedelic drugs. However, there are several naturally occurring, random genetic variations, known as single nucleotide polymorphisms, or SNPs, that can affect the function and structure of the 5-HT2A receptor.
Site of the 5-HT2A serotonin receptor.
Roth and colleagues wanted to explore how variation in this one serotonin receptor changes the activity of four psychedelic therapies.
Graduate student Gavin Schmitz and postdoctoral researchers Manish Jain and Samuel Slocum used a series of experimental assays to measure the effect that seven different SNPs had onin vitro binding and signaling of the 5-HT2A serotonin receptor when in the presence of one of the four drugs. Their results indicated that some gene variations even ones far from the exact location where the drug binds to the receptor alter the way that the receptor interacts with the psychedelic drugs.
For example, the SNP Ala230Th had decreased response to one of the four drugs (psilocin the active metabolite of psilocybin) while the Ala447Val mutation showed only reduced effects to two of the drugs.
This is another piece of the puzzle we must know when deciding to prescribe any therapeutic with such dramatic effect aside from the therapeutic effect, Roth said. Further research will help us continue to find the best ways to help individual patients.
The National Institutes of Health and the Defense Advanced Research Projects Agency (DARPA) funded this research.
Read more here:
Genetic variants cause different reactions to psychedelic therapy - The Well : The Well - The Well
Medical treatment is shifting from a traditional symptom-based approach to one thats personalized for you.
This is especially true for cancer care, where personalized medicine is often the first step in treatment decision-making.
Prostate cancer is among the cancer types most impacted by the personalization of medicine. For prostate cancer, special disease markers are used to decide whether treatment is needed before it even begins.
Weve partnered with the Prostate Cancer Foundation (PCF) to learn more about how personalized, or precision, medicine is used for prostate cancer.
Precision medicine is used across the spectrum of prostate cancer care, from screening to treatment.
Precision medicine, or personalized medicine, is an innovative approach to tailoring disease prevention or treatment to account for differences unique to a specific patient or tumor, explains Dr. Rana McKay, a medical oncologist at the University of California San Diego and PCF-funded researcher.
For example, blood tests that detect a protein known as prostate-specific antigen (PSA) are used to screen for early signs of prostate cancer.
Cancer cells tend to release more PSA than healthy prostate cells, so elevated levels in the blood may suggest that more regular or additional types of testing are needed.
PSA can be high even if you dont have cancer, though. Observing trends in PSA levels over time is most helpful.
Taking your age and other personal characteristics into account, doctors can understand when a person with high PSA levels may have cancer versus another condition, such as prostate enlargement (benign prostatic hyperplasia) or prostatitis.
The best age to begin screening for prostate cancer can be personalized based on your risk factors. The PCF recommends:
The role of precision medicine becomes even more important during treatment. It helps doctors match the right treatment to the exact cancer that you have.
The goal of precision medicine is to target the right treatments to the right patients at the right time, McKay says.
This is important because there are several treatments and clinical trials that are [designed for] people with specific molecular changes in their tumor.
Oncologists and their teams may consider a variety of factors to evaluate the unique characteristics of a persons prostate cancer type, such as:
Some types of tests that may be used to evaluate these factors include:
Results from these tests can help healthcare professionals understand:
For instance, tumors that contain mutations in certain DNA damage repair genes may be more likely to respond to a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, such as rucaparib (Rubraca) or olaparib (Lynparza).
On the other hand, tumors that contain mutations in mismatch repair genes are more likely to respond to pembrolizumab (Keytruda).
Knowing which medication is likely to work for a specific tumor helps doctors avoid treatments that are unlikely to be effective and minimize potentially unpleasant and unnecessary side effects.
Doctors will also consider things like age and other health conditions when tailoring treatment plans to individuals.
For example, prostate cancer is known to be more aggressive and can be fatal when diagnosed in younger men, whereas men over 70 can live with the disease for many years.
However, men who are younger and otherwise healthy have the potential to live for a long time after treatment, which may also influence treatment decisions.
Understanding these factors and taking a personalized approach helps your care team determine how aggressive to be with different cancer therapies.
Personalized medicine relies on doctors finding a specific feature in a persons tumor thats known to predict response to a specific treatment.
While many advancements have been made in the field of precision medicine for prostate cancer, theres a lot left to learn.
Currently, there are only a handful of gene alterations (mutations or abnormalities) in prostate cancer that can help guide clinical decision-making and predict response to treatment.
However, if we were to actually take all possible alterations that we can target with a drug, the majority of patients likely have a genomic alteration that could potentially be targeted with a specific drug or combination of drugs, McKay estimates.
