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BLA Includes Substantial Body of Data from Pivotal Phase 3 and Ongoing Phase 1/2 Studies

If Approved, Would Be 1st Gene Therapy in U.S. for Treatment of Severe Hemophilia A

SAN RAFAEL, Calif., Sept. 29, 2022 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced today that the Company resubmitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for its investigational AAV gene therapy, valoctocogene roxaparvovec, for adults with severe hemophilia A. The resubmission incorporates the Company's response to the FDA Complete Response (CR) Letter for valoctocogene roxaparvovec gene therapy issued on August 18, 2020, and subsequent feedback, including two-year outcomes from the global GENEr8-1 Phase 3 study and supportive data from five years of follow-up from the ongoing Phase 1/2 dose escalation study.

BioMarin anticipates an FDA response by the end of October on whether the BLA resubmission is complete and acceptable for review. 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. If approved, valoctocogene roxaparvovec would be the first commercially-available gene therapy in the U.S. for the treatment of severe hemophilia A.

The FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to valoctocogene roxaparvovec in March 2021. RMAT is an expedited program intended to facilitate development and review of regenerative medicine therapies, such as valoctocogene roxaparvovec, that are expected to address an unmet medical need in patients with serious conditions. The RMAT designation is complementary to Breakthrough Therapy Designation, which the Company received for valoctocogene roxaparvovec in 2017.

In addition to the RMAT Designation and Breakthrough Therapy Designation, BioMarin's valoctocogene roxaparvovec also received orphan drug designation from the EMA and FDA for the treatment of severe hemophilia A. Orphan drug designation is reserved for medicines treating rare, life-threatening or chronically debilitating diseases. The European Commission (EC) granted conditional marketing authorization to valoctocogene roxaparvovec gene therapy under the brand name ROCTAVIAN on August 24, 2022 and endorsed the recommendation from the European Medicines Agency (EMA) to maintain orphan drug designation, thereby granting a 10-year period of market exclusivity in the European Union.

"We are pleased to reach this point in the development program for valoctocogene roxaparvovec and look forward to working with the FDA with the goal of bringing a potentially transformative therapy to people with severe hemophilia A in the United States," said Hank Fuchs, M.D., President of Worldwide Research and Development at BioMarin. "This large and robust data set provided in this BLA resubmission shows an encouraging efficacy profile. We remain committed to sharing these data with the public, along with even longer-term data generated through our ongoing clinical trials and any post-approval studies, to further our understanding of AAV gene therapy in severe hemophilia A and of gene therapies more broadly."

The resubmission includes a substantial body of data from the valoctocogene roxaparvovec clinical development program, the most extensively studied gene therapy for severe 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 package included supportive evidence from five years of follow-up from the 6e13 vg/kg dose cohort in the ongoing Phase 1/2 dose escalation study. The resubmission alsoincludesaproposedlong-term extension studyfollowingall clinicaltrialparticipantsfor up to 15years, as well astwo post-approval registry studies.

Robust Clinical Program

BioMarin has multiple clinical studies underway in its comprehensive gene therapy program for the treatment of severe 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 3, single arm, open-label study to evaluate the efficacy and safety of valoctocogene roxaparvovec at a dose of 6e13 vg/kg with prophylactic corticosteroids in people with severe hemophilia A (Study 270-303). Also ongoing are a Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene roxaparvovec in people with severe hemophilia A with pre-existing AAV5 antibodies (Study 270-203) and a Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene roxaparvovec in people with severe hemophilia A with active or prior Factor VIII inhibitors (Study 270-205).

Safety Summary

Overall, to date, a single 6e13 vg/kg dose of valoctocogene roxaparvovec has been well tolerated with no delayed-onset treatment related adverse events. The most common adverse events (AE) associated with valoctocogene roxaparvovec have 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, a laboratory test of liver function, has remained the most common adverse drug reaction. Other adverse reactions have included aspartate aminotransferase (AST) elevation (101 participants, 63%), nausea (55 participants, 34%), headache (54 participants, 34%), and fatigue (44 participants, 28%). No participants have developed inhibitors to Factor VIII, thromboembolic events or malignancy associated with valoctocogene roxaparvovec.

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 injections or shots 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.

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 visitwww.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: BioMarin anticipating an FDA response by the end of October on whether the BLA resubmission is complete and acceptable for review, BioMarin's expectations regarding the duration of the review procedure, valoctocogene roxaparvovec being the first commercially-available gene therapy in the U.S. for the treatment of severe hemophilia A, if approved, BioMarin's commitment to sharing longer-term data generated through its ongoing clinical trials and any post-approval studies. 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 valoctocogene roxaparvovec; additional data from the continuation of the clinical trials of valoctocogene roxaparvovec, 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 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 valoctocogene roxaparvovec for the clinical trials and commercially; 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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BioMarin Pharmaceutical Inc.

BioMarin Pharmaceutical Inc.

(415) 455-7558

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SOURCE BioMarin Pharmaceutical Inc.

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BioMarin Resubmits Biologics License Application (BLA) for Valoctocogene Roxaparvovec AAV Gene Therapy for Severe Hemophilia A to the FDA - PR...

Of the 1.5 million people living with lupus in the United States, 90% are women. This disease turns the bodys immune system against itself, potentially causing extreme pain, fatigue, difficulty thinking clearly, and cardiovascular disease.

Officially known as systemic lupus erythematosus, lupus is distinct among autoimmune diseases in the way circulating antibodies proteins that when functioning properly help to protect against disease react against DNA, the bodys instructions for building cells and passing traits from parents to children.

Drs. Peter M. Glazer and James Hansen discovered that one specific lupus antibody, known as 3E10, can penetrate cancer cells and make them sensitive to and killed by standard radiation and chemotherapy methods. Notably, this technique has shown significant effectiveness in killing cancer cells with DNA repair deficiencies, such as those with mutations in the tumor-suppressing BRCA2 gene that lead to higher rates of breast and ovarian cancer.

Now, nearly a decade since this discovery and with he help of a grant from Womens Health Research at Yale, researchers are close to advancing a treatment toward clinical trials while learning more about how this lupus antibody penetrates and kills cancer cells.

This discovery has unlocked promising new pathways for treatment of BRCA-related cancers that affect so many women around the world, said Glazer, the Robert E. Hunter Professor of Therapeutic Radiology, professor of genetics, and chair of the Department of Therapeutic Radiology. We have learned a great deal about how 3E10 interacts with DNA, and we continue to explore how this knowledge could be used to create therapies for other types of difficult-to-treat cancers.

Dr. Glazer and his colleague Dr. James E. Hansen, associate professor of therapeutic radiology, licensed the rights for their antibody discovery to a company, Patrys, Ltd., that has validated the work and developed 3E10 as a cancer therapy for human use. An earlier human study in Switzerland attempting to use 3E10 as a vaccine for lupus had already demonstrated that it is nontoxic. Phase 1 clinical trials could begin as early as next year, Dr. Glazer said, likely for patients with cancers related to mutations of BRCA1/2 genes or of another tumor suppressing gene known as PTEN.

This is very promising, Glazer said. I think it will be important to identify the right subgroup of patients for which this is most effective.

After publishing the results, Dr. Glazer and his colleagues leveraged the data to obtain a pair of large multiyear grants from the National Institutes of Health. With this funding and the help of Yale graduate student Audrey Turchick, the team has discovered that inside a cancer cell, 3E10 sticks to a DNA repair protein called RAD51. This causes the lethality for cancer cells that are deficient in BRCA1 and BRCA2 genes by preventing the cells from conducting the routine DNA repair necessary to sustain themselves.

With ongoing funding from the NIH, Dr. Glazers team, including structural biologist Dr. Franziska Bleichert, is building on these findings to enhance the anti-cancer potency of 3E10 and develop therapeutic strategies by identifying ways for the antibody to stick more strongly to RAD51.

