A prominent investigator at the University of Missouri School of Medicine received $200,000 in grants from four grassroots organizations to develop next generation gene therapy vectors for Duchenne muscular dystrophy (DMD). Dongsheng Duan, PhD, professor of microbiology and immunology, has spent twenty years studying possible gene therapy treatments for DMD utilizing harmless adeno-associated viral vectors (AAV).
What is DMD?
DMD is a severe type of muscular dystrophy starting with symptoms of muscle weakness around the age of four in boys and typically worsens quickly. Ultimately, patients have trouble standing up and most are unable to walk by age 12. Scoliosis is common and some patients combat intellectual disabilities associated with the genetic disease. The disorder is X-linked recessive and two thirds of cases are inherited from a person’s mother while one third of cases are due to a new mutation. It is caused by a mutation in the gene for the protein dystrophin. Dystrophin is important for the maintenance of the muscle fiber cell membrane. Genetic testing can help make a diagnosis at birth while those affected have a high level of creatine kinase in their blood. There is no known cure. The genetic disease affects about one in 3,500 males at birth and represents the most common types of more than 30 muscular dystrophy.
Emergence of Gene Therapies
The gene therapy drug development boom emerges as the U.S. Food and Drug Administration (FDA) has already approved two pathbreaking gene therapies, delivered via adeno-associated viral vectors (AAV) including Luxturna (Spark Therapeutics and acquired by Roche in 2019 for $4.3b) for an inherited form of vision loss and Zolgensma, the world’s most expensive drug at $2 million designed originally by AveXis for spinal muscular atrophy (SMA) and acquired by Novartis for $8.7 billion in 2018. These revolutionary therapies actually involve the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease.
Back in 1980, Martin Cline sought to modify human DNA while the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, occurred in 1989. And by September, 1990, French Anderson led a clinical trial involving the first therapeutic use of gene transfer while also the first to direct insertion of human DNA into the nuclear genome.
From 1989 through the present, 3,001 gene therapy-based clinical trials have been conducted (or ongoing). Over 50% of them are in Phase I. Most gene therapies utilize adeno-associated viruses (AAVs) and lentiviruses for performing gene insertions.
Gene Therapies in Development for DMD
There are a handful of gene therapy initiatives for DMD, reports Mary Chapman with Muscular Dystrophy News Today. These efforts that involve the delivery of microdystrophin include SRP-9001 micro-dystrophin (Sarepta Therapeutics) and SGT-001 by Solid Biosciences.
DMD Gene Therapy Challenges
Researchers face challenge in developing efficacious and safe gene therapy that ensure that microdystrophin can be delivered safely and efficiently void of dangerous immune response associated adverse reactions, reports Ms. Chapman with Muscular Dystrophy News Today. This is because that the researchers must inject large quantities of vector particles into a single patient to apply to all muscles in the body.
Enter Dr. Dongsheng Duan of University of Missouri
For two decades now, Dongsheng Duan has conducted research investigating gene therapy potential for DMD harnessing harmless AAVs to deliver a gene generating an artificial and functional version of dystrophin known as micro-dystrophin. Now with the new financial support, Duan can take on a new study that employs a novel human muscle platform to identify new AAVs that are more effective for gene delivery to the muscle. Duan noted in the press release, “If we can develop a super-AAV that is much more potent than the AAV currently in use in DMD patients, we will be able to achieve the same therapeutic efficacy at a much lower AAV dosage, and hence greatly reduce safety concerns and AAV manufacture burden(s).”
The Funders: Grassroots Patient Advocacy Groups
Four patient advocacy-based organizations contributed to this critical initiative, making the research at this stage possible. They include:
· Powers Promise (NJ)
These grassroots foundations, founded by families affected by Duchenne, raise awareness of the disease while direct funding to the best medical and scientific research in the quest to find better treatments and a future cure. Family-founded and operated, these organizations focus on collaboration between Duchenne patient organizations that is essential to the acceleration of therapies through the drug development pipeline.
Dongsheng Duan, PhD, Margaret Proctor Mulligan Professor in Medical Research Professor
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