A 2015 study reported that samples from almost 90% of prostate cancer cells contained clinically actionable disease markers meaning the researchers could predict response to treatment or use the information to understand a persons diagnosis or prognosis.
The study only included tumor samples from people with advanced prostate cancer. These individuals are at the highest risk of fatal cancer and may benefit a lot from a personalized approach to treatment.
Lifestyle absolutely plays a tremendous role in prostate cancer treatment and also overcoming side effects of therapy, says McKay.
Recently, experts have started to wonder whether guiding lifestyle changes is the next step in precision medicine for various diseases and conditions.
Understanding how certain genetic features affect the likelihood that a person will develop prostate cancer can help them take steps to prevent cancer from developing in the first place.
For example, its known that diet and physical activity affect your chances of developing prostate cancer. These could be factored into a personalized prevention plan.
During treatment for prostate cancer, lifestyle plans tailored to individuals could someday help people deal with different responses to therapy and side effects.
While research hasnt yet advanced to the point that a personalized lifestyle plan can be used to help prevent or treat prostate cancer, such a future may not be far off.
Research on precision medicine for prostate cancer is continually growing.
McKay notes that there are many exciting studies on treatments, biomarkers, imaging, and other approaches on the horizon.
Shes particularly excited about the PREDICT study through the Alliance for Clinical Trials, which will launch in January of 2023.
This is a novel phase 2 biomarker-based umbrella study that uses DNA and RNA tumor profiling to guide therapy selection, she explains.
There are several other areas of prostate cancer research that one day will be used to guide personalized treatment approaches. Some of the remaining questions include:
McKay adds that having enough people from diverse backgrounds to conduct studies is what helps advance prostate cancer research and the field of precision medicine.
Participation in clinical research is really paramount for helping optimize treatment for patients, she says.
Prostate cancer care has been revolutionized by a personalized approach to treatment.
These advancements can help improve outcomes, reduce the occurrence of unnecessary side effects, and set people on the path to recovery sooner.
If you or a loved one has prostate cancer, your doctor should discuss the testing options available to help guide your personalized treatment decision-making.
Its important to engage with your healthcare clinicians to optimize treatment and ensure the best outcomes, recommends McKay.
Excerpt from:
Personalized Medicine for Prostate Cancer: What It Is and How It Works - Healthline
The fertility watchdog is pushing for the biggest overhaul of fertility laws in 30 years and discussing how to future proof any new fertility laws to make sure they can deal with current and future radical scientific advances.
Here are four of the new reproductive treatments that scientists say could be just a few years away from the clinic.
Scientists are making significant advances in the ability to grow eggs and sperm in the laboratory. The ultimate goal is to take adult skin cells, transform them into induced pluripotent stem cells that have the ability to turn into other cell types and then, using a cocktail of chemicals, coax these cells along the developmental pathway to becoming either eggs or sperm cells.
This may sound biologically improbable, but scientists have already achieved the feat in mice, producing healthy pups. In theory, a female skin cell could be used to produce a sperm cell and vice versa, which would be revolutionary.
Translating this work into human cells is not straightforward. There are still big scientific hurdles to overcome, and demonstrating safety would be a lengthy process. But there is growing confidence that this will eventually be possible and already there are companies, such the US-based Conception, aiming to bring the most recent advances to the clinic.
Genome editing is a method for making specific changes to the DNA of a cell or organism. Gene therapy, where new genes are added or faulty genes disabled in specific cells, is already used in medicine to treat genetic diseases.
Changing the DNA of an embryo goes a step further because the genetic changes would occur in every cell in the body, meaning the edits would be passed on to subsequent generations. The technique could allow people to avoid passing on heritable diseases.
However, in many cases, pre-implantation screening of embryos can achieve this goal and research has shown that gene editing tools risk producing off target changes. So there will be a very high bar for demonstrating that the technology is safe enough to be medically justified.
The last big amendment to UK fertility law came in 2015 when MPs voted for an amendment to allow a technique called mitochondrial transfer, designed to eliminate certain incurable genetic diseases. The technique involves swapping the eggs mitochondrial DNA (a tiny fraction of the total DNA, which sits outside the eggs nucleus) with that of a healthy donor.
At present, only two specific techniques are permitted, but many people would like the law made more flexible so that new techniques with the same objective could be licensed.
It is possible that in future the technique could have wider applications, for instance if faulty mitochondria were identified as a cause of infertility.
UK fertility laws regulate the use of embryos in research, and place a 14-day limit on how far into development embryos can be cultivated in the lab. However, the HFEA has no remit over so-called synthetic embryos.