In addition, an MD/PhD student in the lab, Elias Quijano, helped identify the capacity of 3E10 to bind with RNA a type of molecule used to carry out DNA instructions and carry RNA into a cancer cell, potentially with instructions that can kill the cell. Quijano and Drs. Glazer, Stephen Squinto, and Bruce Turner co-founded Gennao Bio, a company seeking to develop this method of cancer-fighting therapy.

This was an unexpected discovery that turns out may be very useful, Glazer said. We have some data showing the efficacy of this method against tumors in a laboratory model. It is a versatile platform, because it can deliver different types of RNA in a similar way to how the COVID-19 mRNA vaccines work.

The research continues, thanks in large part to the investment WHRY made so many years ago.

I think that type of funding is extremely valuable, Glazer said of his WHRY grant. It allowed us to do the sets of exploratory experiments we needed to do to demonstrate our approach was viable and get the larger grants. We showed this is feasible, this is promising.

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Fighting Breast and Ovarian Cancer With a Lupus Antibody - Yale School of Medicine

What if people who need regular injections to treat chronic diseases could instead take a pill that precisely controls the production of the right proteins and hormones inside their bodies?

A promising new gene therapy technology that aims to turn the human body into such a medicine-making factory could, if successful, push the boundaries of medicine and make certain treatments much more convenient and potentially less expensive.

MeiraGTx, a gene therapy company, is working to make this futuristic vision a reality.

The British company already develops traditional gene therapy, which replaces missing or broken genes in people with inherited disorders. That side of business is booming, and the firm just opened a manufacturing facility in Ireland that could employ up to 300 people.

But MeiraGTx is also making strides in what it calls gene regulation therapy, which it says could help control much more precisely the genes that instruct cells to make or stop making certain proteins.

Its no easy feat and the technology would take years to bring to market, but it has the potential to make gene therapy even more life-changing for patients.

When you put a gene or replace a missing gene into a cell today, you put the gene in and it is expressed for the rest of that cell's life, MeiraGTx CEO Alexandria Forbes told Euronews Next.

Its very hard to build a gene therapy that is switched on and off when it's needed, particularly in a disease. And what's even harder is to create a gene therapy which is switched on or off when you, the doctor or patient, want it to be.

MeiraGTx says it has developed a switch of this sort that could help make patients lives much easier: rather than injecting synthetic hormones and proteins into them, it could insert the gene that tells their body to make those, while a pill activates the gene only when the specific protein or hormone is needed.

Take Epogen (epoetin alfa) a well-known injectable drug that helps create more red blood cells when you're anaemic, with kidney disease or you're being treated for cancer.

What you can do, for example, is put the gene for Epogen into the body, into the muscle, and have a switching system that only allows your body to make the natural form of Epogen when you take a pill, Forbes explained.

So we don't have to make unnatural forms of these drugs because what we're doing is we're providing the body with the message to make the drug, and that message is only switched on when we give the body a pill.

MeiraGTx told Euronews Next it has already tested this technology in animals and is hoping to start trialling it on humans in 2023.

If successful, it could have huge, broad-ranging implications, Forbes said.

This isn't only for gene therapy. It allows you to control cell therapy, immuno-oncology, antibody production anything that is a protein or peptide that can be made by the body.

Many traditional drugs involve making a protein outside the body, like insulin to fight diabetes or antibodies to fight cancer. That protein is manufactured in cells or bacteria outside the body and then is injected into the body on a regular basis as a treatment.

Gene therapy, by contrast, involves putting into the body a gene encoding the therapeutic protein: rather than injecting the protein over and over and over again, you put the gene for the protein into the person and the protein is made in the person's body.

Gene therapies are typically used against inherited diseases, where a gene is missing or not functioning well. Gene therapy inserts into a patient a perfect copy of that gene to replace the missing or broken one.

So our drugs are actually genes - DNA - and they're delivered into the body by being encapsulated in viral proteins which act like a little spaceship and insert those genes that we've made into the appropriate cell, Forbes said.

This type of technology requires a very specific manufacturing process to ensure through rigorous testing that every single batch of these genes always has the same identical quality, safety and potency, she explained.

MeiraGTx controls this manufacturing in-house and has just inaugurated a new commercial-scale facility in Shannon, Ireland, thats set to employ 100 people initially and up to 300 as business grows.

The company hopes the new site will help accelerate its development and delivery of gene therapy treatments to patients with an initial focus on rare inherited disorders affecting the eye, central nervous system, and salivary gland.

But MeiraGTx argues that adding a switch to be able to fine-tune gene therapy has the potential to considerably expand this range to also tackle non-hereditary diseases that affect hundreds of millions of people worldwide, including heart disease, cancer and diabetes.

It says it could even help fight obesity, arguably one of the biggest global health challenges.

The causes behind obesity are complex and multi-faceted, genetic factors mean some people are more at risk than others, and the hormones that control appetite are very unstable and short-lasting.

A class of injectable diabetes drugs currently proving highly effective against obesity are GLP- 1 drugs, which help control blood sugar levels. But they work better in combination with several other gut peptides that affect metabolism.

The challenge, once again, is to precisely control the levels of these peptides.

MeiraGTx claims its technology may someday allow those hoping to lose weight to switch on the combination of genes that produce the hormones and peptides controlling their appetite, blood sugar levels and ultimately their fat.

We can now put the genes for three natural gut peptides that control metabolism into the body and give a pill when we want those drugs, Forbes said.

In theory, if clinical trials go well, the potential applications for other diseases are dizzying and they directly raise the question of extending human life expectancy. But that should not be the priority right now, Forbes said.

I think that currently we have really big problems with obesity, with Alzheimer's, with ways of living that mean we are young and living poorly, she said.

And these sorts of products can be used to help address those really large indications, not just the rare gene replacements.

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This gene therapy company is testing new tech to 'switch off' diabetes and obesity with a pill - Euronews

Tenaya Therapeutics, Inc.

Encore Presentation of Lead Gene Therapy TN-201 Preclinical Data to be Featured in Late-Breaking Trials Session

SOUTH SAN FRANCISCO, Calif., Sept. 29, 2022 (GLOBE NEWSWIRE) -- Tenaya Therapeutics, Inc. (NASDAQ: TNYA), a clinical-stage biotechnology company with a mission to discover, develop and deliver potentially curative therapies that address the underlying causes of heart disease, announced today that it is scheduled to participate in the Hypertrophic Cardiomyopathy Medical Societys (HCMS) inaugural 2022 Scientific Sessions taking place September 30, 2022, virtually and in National Harbor, MD.

Milind Desai, M.D., MBA, Director of the Center for Hypertrophic Cardiomyopathy and Director of Clinical Operations, Heart, Vascular & Thoracic Institute at Cleveland Clinicwill present preclinical data for Tenayas TN-201, a gene therapy candidate intended to correct the underlying genetic cause of HCM, MYBPC3 gene mutations. Variants in the MYBPC3 gene are the most common genetic cause of HCM, believed to contribute to approximately 20 percent of all HCM cases. Whit Tingley, M.D., Ph.D., Tenayas Chief Medical Officer, will join an industry panel to discuss advances in genetic therapies and its potential in individuals with HCM.

Details of Tenayas participation are as follows:

September 30, 2022Time: 10:50 a.m. 11:10 a.m. ETSession: Late-Breaking TrialsTitle: Early Breaking Trial 3 Gene Therapy Candidate for Hypertrophic Cardiomyopathy Patients with MYBPC3 MutationPresenter: Dr. Milind Desai, Cleveland Clinic

Time: 12:15 p.m. 12:55 p.m. ETSession: Industry RoundtableSpeaker: Whit Tingley, M.D., Ph.D., Tenaya Therapeutics

The HCMS Sessions are intended to highlight the history, major developments and emerging concepts in hypertrophic cardiomyopathy (HCM), including learning about genetic forms of HCM and emerging treatments. A copy of the presentation will be posted to Tenayas website. To view full event programming, please visit the HCMS website.