This month, two teams of scientists report creating these embryo-like structures, featuring a beating heart and primitive brain, from mouse cells. The synthetic embryos look essentially the same as real embryos but do not require an egg or sperm to produce. The same scientists are trying to replicate the work in human cells, and some think new legal guidelines are required.
Separately, many scientists would like to see the 14-day rule relaxed to allow them to get a better understanding of human development, including why many pregnancies fail at an early stage.
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Four radical new fertility treatments just a few years away from clinics - The Guardian
26 Aug Why are Rats Used in Medical Research?
Rodents have long been the preferred species of animal to use in lab research, with experiments on the common brown rat starting around 150 years ago. While there are still many questions regarding the ethics of using live specimens for scientific experimentation, the achievements attributed to the use of rats are undeniable. But why are rats so important to human medicine, and what benefits do they hold over other species?
On top of all these benefits, rats offer more potential for genetic manipulation, which is why transgenic rats are often used in medical research rather than mice. The simple truth is that rats have a far wider range of effective uses in a large variety of research applications than their mouse counterparts.
The Advantages of Rats in Medical Research
The success found through experiments using lab rats is attributed to the amazing comparison in the physiological, anatomical, and genetic similarities found between rodents and humans. These similarities are key in being able to compare the results from rat experiments to the potential effects of the same treatment or condition in human beings.
Rats are also easier and cheaper to feed and house than other suitable creatures, such as primates, due to their smaller size, which also makes them easier to handle and transport too. Rats also reproduce rapidly and have relatively short reproduction cycles, making them readily available at all times. Since genetically sequencing the Brown Norway rat in 2004, it has been shown that most human genes that are linked to disease also have counterparts present in rats, which leads to a better understanding of diseases that afflict humans.
Rats are commonly used in many avenues of medical research, but one interesting study at the moment is helping researchers understand addiction in humans. Using rats, research has shown that addiction manifests differently in individuals and that compulsive narcotic-seeking efforts continue even in the face of adversity. Throughout this study, researchers were able to show, for the first time, that long-term exposure to narcotics altered the basolateral amygdala, an area of the brain that has been associated with the connection of stimulation and emotion. Using this same rat model, there has been a completely new path identified in the brain that connects an impulse with a habit.
Rats will continue to play a critical role in medical research for as long as there is research to be carried out and questions to be answered. The lab rat has helped mankind make numerous advances in the understanding and treatment of neural regeneration, diabetes, behavioral studies, cardiovascular medicine, wound healing, transplantation, and space motion sickness, and humanity owes many of our medical advancements to these understated champions of life.
The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.
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Why are Rats Used in Medical Research? - MedicalResearch.com
By Kelsey GoodwinAugust 22, 2022
Being able to see and experience the direct patient impact of this research has been incredibly rewarding, and further inspires me to pursue a career within the biomedical field.
~Bonner Kirkland 23
Name: Bonner Kirkland 23Hometown: Nashville, TennesseeMajor: Engineering Integrated with Biology
Q: What factors led you to choose W&L?I was immediately drawn to W&L by the strong sense of community on campus, as the honor system and speaking tradition reinforce a sense of trust and camaraderie among students and faculty. I was also drawn to the small class sizes, which Ive found to be extremely valuable to my learning process. I knew I wanted to pursue a science, technology, engineering and mathematics (STEM) major, and that being able to work in smaller groups of students closely alongside professors would greatly facilitate my ability to learn and develop skills that can be applied later in life. W&Ls strong alumni network was also very appealing to me, and the ability to connect with and seek career advice from alums is another valuable aspect of our community.
Q: Why did you choose your course of study?I knew I wanted to pursue a major within the STEM field when I arrived at college, but was undecided on what specific topics I was interested in. After taking Physics I in my first semester with Professor Irina Mazilu, I immediately fell in love with not only the subject matter, but also the Physics and Engineering Department. Each of the professors in this department genuinely care about their students growth, both in and outside of the classroom. They constantly volunteer their time to ensure students reach mastery of the difficult subject matter. My love for problem solving, math and science partnered with wonderful professors prompted me to pursue an engineering major. Ive thoroughly enjoyed the engineering coursework Ive taken which has exposed me to a variety of engineering topics, from electrical circuits to fluid mechanics.
The ability to integrate the engineering major with another science discipline in my case, biology enabled me to take a variety of biology courses in addition to engineering classes. Ive always wanted to pursue a career within the medical field, specifically biomedical engineering, so this major has allowed me to supplement my engineering skillset with biological knowledge that will help me in the future.