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About TN-201 for MYBPC3-associated Hypertrophic CardiomyopathyTN-201 is an adeno-associated virus-based gene therapy being developed to treat hypertrophic cardiomyopathy (HCM) due to disease-causing variants in the Myosin Binding Protein C3 (MYBPC3) gene. HCM is a chronic, progressive condition in which the walls of the left ventricle become significantly thickened, leading to abnormal heart rhythms, cardiac dysfunction, heart failure and increased risk of sudden cardiac death, accompanied by symptoms such as shortness of breath, fainting and palpitations. Variants in MYBPC3 are the most common genetic cause of HCM, estimated to represent approximately 20 percent of the overall HCM population and to affect approximately 115,000 patients in the United States alone. In preclinical studies, following a one-time injection of TN-201 in a severely diseased knock-out model of MYBPC3-associated HCM, a reversal of cardiac dysfunction and improvement in survival was observed. Tenaya plans to submit an Investigational New Drug application for TN-201 to the U.S. Food and Drug Administration in the second half of this year.

AboutTenaya TherapeuticsTenaya Therapeuticsis a clinical-stage biotechnology company committed to a bold mission: to discover, develop and deliver curative therapies that address the underlying drivers of heart disease. Founded by leading cardiovascular scientists fromGladstone Institutesand theUniversity of Texas Southwestern Medical Center, Tenaya is developing therapies for rare genetic cardiovascular disorders as well as for more prevalent heart conditions through three distinct but interrelated product platforms: Gene Therapy, Cellular Regeneration and Precision Medicine. For more information, visitwww.tenayatherapeutics.com.

InvestorsMichelle CorralTenaya TherapeuticsIR@tenayathera.com

MediaWendy RyanTenBridge Communicationswendy@tenbridgecommunications.com

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Tenaya Therapeutics to Participate in Inaugural Hypertrophic Cardiomyopathy Medical Societys 2022 Scientific Sessions - Yahoo Finance

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Demographic data, imaging results, biomarkers of study participants help determine risk

When people participate in studies of aging, they often want to know what their individual risks of developing dementia from Alzheimers disease are. Washington University researchers have developed an algorithm that can help provide them with information about what their risks may be.

Using demographic information, brain imaging test results and genetic biomarkers, researchers at Washington University School of Medicine in St. Louis have developed an algorithm that can help provide people who volunteer for studies of aging with information about the risk each faces of developing dementia due to Alzheimers disease.

Published Sept. 30 in the Journal of Alzheimers and Dementia, the findings from researchers with the universitys Knight Alzheimer Disease Research Center (Knight ADRC) may help study participants learn more about what their futures hold, in terms of risk for dementia related to Alzheimers. The research also eventually may help others determine whether they face risk of the debilitating disorder.

Thousands of adults have volunteered for studies at Alzheimers research centers around the country, said principal investigator Sarah M. Hartz, MD, PhD, an associate professor of psychiatry. They come back and undergo tests year after year, including PET (positron emission tomography) and MRI scans, blood draws, cognitive tests, and lumbar punctures that measure proteins in spinal fluid. Those studies advance the overall understanding of Alzheimers disease, but they give participants relatively little information about their own risk. This algorithm is a way to help illuminate that information and to let individuals know whether they have a significant risk for dementia related to Alzheimers disease.

Hartz and co-principal investigator Jessica Mozersky, PhD, an assistant professor of medicine in the universitys Bioethics Research Center, examined the various factors that contribute to Alzheimers dementia, and they used that information to create an algorithm aimed at estimating an individuals absolute risk of developing early symptoms of dementia from Alzheimers. They developed the algorithm for use in a clinical trial to learn whether they could help volunteers participating in aging studies at the Knight ADRC better understand what biomarkers for disease they might have, and whether researchers then could evaluate participants eventual outcomes.

We developed the algorithm because study participants wanted more than just a report of whether their test results were normal or abnormal, Mozersky said. Weve performed studies with people who receive results reporting elevated amyloid, for example. They tell us, You know what I really want to know? My risk.

The website with the risk algorithm uses demographic information, along with specific test results, to help study volunteers better understand their risk.

Over the years, there have been ethical debates about how much information to release to people who participate in such studies because there arent yet any treatments to prevent or cure Alzheimers dementia. Further, how well various biomarkers predict the problem in people who have no symptoms of the disorder has not been well studied.

We developed the algorithm so that we can tell participants what currently is known in a meaningful way, and so that the algorithm can be updated easily as new research or data emerges, Hartz said.

The algorithm, accessible on the Knight ADRCs website at https://alzheimerdementiacalculator.wustl.edu/, provides greater detail for researchers and individuals who want to learn more about Alzheimers dementia risk. For example, a 69-year-old woman who went to college and had a parent with dementia from Alzheimers has about a 6% risk of developing the early symptoms of Alzheimers dementia in the next five years. That, of course, means she also has a 94% chance of not developing dementia from Alzheimers in the next five years.

The algorithm incorporates amyloid PET scan results and brain hippocampal volumes a smaller hippocampus often suggests an increased risk for damage related to Alzheimers dementia to show how risk changes when such extra information is known. If that same 69-year-old woman also had a PET scan revealing elevated levels of amyloid, and a decrease in hippocampal volume, her risk would rise to about 33%.

Still, age is the biggest demographic risk factor, Hartz said.

If the woman was 85 years old rather than 69, her risk of developing dementia from Alzheimers in the next five years would climb from about 6% to about 32%, even without knowing any biomarker-related results.

The researchers also looked at a gene known to influence risk of Alzheimers dementia. Risk increases significantly depending on the type of APOE gene a person has. But when the researchers included APOE genotype in their model, they found it didnt tell them anything that data from imaging tests hadnt already revealed. This is likely because brain changes seen on imaging tests occur in part because of the APOE gene.

Hartz and Mozersky are continuing their work to improve the ability to predict Alzheimers dementia risk based on these variables. They have grants totaling more than $5 million from the National Institute on Aging to run a clinical trial to better understand the impact of providing these risk assessments to people participating in research and to validate their algorithm in larger samples.

Researchers worry about how such information will affect study participants, Hartz said. We want to learn how the information might affect them and whether providing this sort of information actually may help them.

Hartz SM, Mozersky J, Schindler SE, Linnenbringer E, Wang J, Gordon BA, Raji CA, Moulder KL, West T, Benzinger TLS, Cruchaga C, Hassenstab JJ, Bierut LJ, Xiong C, Morris JC. A flexible modeling approach for biomarker-based computation of absolute risk of Alzheimer disease dementia. The Journal of Alzheimers and Dementia, Sept. 30, 2022.

This work is supported by the National Institute on Aging and the National Cancer Institute of the National Institutes of Health (NIH). Grant numbers include R01 AG065234, P01 AG026276, 5P01 AG003991, P30 AG066444, 1UL1 TR002345, R44 AG059489, R01 AG07094 and U01 AG016976, with additional grants that provide funding for the Alzheimers Disease Research Centers involved in these studies (for a complete list, refer to the paper). Other funding sources include BrightFocus CA2016636, the Gerald and Henrietta Rauenhorst Foundation and the Alzheimers Drug Discovery Foundation.

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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Risk of Alzheimer's dementia may be predicted with help of new tool Washington University School of Medicine in St. Louis - Washington University...

9/27/2022

PITTSBURGH How a tiny marine invertebrate distinguishes its own cells from competitors bears striking similarities to the human immune system, according to a new study led by University of Pittsburgh School of Medicine researchers.

The findings, published now in Proceedings of the National Academy of Sciences, suggest that the building blocks of our immune system evolved much earlier than previously thought and could help improve understanding of transplant rejection, one day guiding development of new immunotherapies.