Q: How did you find out about this opportunity? Did anyone at W&L help?I briefly worked in the same lab through a program offered by my high school in 2018. Knowing I wanted to pursue a medical research position this summer, I reached out to my previous lab supervisor to see if he had any open positions for student research and he graciously welcomed me back into his lab. Because this is an unpaid position, this experience was made possible entirely through the generosity of W&L donors and summer funding opportunities, particularly the Johnson Opportunity Grant, Department of Physics and Engineerings supplemental summer funding, and Career and Professional Development funding. I am incredibly grateful for financial support from both the school and generous donors, allowing me to pursue this research position by offsetting the costs of living and working in Washington, D.C.
Q: What kind of work are you doing?This summer I conducted research in the Childrens National Hospitals Department of Genetic Medicine, where we are working on developing a quicker and more cost-effective method for determining abnormalities in amino acid concentrations in newborns. Traditional methods for evaluating amino acid concentrations in patients have been costly, timely and often require a large volume of sample. The method we are developing, on the other hand, requires a small sample and allows for the quick and proactive diagnosis of various genetic conditions in newborns marked by unique amino acid levels.
We are also working on a project to evaluate how glutathione, a combination of three amino acids, works to relieve cellular damage caused by oxidative stress in cells. Glutathione acts as an antioxidant defense against oxidative stress, preventing damage to the cells. This project will reveal how glutathione may work as an anti-aging mechanism that strengthens the immune system, detoxifies the body and eliminates carcinogens. All summer, I have been maintaining, growing, and plating HepG2 cells, then treating them with various concentrations of hydrogen peroxide to cause oxidative damage. Then I either pre- or post- treat these cells with gamma-glutamylcysteine a precursor amino acid to glutathione and analyze how this facilitates cell recovery. This work requires close attention to detail and sterile technique as to not contaminate the cells.
Q: What do you like most about it, and what has been most challenging so far?Having the opportunity to work with patient samples has definitely been a highlight of this internship. Recently, through use of this new method, researchers in the lab noticed that patients suffering from sickle cell anemia had low levels of citrulline, a critical amino acid which regulates vasodilation. These low levels of citrulline cause vasoconstriction and thus, we hypothesize chronic pain. After administering a dose of citrulline to several patients suffering from severe pain, they reported significantly reduced pain levels. The prospect of being able to use a naturally occurring amino acid rather than morphine to mitigate pain in these young patients is extremely valuable. Being able to see and experience the direct patient impact of this research has been incredibly rewarding, and further inspires me to pursue a career within the biomedical field.
I have also enjoyed being able to work on a project of my own, analyze the data and present my findings. The glutathione project Im currently working on has been challenging, confusing and frustrating at times, particularly when the data comes out differently than expected. However, it has taught me that research is rarely clean cut and perfect on the first try. It takes frequent repetition and minor tweaking of procedures to yield the desired results. Towards the end of the summer, I was able to present my results in our departments lab meeting, which was an exciting and meaningful experience. Sharing the culmination of my summers work with people working in different labs allowed me to gain more experience giving scientific presentations to people of different backgrounds.One of the most difficult elements of this research experience has been having to quickly familiarize myself with complex biochemistry and genetic topics. The majority of my coursework focuses on standard engineering classes and some biology classes, whereas this research is heavily based in chemistry. Becoming familiar with the different chemical and biological pathways involved in this project has definitely been a steep learning curve. However, I make up for my lack of prior chemistry coursework by reading relevant literature to the project and papers this lab has published in the past, as well as actively communicating any questions I have with my lab supervisor.
Q: Tell us about previous summer experiences youve had at W&L.Last summer, I worked as a compliance engineer intern for TVP Health, formerly known as The Ventilator Project. This nonprofit organization was founded in March 2020 in response to the COVID-19 pandemic with the mission of ensuring all people have access to quality medical care amid a global ventilator shortage. TVP Health developed a lower-cost ventilator, called AIRA, to combat this global issue. As a compliance engineer, I worked to ensure AIRA met various ISO medical device standards. This initial exposure to the medical device industry piqued my interest in the field and prompted me to consider a career path in biomedical engineering, as the intersection between engineering and direct patient impact is very important to me.
Q: How do you think your current summer experience and others youve had in the past, if applicable will impact your future career path?I have been interested in the sciences and problem solving for as long as I can remember, but my passion for integrating medicine with engineering began through my aforementioned internship with TVP Health. Last summers experience dealt with the more technical, regulatory side of the medical device industry, so I have really enjoyed this summers research, as it pertains more to the hands on, biological side of medical research. Gaining exposure to these two aspects of the industry will be incredibly formative in my future career endeavors.
My research experience at Childrens National Hospital immersed me in the field of biomedical research. I was given the opportunity to learn and practice sterile lab technique, the scientific method and the problem-solving methods used in the scientific world. This internship has also taught me the importance of communication with coworkers and superiors, as well as how to proactively avoid problems in a lab setting and think critically to respond in unfamiliar situations. After graduation, I hope to pursue a masters degree in biomedical engineering, and everything I have learned from my summer experiences will be incredibly valuable throughout graduate school and beyond.
I hope to focus my skillset on the medical device industry, particularly within the realm of womens health and medicine. Women are often underrepresented in clinical trials due to the complex, variable female hormone system. This can lead to women being misdiagnosed and prescribed the wrong medication, resulting in further health complications because women may react differently to a medication or medical device tested in a predominantly-male clinical trial. This injustice inspires me to develop female-centered medical devices and treatment methods, and I believe my current research opportunity is an early steppingstone to the field of medical research for me.
Q: Outside of your internship, what have you enjoyed the most about living and working in Washington D.C.?One of my favorite parts about Washington D.C. is the walkability of the city and the access to public spaces. In my free time, Ive loved going to Smithsonian museums, walking on the National Mall, going to the farmers market, and running in Rock Creek Park. I especially loved visiting the National Arboretum and seeing their current Ikebana exhibit. Ive learned that having access to quality outdoor spaces is something that is a very important factor to me when choosing a city to live in after graduation.
Q: What do you miss most about W&L when youre away for the summer?While being in a bigger city is exciting and lively, I definitely do miss W&L when Im away. Living on a small, welcoming and safe campus like ours is something I often take for granted during the academic year. The sense of community on campus is one of my favorite parts about being a W&L student. Having time away from school makes me grateful for aspects of our community like the honor system and speaking tradition, which unfortunately are not as prevalent in other places. I also miss the day-to-day interactions with people on campus, whether its grabbing lunch at Caf 77 with a friend or catching up with a professor between classes.
If you know any W&L students who would be great profile subjects, tell us about them! Nominate them for a web profile.
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Could aid efforts to find treatments for Alzheimers, other diseases
An extended form of the protein aquaporin 4 (red) lines the edges of tiny blood vessels in the brain. Cell nuclei are visible in blue. Researchers at Washington University School of Medicine in St. Louis have found a new druggable pathway that enhances the amount of long aquaporin 4 near blood vessels and increases the clearance of waste from the brain. The findings potentially could lead to new therapies to prevent Alzheimers dementia.
Researchers at Washington University School of Medicine in St. Louis have found a new druggable pathway that potentially could be used to help prevent Alzheimers dementia.
Amyloid beta accumulation in the brain is the first step in the development of Alzheimers dementia. Scientists have poured countless hours and millions of dollars into finding ways to clear amyloid away before cognitive symptoms arise, with largely disappointing results.
In this study, published Aug. 24 in the journal Brain, researchers found a way to increase clearance of waste products from the brains of mice by ramping up a genetic quirk known as readthrough. This same strategy also may be effective for other neurodegenerative diseases characterized by the buildup of toxic proteins, such as Parkinsons disease, the researchers said.
Every once in a while, the brain protein aquaporin 4 is synthesized with an extra little tail on the end. At first, Darshan Sapkota, PhD who led this study while a postdoctoral researcher at Washington University but is now an assistant professor of biological sciences at the University of Texas, Dallas thought this tail represented nothing more than an occasional failure of quality control in the protein-manufacturing process.
We were studying this very wonky basic science question How do proteins get made? and we noticed this funny thing, said senior author Joseph D. Dougherty, PhD, a Washington University professor of genetics and of psychiatry, and Sapkotas former mentor. Sometimes the protein-synthesizing machinery blew right through the stop sign at the end and made this extra bit on the end of aquaporin 4. At first, we thought it couldnt possibly be relevant. But then we looked at the gene sequence, and it was conserved across species. And it had this really striking pattern in the brain: It was only in structures that are important for waste clearance. So thats when we got excited.
Scientists already knew that the cells protein-building machinery occasionally fails to stop where it should. When the machinery doesnt stop a phenomenon known as readthrough it creates extended forms of proteins that sometimes function differently than the regular forms.
Sapkota and Dougherty created tools to see whether the long form of aquaporin 4 behaved differently in the brain than the regular form. They found the long form but not the short one in the so-called endfeet of astrocytes. Astrocytes are a kind of support cell that help maintain the barrier between the brain and the rest of the body. Their endfeet wrap around tiny blood vessels in the brain and help regulate blood flow. Astrocytic endfeet are the perfect place to be if your job is to keep the brain free of unwanted proteins by flushing waste out of the brain and into the bloodstream, where it can be carried away and disposed of.