For decades, researchers have wondered whether self-recognition in a marine creature called Hydractinia symbiolongicarpus was akin to the processes that control whether a piece of skin can be successfully grafted from one person to another, said senior author Matthew Nictora, Ph.D., assistant professor of surgery and immunology at the Thomas E. Starzl Transplantation Institute. Our study shows for the first time that a special group of proteins called the immunoglobulin superfamily which are important for adaptive immunity in mammals and other vertebrates are found in such a distantly- related animal.

Hydractinia symbiolongicarpus belongs to the same group as jellyfish, corals and sea anemones. With tube-like bodies adorned with tentacles for catching prey, the animals look a bit like tiny versions of wacky inflatable tube men dancing outside of a car dealership. They grow as colonies encrusting the shells of hermit crabs like lichen on a rock.

As colonies grow and compete for space on crab shells, they often bump into each other, explained Nicotra, who is also associate director of the Center for Evolutionary Biology and Medicine in Pitts School of Medicine. If two colonies recognize each other as self, they fuse together. But if they identify each other as non-self, the colonies fight by releasing harpoon-like structures from special cells.

Nicotra and his colleagues previously identified two genes called Alr1 and Alr2 involved in Hydractinias fuse-or-fight system, but they predicted that there was more to the story.

If you imagine that the genome of the animal is spread out in front of us, we had a flashlight on these two little points, but we didnt know what else was there, said Nicotra. Now weve been able to sequence the whole genome and illuminate the whole region around these genes. It turns out that Alr1 and Alr2 are part of a huge family of genes.

In the new study, the researchers identified and sequenced 41 Alr genes, which form a complex that likely controls self- versus non-self-recognition in Hydractinia.

Next, the team wanted to see how the proteins that Alr genes encode compared to those found in vertebrates. Until recently, it was nearly impossible to accurately predict the 3D structure of proteins based on a genes sequence, but in 2021, the release of a tool called AlphaFold changed that.

Using this tool, the researchers compared the structure of Alr proteins to immunoglobulin superfamily (IgSF) proteins, an important group that includes antibodies and receptors on B and T cells of the immune system. IgSF proteins have three characteristic regions, or domains, including the V-set domain.

The V stands for variable, said Nicotra. When a B or T cell becomes specialized to fight a particular pathogen, V-set domains are rearranged to make a variable sequence, which the immune system uses to recognize specific pathogens or cells.

Nicotra was surprised to find that the domains in Alr proteins had 3D structures remarkably similar to V-set domains, even though they lacked telltale features usually found in IgSF proteins.

Unmistakably, these are V-set domains, he explained. Theyre just very, very strange.

Until now, it was thought that V-set domains had arisen in the branch of the animal kingdom known as Bilateria. This group originated about 540 million years ago and includes most familiar animals, including mammals, insects, fish, mollusks and all others with right and left sides.

The finding of V-set domains in Hydractinia which is part of a group that appeared earlier in the evolution of animals suggests that V-set domains arose further back in the evolutionary tree than previously thought.

Several Alr proteins also had signatures associated with immune signaling in other animals, another clue that this protein complex is involved in self-recognition.

We know lots about the immune systems of mammals and other vertebrates, but weve only scratched the surface of immunity in invertebrates, said Nicotra. We think that a better understanding of immune signaling in organisms like Hydractinia could ultimately point to alternative ways to manipulate those signaling pathways in patients with transplanted organs.

Other authors who contributed to the study were Aidan L. Huene, Ph.D., Steven M. Sanders, Ph.D., Zhiwei Ma, B.S., Manuel H. Michaca, B.S., all of Pitt; Anh-Dao Nguyen, Sergey Koren, Ph.D., Adam M. Phillippy, Ph.D., and Andreas D. Baxevanis, Ph.D., all of the National Human Genome Research Institute (NHGRI); James C. Mullikin, Ph.D., of the NHGRI and the National Institutes of Health (NIH); and Christine E. Schnitzler, Ph.D., of the University of Florida.

This research was funded by the National Science Foundation (1557339 and 1923259) and the NIH (ZIA HG000140, ZIA HG200398 andT32 AI074490).

PHOTO DETAILS: (click images for high-res versions)

CREDIT: Matthew Nictora

CAPTION:Matthew Nictora, Ph.D., assistant professor of surgery and immunology at the University of Pittsburgh Thomas E. Starzl Transplantation Institute and associate director of the Center for Evolutionary Biology and Medicine.

Right:

PHOTO DETAILS: (click images for high-res versions)

CREDIT:Huene, A. L. et al., PNAS, 2022

CAPTION:When compatible Hydractinia symbiolongicarpus colonies recognize each other as self, via Alr genes, they fuse together.

Bottom left:

PHOTO DETAILS: (click images for high-res versions)

CREDIT:Huene, A. L. et al., PNAS, 2022

CAPTION:When incompatible Hydractinia symbiolongicarpus colonies identify each other as non-self via Alr genes, they fight. As a result, the colony on the left has started to grow over the colony on the right.

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Tiny Sea Creature's Genes Shed Light on Evolution of Immunity - UPMC

We live in a time where the rate of medical and superlative scientific advances is accelerating by more than 1,300% since 1985, according to one recent estimate. With so many unprecedented, transformative breakthroughs happening, forecasting which one will be awarded top research honors isnt getting any easier. But with the naming of this years Nobels fast approaching the medicine award will be announced on Oct. 3, physics on Oct. 4, chemistry on Oct. 5 prize prognosticating for the World Series of Science is once again in full swing.

Public polls, tallies of other elite awards, and journal citations have helped betting-minded people collect the names of whos most likely in the running. The shortlist includes researchers who elucidated how cells make energy, those who discovered the chemical chatter of bacteria, many of the brilliant minds who shepherded us into the era of the genome, and most prominently, the pioneers behind the mRNA Covid vaccines.

How Nobels are decided is a matter of grave secrecy records of who nominated and voted for whom are sealed for 50 years making forecasting new winners even more of a challenge. Still, some experts have developed systems that do a decent job.

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David Pendlebury of Clarivate looks at how often a scientists key papers are cited by peers and awarded so-called predictive prizes like the Lasker or Gairdner awards. Each year he comes up with a group of Citation Laureates, and since 2002, 64 of his picks have gone on to receive a Nobel Prize.

Using that strategy, Pendlebury thinks the medicine Nobel could go to the researchers who discovered that different kinds of malformed protein aggregates, in different cell types, underlie a number of neurological diseases including Parkinsons, ALS, and frontotemporal dementia. Virginia Man-Yee Lee of the University of Pennsylvania published a seminal Science paper in 2006, which has now been cited more than 4,000 times. When Pendlebury dug into those citations, he noticed that researchers almost always mentioned that paper in tandem with a very similar but much lower-profile study published a few months later by Masato Hasegawa of the Tokyo Metropolitan Institute of Medical Science.

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This phenomenon of simultaneous independent discovery is very common in science, more than I think people understand, Pendlebury told STAT. So the citations tend to go to the first mover, but they are really a pair. And since their papers, the field has blossomed in many directions, because it was a big step forward for trying to find therapies for these kinds of diseases.

For similar reasons, Pendlebury also has his eyes on two scientists who made groundbreaking discoveries about the genetic basis of disease: Mary-Claire King of the University of Washington for uncovering the role of mutations in the BRCA genes in breast and ovarian cancers, which revolutionized cancer screening, and Stuart Orkin of Harvard Medical School for identifying the genetic changes behind the various types of thalassemia leading to promising new gene-based therapies for inherited blood disorders.

Another thing that Pendlebury takes into account in his predictions is periodicity. The committees tend to take turns rewarding different disciplines; neuroscience, cancer, or infectious-disease discoveries win every decade or so. For the medicine prize, periodicity also shows up between discoveries of basic molecular biology and ones that lead to people actually being treated or cured of the things that ail them.