Thinking that increasing the amount of long aquaporin 4 might increase waste clearance, Sapkota screened 2,560 compounds for the ability to increase readthrough of the aquaporin 4 gene. He found two: apigenin, a dietary flavone found in chamomile, parsley, onions and other edible plants; and sulphaquinoxaline, a veterinary antibiotic used in the meat and poultry industries.
Sapkota and Dougherty teamed up with Alzheimers researchers and co-authors John Cirrito, PhD, an associate professor of neurology, andCarla Yuede, PhD, an associate professor of psychiatry, of neurology and of neuroscience, to figure out the relationship between long aquaporin 4 and amyloid beta clearance.
The researchers studied mice genetically engineered to have high levels of amyloid in their brains. They treated the mice with apigenin; sulphaquinoxaline; an inert liquid; or a placebo compound that has no effect on readthrough. Mice treated with either apigenin or sulphaquinoxaline cleared amyloid beta significantly faster than those treated with either of the two inactive substances.
Theres a lot of data that says reducing amyloid levels by just 20% to 25% stops amyloid buildup, at least in mice, and the effects we saw were in that ballpark, Cirrito said. That tells me that this could be a novel approach to treating Alzheimers and other neurodegenerative diseases that involve protein aggregation in the brain. Theres nothing that says this process is specific for amyloid beta. It may be enhancing, say, alpha-synuclein clearance, too, which could benefit people with Parkinsons disease.
Sulphaquinoxaline is not safe for use in people. Apigenin is available as a dietary supplement, but its not known how much gets into the brain, and Cirrito cautions against consuming large amounts of apigenin in an attempt to stave off Alzheimers. The researchers are working on finding better drugs that influence the production of the long form of aquaporin 4, testing several derivatives of sulphaquinoxaline and additional compounds.
Were looking for something that could be quickly translated into the clinic, Sapkota said. Just knowing that its targetable at all by a drug is a helpful hint that theres going to be something out there we can use.
Sapkota D, Florian C, Doherty BM, White KM, Reardon KM, Ge X, Garbow JR, Yuede CM, Cirrito JR, Dougherty JD. Aqp4 stop codon readthrough facilitates amyloid- clearance from the brain. Brain. Aug. 24, 2022. DOI:10.1093/brain/awac199
This work was supported by the National Institute of Neurological Disorders and Stroke, grant number 1R01NS102272; the Mallinckrodt Institute of Radiology; the Hope Center for Neurological Disorders; the National Institute on Aging, grant numbers K99AG061231 and R01AG064902; Coins for Alzheimers Research Trust; and the Rotary Club International.
About Washington University School of Medicine
WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% in the last five years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,790 faculty physicians practicing at over 60 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Childrens hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.
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Study points to new approach to clearing toxic waste from brain Washington University School of Medicine in St. Louis - Washington University School...
Treatment with gene therapy candidate SynCav1 delayed disease onset and extended survival in a mouse model ofamyotrophic lateral sclerosis(ALS), according to a new study.
The experimental therapy aims to improve the survival of motor neurons in people with ALS irrespective of the underlying cause.
These data suggest that SynCav1 might serve as a novel gene therapy for neurodegenerative conditions in ALS and other forms of central nervous system disease of unknown etiology [cause], the researchers wrote.
The study, Subpial delivery of adeno-associated virus 9-synapsin-caveolin-1 (AAV9-SynCav1) preserves motor neuron and neuromuscular junction morphology, motor function, delays disease onset, and extends survival in hSOD1G93A mice, was published inTheranostics.
Certain genetic mutations are known to cause ALS, and numerous research projects have explored whether gene therapies could be used to treat these cases for example, by delivering a healthy copy of a mutated gene to a persons cells.
While these approaches could address the underlying cause of disease in some patients, in the vast majority of ALS cases there is no known mutation. Therefore, this therapeutic strategy is unlikely to be beneficial for many patients.
The overall aim of SynCav1, meanwhile, is to help keep nerve cells healthier, regardless of the underlying disease cause.
SynCav1 is an experimental gene therapy designed to deliver a copy of the gene encoding Caveolin-1 (Cav-1) to nerve cells using a specifically engineered viral vector. Cav-1 is a cell membrane protein that is important for maintaining the health of nerve cells.
Increasing the production of Caveolin-1 specifically in nerve cells was found in a previous study to preserve motor function in animal models of ALS. It also significantly extended survival.
Delivering the experimental gene therapy via a viral vector also showed promise in preclinical models of Alzheimers.
Eikonoklastes Therapeutics acquired the license to SynCav1 earlier this year, with the company noting that the therapy had been found to delay neurodegeneration and cognitive deficits in an Alzheimers mouse model.