In the past decade, the medicine prize has more times than not gone back to basics. In 2013, it went to intra-cell transportation, in 2016 to the process of cellular self-destruction, in 2017 to the genetic clocks that control circadian rhythms, in 2019 to how cells sense and adapt to oxygen availability, and last year to how cells sense temperature and touch. Prizes with a more clinical focus have been awarded in 2015, (roundworm and malaria therapy), 2018 (immuno-oncolgy), and 2020 (hepatitis C).

Thats just one reason why cancer biologist Jason Sheltzer of the Yale School of Medicine is so bullish on this years medicine prize going to Katalin Karik of BioNTech and Drew Weissman of Penn Medicine for taking messenger RNA, or mRNA, on a 40-year journey from an obscure corner of cell biology to a pandemic-halting vaccine technology. Its such a radical change in vaccine technology, at this point billions of doses have been given, and it has incontrovertibly saved millions of people from dying of Covid, Sheltzer said. To me, its just a slam dunk.Sheltzer has been making Nobel predictions on Twitter since 2016 and correctly chose immuno-oncology pioneer James Allison for the 2018 medicine prize. His methodology is a bit more straightforward; he tracks winners of seven major science prizes the Horwitz, Wolf, Albany, Shaw, and Breakthrough Prize, in addition to the Lasker and Gairdner because the data show that theres only so long the Nobel Committee can ignore people whove won at least two. Karik and Weissman have won five of the six. Its not a question of if it will happen, its just a question of when, he said.

Hes less certain about the chemistry prize. Might David Allis of Rockefeller and Michael Grunstein of UCLA finally get the call to Stockholm? They discovered one way genes are activated through proteins called histones for which they shared a 2018 Lasker and a 2016 Gruber Prize in genetics. The control of gene expression, otherwise known as epigenetics, is a fundamental process in cell biology that researchers and industry are just beginning to harness to treat human disease. But the last time epigenetics got the Nobel nod was in 2006, with Roger Kornbergs win in chemistry for his work unlocking the molecular mystery of how RNA transcripts are assembled.

Its been nearly 20 years since that field has been recognized with a prize, so you could make the case that its very much due this year, said Sheltzer.

Thats even more true for DNA sequencing, which was last awarded a Nobel in 1980 to Wally Gilbert and Frederick Sanger for their work developing the first (eponymously named) method for determining the order of base pairs in nucleic acids. But so much has happened in the field since then, that the slate of worthy sequencing successors is practically overflowing.

Should it go to the scientists who gave us the first-ever draft of the human genome, and if so, which ones? Hundreds of researchers all over the world aided in the effort, which was a feat of engineering and mass production as much as scientific innovation. If the chemistry or medicine Nobel committees takes a cue from their physics counterpart, who in 2017 honored the organizers of the international project that discovered gravitational waves, then the top contenders would likely be the Human Genome Projects cat-herder-in-chief and recently departed director of the National Institutes of Health, Francis Collins, and Eric Lander, whose lab at the Broad Institute churned out much of the draft sequence. A third might be Craig Venter, whose competing private sequencing push at Celera raced the public effort to a hotly contested draw.

Perhaps a more deserving trio would be Marvin Caruthers of the University of Colorado, Leroy Hood of the Institute for Systems Biology, and Michael Hunkapiller, former CEO of DNA-sequencing behemoth Pacific Biosciences. They invented the technology behind the first automated sequencers, which powered the Human Genome Project (and were Pendleburys pick for the chemistry Nobel in 2019).

Or perhaps the call from Stockholm will go out to David Klenerman and Shankar Balasubramanian of the University of Cambridge, who developed the sequencing-by-synthesis technology that came after the Human Genome Project and is now the workhorse of the modern sequencing era (and for which they won the 2020 Millennium Technology Prize and this years Breakthrough Prize in life sciences). More recent inventions, like the nanopore sequencing technologies that have enabled the construction of the first actually complete human genomes in the last few years are also in the running, but probably a longer shot, despite their obvious contributions to both chemistry and medicine. Thats because the Nobel committees tend to tilt toward true trailblazers and away from those who extend an initial, foundation-laying discovery or insight.

The Human Genome Project, a perennial topic of conversation among Nobel-casters, has inspired even more intrigue than usual this year, following the surprise exit of Eric Lander from his position as White House science adviser in the wake of workplace bullying allegations.

Although the rare Nobel has been awarded to well-known jerks or kooks Kary Mullis, the eccentric inventor of PCR, and James Watson, the dubious co-discoverer of the double-helix structure of DNA (and frequent maker of racist, sexist remarks) come to mind the Royal Swedish Academy of Sciences, which selects the physics and chemistry laureates, and the Nobel Assembly at the Karolinska Institute, which chooses the physiology/medicine winner, tend to steer clear of controversy.

Its hard to find many examples of a Nobel being awarded to someone whos been super controversial, said Sheltzer.

Among Pendleburys picks, the person who skirts closest is perhaps Stephen Quake of Stanford University and the Chan Zuckerberg Initiative, who provided advice to He Jiankui, the Chinese scientist who created the worlds first CRISPR babies. Stanford later cleared Quake of any misconduct. Quake has made important discoveries in microfluidics which led to rapid advances in noninvasive testing and single cell sequencing, and Pendlebury sees him as a favorite for a physics Nobel.

In chemistry, Pendlebury likes another Stanford University engineer, Zhenan Bao, for her paradigm-shifting work in the field of semiconducting polymers making stretchable electronic skin. Hes also got his eye on Daniel Nocera at Harvard University for foundational work illuminating the proton-coupled electron transfer process that powers cells, and the team of Bonnie Bassler from Princeton University and E. Peter Greenberg of the University of Washington for their discovery of quorum sensing a chemical communication system between bacteria.

Besides citations, prediction prizes, and periodicity, Pendlebury is also playing the long game. I pay special attention to papers that are 15, 20, 25, 30 years old, because it usually takes a decade or two for research to be selected by the Nobel Prize Committee, he said.

That might complicate things for one of the leading vote-getters in an online poll for the chemistry Nobel John Jumper of the Alphabet-owned company DeepMind and a 2023 Breakthrough Prize in life sciences winner. His work leading the AlphaFold artificial intelligence program stunned the world two years ago by essentially solving one of biologys most enduring challenges: quickly and accurately predicting the 3D structure of a protein from its amino acid sequence.

Thats why this first-time Nobel forecaster is betting on another top vote-getter for the chemistry prize, Carolyn Bertozzi of Stanford University, who has spent much of her illustrious career devising methods to understand an elusive but critical class of sugar-coated molecules called glycans found on the surface of almost all living cells. Shes been a member of the National Academy of Sciences since 2005 and won the Wolf prize earlier this year, in recognition of founding the field of bioorthogonal chemistry a term Bertozzi coined two decades ago that refers to reactions scientists can perform within living organisms without interfering with their normal functions.

Sticking with dark-horse picks (because, why not), Im going with Yuk Ming Dennis Lo of the Chinese University of Hong Kong for the medicine prize. In 1997, he reported that a growing fetus sheds cell-free DNA into the mothers blood. Ten years later, he found a way to use that DNA to detect the signature abnormalities associated with Down syndrome. Together, these discoveries revolutionized clinical practice of screening for fetal genetic abnormalities, leading to the development of non-invasive prenatal testing now used by millions of people every year. Lo has only just begun to be recognized for that work, winning last years Breakthrough Prize for life sciences and this years Lasker Award for clinical medical research, which was announced on Wednesday. He also founded companies based on this same principle for the early detection of multiple cancers, one of which was acquired by pioneering liquid biopsy giant Grail.