Now, an international team of scientists, including several stockholders and consultants at Eikonoklastes, tested SynCav1 in a mouse model of ALS caused by a mutation in the SOD1 gene. Mutations in this gene account for about 1220% of familial ALS cases and 12% of sporadic cases.
At eight weeks of age before symptom onset in this model the mice were given a single injection of SynCav1, administered via subpial delivery, or an injection through the spine and under the membrane that surrounds the spinal cord. Other mice were given sham surgery as a control.
In an initial set of experiments, the researchers tested several doses of the gene therapy, and determined that a dose of approximately 200 billion individual SynCav1 viral vectors could increase Cav-1 expression in the spinal cord by about fourfold.
The team then tested the therapeutic effect of this dosage. Disease onset, defined by the first sign of weight loss, occurred at around 1516 weeks of age, on average, in untreated mice. Treatment with SynCav1 delayed disease onset by about 15%, with an average onset age of 18 weeks.
SynCav1 treatment also extended average survival times by about 10%, from 162 days to 178 days in male mice and from 165 to 181 days in females. The treated mice performed better on standardized measures of motor function, and analyses of their spinal cords indicated that the treatment helped preserve nerve health as intended. It also preserved neuromuscular junctions, the site of communication between nerve and muscle cells.
Generally, similar results were seen in both male and female mice.
The researchers also conducted some similar tests using a rat model of ALS caused by mutations inSOD1. Results showed the therapy candidate improved rats grip strength, which provides further direct evidence of the therapeutic potential properties afforded by SynCav1 in a larger ALS animal model, the researchers wrote.
Notably, the team said that these results are comparable to findings from studies in rodent models testing therapies that directly targeted the mutated SOD1 gene. In combination with previous findings in Alzheimers models, the results broadly suggest that SynCav1 may have utility in treating neurological diseases even when the underlying cause is unclear.
Because the neuroprotective efficacy afforded by SynCav1 occurred independent of targeting the known toxic monogenic protein (i.e., mutant [SOD1]), these findings suggest that SynCav1 may serve as a novel gene therapy for other neurodegenerative conditions in addition to ALS and [Alzheimers disease], Brian Head, PhD, a professor at the University of San Diego School of Medicine and co-author of the study, said in a university press release.
However, it is essential for further studies to determine the effect of SynCav1 on disease progression at later stages of the disease, added Head, who invented the gene therapy technology and provided funding for this research.
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ALS Gene Therapy SynCav1 Found to Extend Survival in Mouse Model |... - ALS News Today
Chemotherapy sucks. The treatments generally have awful side effects, and its no secret that the drugs involved are often toxic to the patient as well as their cancer. The idea is that, since cancers grow so quickly, chemotherapy will kill off the disease before its side effects kill the patient. Thats why scientists and doctors are constantly searching for more effective therapies.
A team led by researchers at UC Santa Barbara, and including collaborators from UC San Francisco and Baylor College of Medicine, has identified two compounds that are more potent and less toxic than current leukemia therapies. The molecules work in a different way than standard cancer treatments and could form the basis of an entirely new class of drugs. Whats more, the compounds are already used for treating other diseases, which drastically cuts the amount of red tape involved in tailoring them toward leukemia or even prescribing them off-label. The findings appear in the Journal of Medicinal Chemistry.
Our work on an enzyme that is mutated in leukemia patients has led to the discovery of an entirely new way of regulating this enzyme, as well as new molecules that are more effective and less toxic to human cells, said UC Santa Barbara Distinguished Professor Norbert Reich, the studys corresponding author.
The epigenome
Methyl group markers are one aspect of the epigenome that can turn off a gene.
Photo Credit: AV LENE MARTINSEN/ BIORENDER
All cells in your body contain the same DNA, or genome, but each one uses a different part of this blueprint based on what type of cell it is. This enables different cells to carry out their specialized functions while still using the same instruction manual; essentially, they just use different parts of the manual. The epigenome tells cells how to use these instructions. For instance, chemical markers determine which parts get read, dictating a cells actual fate.
A cells epigenome is copied and preserved by an enzyme (a type of protein) called DNMT1. This enzyme ensures, for example, that a dividing liver cell turns into two liver cells and not a brain cell.
However, even in adults, some cells do need to differentiate into different kinds of cells than they were before. For example, bone marrow stem cells are capable of forming all the different blood cell types, which dont reproduce on their own. This is controlled by another enzyme, DNMT3A.
This is all well and good until something goes wrong with DNMT3A, causing bone marrow to turn into abnormal blood cells. This is a primary event leading to various forms of leukemia, as well as other cancers.