Other crowdsourced efforts to predict Nobel winners arent making a return appearance, including the March Madness-style brackets run for many years by the scientific research honors society Sigma Xi. (Last year saw Bertozzi lose in the finals to Omar Yaghi and Makoto Fujita, pioneers of metal-organic self-assembling structures.) Sigma Xi couldnt be reached for comment, but the change comes amid increasingly loud criticism of the Nobel Prizes, for the way they distort the collaborative nature of the scientific enterprise and overlook many of its important contributors (including many women and people of color).

Even Nobel obsessives like Sheltzer admit those arguments are becoming more compelling. But he likes how, at least for a few days every October, he can count on scientific discoveries splashing across the front page of the New York Times and leading the hour on the nightly news. There are amazing things happening in the scientific world right now, like CRISPR gene editing and immunotherapy for cancer, that I think should really be front-page news much more frequently than they are, said Sheltzer. But Im glad that the Nobel Prize shines a spotlight on them and elevates them into the national consciousness, even if just for a brief period of time.

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Who will get the call from Stockholm? It's time for STAT's 2022 Nobel Prize predictions - STAT

SAN FRANCISCO, Sept. 29, 2022 (GLOBE NEWSWIRE) -- Excision BioTherapeutics, Inc., a clinical-stage biotechnology company developing CRISPR-based therapies intended to cure viral infectious diseases, todayannounced that the California Institute for Regenerative Medicine (CIRM) has awarded Excision a $6.85 million grant to support the clinical development of the EBT-101 program for human immunodeficiency virus type 1 (HIV-1).

Daniel Dornbusch, Chief Executive Officer of Excision, commented, We are honored that CIRM has recognized the potential value of the EBT-101 program and our dual-guide RNA CRISPR approach to developing curative therapies for HIV-1 as well as other serious viral diseases with significant unmet needs. The CIRM grant provides further validation for the EBT-101 clinical trial, which is the first ever to evaluate an in vivo CRISPR-based therapy in an infectious disease. The grant will provide Excision with important funding to advance the trial and potentially demonstrate the safety and efficacy of removing viral DNA from people affected by the HIV pandemic.

Excision recently reported the first participant in the EBT-101 Phase 1/2 clinical trial was dosed in July 2022, with initial findings indicating the therapeutic has been well tolerated to-date. The participant continues to be monitored for safety and is expected to qualify for analytical treatment interruption (ATI) of their background anti-retroviral therapy (ART) in an evaluation of a potential cure.

To date only a handful of people have been cured of HIV/AIDS, so this proposal of using gene editing to eliminate the virus could be transformative, says Maria T. Millan, MD, President and CEO of CIRM. In California alone there are almost 140,000 people living with HIV. HIV infection continues to disproportionately impact marginalized populations, many of whom are unable to access the medications that keep the virus under control. A functional cure for HIV would have an enormous impact on these communities, and others around the world.

About EBT-101EBT-101 is a unique, in vivo CRISPR-based therapeutic designed to cure HIV infections after a single intravenous infusion. EBT-101 employs an adeno-associated virus (AAV) to deliver CRISPR-Cas9 and dual guide RNAs, enabling a multiplex editing approach that simultaneously targets three distinct sites within the HIV genome. This allows for the excision of large portions of the HIV genome, thereby minimizing potential viral escape.

About the EBT-101 Clinical ProgramThe EBT-101 Phase 1/2 trial is an open-label, multi-center single ascending dose study designed to evaluate the safety, tolerability and preliminary efficacy of EBT-101 in approximately nine participants with HIV-1 who are suppressed on antiretroviral therapy. The clinical program is supported by preclinical studies that included positive long-term non-human primate safety data and efficacy data in humanized mice showing the potential to cure HIV when treated with EBT-101. The primary objective of the trial is to assess the safety and tolerability of a single dose of EBT-101 in study participants with undetectable viral load on antiretroviral therapy (ART). Biodistribution, pharmacodynamic, and efficacy assessments will also be conducted. All participants will be assessed for eligibility for an analytical treatment interruption (ATI) of their background ART at Week 12 post EBT-101 administration. Following the initial 48-week follow up period, all participants will be enrolled into a long-term follow up protocol. For more information, see ClinicalTrials.gov identifiers NCT05144386 (Phase 1/2 trial) and NCT05143307 (long-term follow up protocol).

About CIRMAt CIRM, we never forget that we were created by the people of California to accelerate stem cell treatments to patients with unmet medical needs, and act with a sense of urgency to succeed in that mission.To meet this challenge, our team of highly trained and experienced professionals actively partners with both academia and industry in a hands-on, entrepreneurial environment to fast track the development of todays most promising stem cell technologies.With $5.5 billion in funding and more than 150 active stem cell programs in our portfolio, CIRM is one of the worlds largest institutions dedicated to helping people by bringing the future of cellular medicine closer to reality. For more information go towww.cirm.ca.gov.

About Excision BioTherapeutics, Inc.Excision BioTherapeutics, Inc. is a clinical-stage biotechnology company developing CRISPR-based therapiesas potentialcures for viral infectious diseases. EBT-101, the Companys lead program, is anin vivoCRISPR-based therapeutic designed to cure HIV infections after a single intravenous infusion. Excisions pipeline unites next-generation CRISPR nucleases with a novel gene editing approach to develop curative therapies for Herpes Virus, JC Virus,which causes PML, and Hepatitis Bvirus. Excisions foundational technologies were developedin the laboratories of Dr. KamelKhaliliat Temple University andDr. JenniferDoudnaatthe University of California, Berkeley.For more information, please visitwww.excision.bio.

Contact:InvestorsJohn Fraunces - LifeSci Advisors917-355-2395jfraunces@lifesciadvisors.com

MediaRobert Flamm, Ph.D.Burns McClellan, Inc.212-213-0006 ext. 364rflamm@burnsmc.com

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Excision BioTherapeutics Awarded California Institute for Regenerative Medicine (CIRM) Grant to Support Ongoing Phase 1/2 Trial Evaluating EBT-101 as...

Duchenne muscular dystrophy (DMD) was first described by the French neurologist Guillaume Benjamin Amand Duchenne in the 1860s, though it took until 1986 for researchers to identify a particular gene flaw that leads to the condition. The identification of the dystrophin gene by Louis Kunkel and Jerry Louis opened the door for disease-modifying therapies such as exon-skipping, stop codon readthrough, gene therapy, and CRISPR/cas9 mediated gene editing that focus in on dystrophin restoration.

Currently, there are 4 drugs approved in the United States for mutations amenable to skipping of exons 51, 53, and 45, which are applicable to about 30% of patients total with DMD. Each of these were approved through the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases. At the recently concluded 2022 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) annual meeting, September 21-24, in Nashville, Tennessee, Emma Ciafaloni, MD, gave the Reiner Lecture to a crowd of a few hundred clinicians, highlighting new treatments for DMD.

In her talk, she summarized the expanding pipeline of agents for DMD, how each differs mechanistically, and whether any are more advantageous than another. Ciafaloni, a professor of neurology and pediatrics at the University of Rochester Medical Center, also discussed how to translate new treatments from trials to clinics, the need to improve clinical trial design and process, and how researchers can build on previous successes. Prior to her presentation, as part of a new NeuroVoices, Ciafaloni provided commentary on several topics regarding the DMD pipeline, including the differences and advantages each approach brings, as well as ways to overcome complexities with conducting clinical trials.

Emma Ciafaloni, MD: The exciting research development in the field of Duchenne muscular dystrophy is extraordinary. Many years after understanding the pathophysiology of Duchennewhich the gene wasnt discovered until the late 1980sall that knowledge is finally paying off and opening a window on therapeutic strategies that have to do with disease-modifying gene editing. There are many different approaches now, some like exon skipping, which are already used in the clinics. Some are different stages of development, such as gene therapy in phase three trials. I would be surprised if we didnt have a gene therapy drug in the clinic in the near future. And then CRISPR, which has not been used yet in humans, but has made major milestones and proof of concept in animal models that are highly promising. These are all strategies that are advancing very rapidly, I think that the field is moving much faster than in the past because of the collaboration between pharma and academia, and the patients and the families. There are many clinical trials in Duchenne, and it's a very exciting time.