Toxic treatments
Most cancer drugs are designed to selectively kill cancer cells while leaving healthy cells alone. But this is extremely challenging, which is why so many of them are extremely toxic. Current leukemia treatments, like Decitabine, bind to DNMT3A in a way that disables it, thereby slowing the progression of the disease. They do this by clogging up the enzymes active site (essentially, its business end) to prevent it from carrying out its function.
Unfortunately, DNMT3As active site is virtually identical to that of DNMT1, so the drug shuts down epigenetic regulation in all of the patients 30 to 40 trillion cells. This leads to one of the drug industrys biggest bottle necks: off-target toxicity.
Clogging a proteins active site is a straightforward way to take it offline. Thats why the active site is often the first place drug designers look when designing new drugs, Reich explained. However, about eight years ago he decided to investigate compounds that could bind to other sites in an effort to avoid off-target effects.
Working together
As the group was investigating DNMT3A, they noticed something peculiar. While most of these epigenetic-related enzymes work on their own, DNMT3A always formed complexes, either with itself or with partner proteins. These complexes can involve more than 60 different partners, and interestingly, they act as homing devices to direct DNMT3A to control particular genes.
Early work in the Reich lab, led by former graduate student Celeste Holz-Schietinger, showed that disrupting the complex through mutations did not interfere with its ability to add chemical markers to the DNA. However, the DNMT3A behaved differently when it was on its own or in a simple pair; it wasnt to stay on the DNA and mark one site after another, which is essential for its normal cellular function.
Around the same time, the New England Journal of Medicine ran a deep dive into the mutations present in leukemia patients. The authors of that study discovered that the most frequent mutations in acute myeloid leukemia patients are in the DNMT3A gene. Surprisingly, Holz-Schietinger had studied the exact same mutations. The team now had a direct link between DNMT3A and the epigenetic changes leading to acute myeloid leukemia.
Discovering a new treatment
Reich and his group became interested in identifying drugs that could interfere with the formation of DNMT3A complexes that occur in cancer cells. They obtained a chemical library containing 1,500 previously studied drugs and identified two that disrupt DNMT3A interactions with partner proteins (protein-protein inhibitors, or PPIs).
Whats more, these two drugs do not bind to the proteins active site, so they dont affect the DNMT1 at work in all of the bodys other cells. This selectivity is exactly what I was hoping to discover with the students on this project, Reich said.
Pyrazolone (compound 1) and pyridazine (compound 2) disrupt the activity of DNMT3A by binding to a non-active site on the enzyme.
Photo Credit: JONATHAN SANDOVAL ET AL.
These drugs are more than merely a potential breakthrough in leukemia treatment. They are a completely new class of drugs: protein-protein inhibitors that target a part of the enzyme away from its active site. An allosteric PPI has never been done before, at least not for an epigenetic drug target, Reich said. It really put a smile on my face when we got the result.
This achievement is no mean feat. Developing small molecules that disrupt protein-protein interactions has proven challenging, noted lead author Jonathan Sandoval of UC San Francisco, a former doctoral student in Reichs lab. These are the first reported inhibitors of DNMT3A that disrupt protein-protein interactions.
The two compounds the team identified have already been used clinically for other diseases. This eliminates a lot of cost, testing and bureaucracy involved in developing them into leukemia therapies. In fact, oncologists could prescribe these drugs to patients off label right now.
Building on success
Theres still more to understand about this new approach, though. The team wants to learn more about how protein-protein inhibitors affect DNMT3A complexes in healthy bone marrow cells. Reich is collaborating with UC Santa Barbara chemistry professor Tom Pettus and a joint doctoral student of theirs, Ivan Hernandez. We are making changes in the drugs to see if we can improve the selectivity and potency even more, Reich said.
Theres also more to learn about the drugs long-term effects. Because the compounds work directly on the enzymes, they might not change the underlying mutations causing the cancer. This caveat affects how doctors can use these drugs. One approach is that a patient would continue to receive low doses, Reich said. Alternatively, our approach could be used with other treatments, perhaps to bring the tumor burden down to a point where stopping treatment is an option.
Reich also admits the team has yet to learn what effect the PPIs have on bone marrow differentiation in the long term. Theyre curious if the drugs can elicit some type of cellular memory that could mitigate problems at the epigenetic or genetic level.
That said, Reich is buoyed by their discovery. By not targeting DNMT3As active site, we are already leagues beyond the currently used drug, Decitabine, which is definitely cytotoxic, he said, adding that this type of approach could be tailored to other cancers as well.
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A New Kind of Chemo | The UCSB Current - The UCSB Current