Also, there has never been a time before in muscular dystrophies in general, not just Duchenne, where there were so many different, new ideas, as well as old ideas that finally started working in humans. The second part of my talk briefly covered other treatments, ideas and strategies that are not directed to restoration of dystrophin. They're not genetic treatments, but they work more on the downstream pathology of muscle degeneration into Duchenne, like the fibrosis, inflammation, and regeneration. There are some interesting drugs out there, probably a few that are going to be approved soon. We're looking at probably a multifactorial type of treatment, it may be a combination treatment. It's never been a richer time in terms of treatments for Duchenne. Also, it's exciting because some of the lessons learn, for example, with the genetic treatments, are extremely helpful for the larger field of neuromuscular diseases and even neurology. The learning has been fantastic.

With spinal muscular atrophy leading the way, we're moving into more muscle-based diseases [with gene therapy], but the lessons learned are still very valuable. Additionally, we have seen this collaboration between different sponsors, pharmaceuticals, and academias to share the learning, because that's just going to help move things faster and better and in a safer way. That is a positive phenomenon that is unprecedented, and it's helping to accelerate the science in a safe and effective way.

There are still many questions that remain. All these genetic modification approaches have been exon skipping, or gene therapy replacement. They don't replace the full-length dystrophin because it's a very large gene. It's a biologically modified type of dystrophin, so there is no doubt that it will have a profound benefit, but I think that there is plenty of room for improvement. Obviously, gene therapy is not approved yet, so remains to be seen in terms of clinical improvement. But even in the exon skipping, I think that we're going to see much more exciting next generation, exon-skipping that people are currently working on very hard on. The field of science and medicine always evolves. What we have now is only going to be much better down the road in a few years. I have no doubt, and the community of Duchenne is working very hard to make even the drugs that we have now, better.

Sometimes, for the more general neurologist or certainly for the general public, it's important to remember that when we talk about Duchenne muscular dystrophy, or many of our neuromuscular diseases that we discuss here at AANEM, these are also rare diseases. The definition from the FDA for a rare disease is less than 200,000 total patients in the United States. For Duchenne, for example, we're talking about maybe around 12,000 patients. This is not [multiple sclerosis], or Parkinson disease or Alzheimer disease. There are challenges in clinical trial designs that are unique, and they need to be understood. Some of the accelerated approval for some of these drugs is part of that challenge and difference. For example, especially with the genetic approach, some of these genetic approaches like exon skipping, only target a specific mutation in maybe 10% to 13% of patients. Now you're taking a subgroup of an ultra-rare disease that is only 10% of that population. Then you need to run clinical trials that are going to have a chance to prove a difference, and so, you restrict the inclusion criteria to a specific age. Then you're really challenged to find enough patients to do well in a placebo-controlled trial. It's important to keep that in mind that there is plenty of room for improvement in making our rare disease clinical trial design more effective, less time consuming for patients, and improving the approval path.

I also want to say that in Duchenne, the amount of data that has been produced in the past several years in terms of motor endpoints, natural history, the six-minute walk test, the North Star [Ambulatory Assessment], etc. These outcome measure prospective cohorts have been incredibly invaluable. This is just to recognize the incredible amount of work that researchers and families and patients have done in the past several years that is helping the field immensely. We are at a different time, its an exhilarating, exciting time. I think that the community of rare diseases like Duchenne have been incredibly, hard-working in a good, cohesive way to advance the field forward, which is very refreshing.

Transcript edited for clarity. Click here for more NeuroVoices.

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NeuroVoices: Emma Ciafaloni, MD, on the Vast Expansion of Innovative Approaches to Duchenne Muscular Dystrophy - Neurology Live

As we know, there are three major categories of medicines according to their sources, including natural medicines, chemically synthesized drugs, and biological therapeutics.

Among them, biological therapeutics (aka. biologics) are drugs developed and manufactured through biotechnology, such genetic engineering, cell engineering, and protein engineering. Two major categories of biopharmaceuticals have been small molecule- and protein/antibody-based biologics.

Recently, fueled by the global use of mRNA-based COVID-19 vaccines and nucleic acid-based testing for the SARS-CoV-2 virus, the new wave of nucleic acid-based medicine development and production has started taking off (pdf). Furthermore, the increasing number of nucleic acid drugs approved by the U.S. Food and Drug Administration (FDA) demonstrates the potential to treat diseases by targeting the genes responsible for them.

Nucleic acid therapeutics are based on nucleic acids or closely related chemical compounds, and they are completely different from small molecule drugs and antibody drugs.

Instead of targeting protein causes of diseases, they target disease on a genetic level.

Nucleic acid drugs are currently classified into four categories, including medicines based on antisense oligonucleotides (ASOs), small interfering nucleic acids (siRNAs), microRNAs (miRNAs), and nucleic acid aptamers (aptamers).

siRNA and miRNA drugs are called RNA interference (RNAi) medicines.

ASO and siRNA drugs have been approved, and both mainly act on cytoplasmic messenger RNAs (mRNA) to achieve regulation of protein expression through base complementary recognition and inhibition of target mRNAs for the purpose of treating unmet medical needs.

According to the central dogma of molecular biology, DNA is transcribed into RNA, which is then translated into proteins. In some specific cases, RNA can be reverse transcribed into DNA. So, we can see that RNA is critical, because it determines what proteins can be expressed.

Therefore, scientists are trying to see if the process of gene expression can be regulated. That is, instead of interfering at the DNA level, scientists try to regulate the RNA, which is produced in the nucleus and then moves to the cytoplasm. The production of proteins is also carried out in the cytoplasm. If drugs can be absorbed by cells, enter the cytoplasm, and influence the process of translating RNA into proteins, then these drugs can also treat related diseases.

Nucleic acid drugs are designed around this rationale to interfere with the synthesis of disease-causing proteins to treat certain diseases.

ASO is a single-stranded oligonucleotide molecule that enters the cell and binds to the target mRNA through sequence complementation. Then, under the action of ribonuclease H1 (RNase H1), this piece of RNA will be degraded and the expression of the disease-causing proteins will be inhibited consequently.

Both siRNA and miRNAtreat diseases through RNA interference, but their molecules have different properties.

siRNAs are encoded by transposons, viruses, and heterochromatin; whereas miRNAs are encoded by their own genes.

miRNAs can regulate different genes, while siRNAs are called the silencing RNAs, as they mediate the silencing of the same or similar genes from which they originate.

miRNAs are single RNAs and have an imperfect stem-loop secondary structure.

siRNA is a class of double-stranded short RNA molecules that bind to specific Dicer enzymes to degrade one strand. Then the other strand will bind to other enzymes including Argonaute Proteins (AGO) to assemble into a RNA-induced silencing complex (RISC).

In the RISC, the single strand RNA will bind to a target mRNA through the principle of base complementary pairing. Subsequently, the target mRNA will be degraded in the RISC complex, thus blocking the expression of the target protein for the purpose of treating a disease.

This mechanism of inhibiting protein expression via siRNA is called RNA interference. The scientists that had discovered RNA interferencegene silencing by double-stranded RNAwere awarded the Nobel Prize in Physiology or Medicine in 2006.

In terms of therapeutic areas, ASO drugs are mostly developed to cure cancers, infections, as well as neurological, musculoskeletal, ocular, and endocrine diseases.

For instance, fomivirsen, manufactured by Ionis/Novartis, was the first FDA-approved ASO drug, and it is currently used as a second-line treatment for cytomegalovirus (CMV) retinitis. Second-line treatment is used after the first-line (initial) treatment for a disease or condition fails or has intolerable side effects.

Several ASO drugs are also used for treatment of certain rare diseases, including Kynamro (phosphorothioate oligonucleotide drug for the treatment of the rare disease of Homozygous familial hypercholesterolaemia [HoFH]), Exondys 51 (for the treatment of a rare disease called Duchenne muscular dystrophy [DMD]), and Spinraza (for the treatment of spinal muscular atrophy [SMA], a rare inherited disease).

Prior to the development of these medicines, these rare diseases didnt have any effective drugs for treatment.

siRNA drugs therapeutic areas include cancers, infections, as well as neurological, ocular, endocrine, gastrointestinal, cardiovascular, dermatologic, and respiratory diseases.

For instance, patisiran, produced by Alnylam/Genzyme, is the first siRNA drug, and it is used for the treatment of polyneuropathy caused by hereditary transthyretin amyloidosis (haTTR). And the worlds second siRNA drug, Givlaari, produced also by Alnylam, was designed and developed for the treatment of acute hepatic porphyria (AHP), which is a family of ultra-rare disease in adults.

The main manufacturer of ASO drugs is the California-based Ionis Pharmaceuticals. The other major ones include ProQR, Sarepta, WAVELife Sciences, Biogen, and Exicure.

The largest manufacturer of siRNA drugs is Alnylam, a Massachusetts-based biopharmaceutical company specializing in the development and manufacturing of RNA interference therapeutics. The other major producers of these medicines include Dicerna, Quark, and Arrowhead.

In terms of the current status of ASO drug development, most of the therapeutics are in the preclinical stage, with their therapeutic areas mainly focused on oncological, neurological, and muscular diseases. The second largest group of ASO drugs are still in their discovery stage, during which medicines are being designed and undergoing preliminary experiments.

The situation with siRNA drugs (pdf) is similar to that of ASO medicines, with the largest group of medicines being in the preclinical stage, and the second largest group in the discovery stage. Currently, five siRNA drugs have been approved, including patisiran, givosiran, inclisiran, lumasiran, and vutrisiran. In addition, around a dozen other drugs are in late stages of phase III clinical trials.

Therefore, in both categories, only a small percentage of drugs have already been launched.

Nucleic acid drugs are considered novel therapeutic modalities, as they have great potential to treat diseases that cannot be treated effectively in the past, such as certain cancers, and some rare diseases for which no small molecule or protein/antibody-based biologics were developed.

In comparison with small molecule drugs and antibody-based biologics, nucleic acid-based therapeutics have high specificity towards RNAs.

Furthermore, they have simple designs and rapid and cost-effective development cycles (which would later translate into lower costs for patients), as their preclinical research and development starts with gene sequence determination and reasonable designs for disease genes, the genes can be targeted and silenced, thus avoiding unnecessary development and greatly saving research and development time.

They can also quickly alter the sequence of the mRNA construct for personalized treatments or to adapt to an evolving pathogen.In addition, they have abundant targets, so they can potentially make a breakthrough for some special targets that were previously undruggable, to treat certain genetic diseases. And the RNA interference technology has already matured in terms of target selection and small RNA segment synthesis.

However, getting the small RNA segment generated is only the initial step of drug development. In order for nucleic acid drugs to be applied clinically, the next important issue is delivering the nucleic acids to target tissues and cells. Since nucleic acids are highly hydrophilic and polyvalent anionic, it is not easy for cell uptake.

The selection of different delivery mechanisms of genes or RNA agents can impact the increase or decrease the expression of proteins in a cell.

The commonly used (pdf) nucleic acid drug delivery systems include drug conjugates (such as antibody-siRNA conjugates and cholesterol-siRNA conjugates), lipid-based nanocarriers (such as stealth liposomes and lipid nanoparticles), polymeric nanocarriers (such as nanoparticles base on degradable or non-degradable polymers and dendrimers), inorganic nanocarriers (such as silica nanoparticles and metal nanoparticles), carbon-based nanoparticles, quantum dots, and natural extracellular vesicles (ECVs).

Just like almost all drugs, nucleic acid therapeutics also have side effects and risks, some of which stem from their delivery methods.

The common adverse drug reactions (ADRs) of FDA-approved ASO drugs include injection site reactions (e.g. swelling), headache, pyrexia, fever, respiratory infection, cough, vomiting, and nausea (pdf). Individual ASO drugs have their own respective side effects. For instance, fomivirsen can potentially increase intraocular pressure and ocular infection. Pegaptanib can cause conjunctival hemorrhage, corneal edema, visual disturbance, and vitreous floaters. The ADRs of mipomersen (Kynamro) resemble flu symptoms. Nusinersen can cause fatigue and thrombocytopenia. And inotersen can also cause contact dermatitis.

Users of ASO drugs should also be aware of hepatotoxicity, kidney toxicity, and hypersensitive reactions (pdf).

Inotersen (Tegsedi) even carries black box warnings, which are required by the FDA for medications that carry serious safety risks, against its severe side effects, including thrombocytopenia, glomerulonephritis, and renal toxicity. Furthermore, users of inotersen are warned against possible reduced serum vitamin A, stroke, and cervicocephalic arterial dissection.

Side effects of siRNA drugs are similar to those of ASO drugs, including nausea, injection site reactions, heart block, vertigo, blurred vision, liver failure, kidney dysfunction, muscle spasms, fatigue, abdominal pain, and the potentially life-threatening anaphylaxis.

Specifically, during clinical trials of givosiran, one siRNA drug, 15 percent of subjects reported alanine aminotransferase (ALT) elevations three times above the normal range, and 15 percent reported elevated serum creatinine levels and reductions in estimated Glomerular Filtration Rate (eGFR), both signs of poor kidney function. Therefore, liver and kidney toxicity was reported during these clinical trials.

The use of siRNA drugs by pregnant mothers may entail risks for their unborn children. So far, although data on using givosiran, patisiran, and lumasiran have not been reported, certain ADRs of these drugs can serve as warning signs for use during pregnancy. For instance, patients using patisiran (Onpattro) will experience a reduction in their vitamin A levels. Vitamin A is essential for the unborn babys developing organs such as eyes and bones, as well asits circulatory, respiratory, and central nervous systems. Also, givosiran is shown to cause unfavorable developmental effects on animals. Furthermore, inclisiran therapy is not recommended for pregnant mothers, as it may harm the fetus.

In order for nucleic acid drugs to be effective, their design and development need to overcome a number of challenges, such as nuclease degradation, short half-life, immune recognition in circulation, accumulation in target tissues, transmembrane transport, and endosomal escape. Although nuclease stability and avoidance of immune recognition can be greatly reduced by combining chemical modifications, other problems remain to be solved.

Since carrier systems can greatly solve the problems that cannot be solved by chemical modifications and enhance the effectiveness and safety of nucleic acid drug therapeutics, these carrier systems are considered by many as the most important for development and overcoming the aforementioned challenges.

Currently, siRNA drug development faces several challenges (pdf), such as efficacy in siRNA delivery, safety, biocompatibility/biodegradability, and issues of their production, standardization, and approval as multi-component systems.

For example, in the case of lipid nanoparticles (LNPs; one type of lipid-based nanocarriers), only 1 to 2 percent of the internalized siRNAs are released into the cytoplasm. Therefore, research should be focusing on making nanoparticles capable of increasing the release of siRNAs.

However, it should also be noted that the safety, biodistribution, biokinetics, clearance or accumulation of LNPs in different tissues and organs are not well characterized for different types of LNPs. Therefore, the side effects or adverse reactions triggered by this delivery system should also be carefully studied.

The unprecedented global usage of mRNA vaccines under the context of pandemic has given a very unusual momentum to drive more RNA-based therapeutic development. However, clear and calm minds are still needed to see the challenges and explore the safety and risks issues comprehensively and longitudinally for any newly designed RNA-based therapeutic drugs.

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COVID mRNA Jabs and Testing Kicked Off This Industry of Drug Development: Here's What You Need to Know - The Epoch Times