Photo Credit: Cure Duchenne

Rare Disease Challenge, REGENXBIO Tackles Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy is a severe degenerative muscle disease that impacts about one in 5,000 boys per year across the globe. The disease causes a progressive loss of muscle strength attributable to a loss of a protein called dystrophin, which normally protects muscle fibers from breaking down.

There are only three approved treatments for the disease, each approved for a subset of DMD patients.  Maryland’s REGENXBIO is aiming to have the fourth such treatment. In January, one month before Rare Disease Day, which takes place the last day of February, REGENXBIO announced it was attempting to develop a potential one-time gene therapy for DMD patients. While the other approved therapies are for patient subsets, the company believes its gene therapy approach will be more applicable to most DMD patients.

“We believe it’s something that all DMD patients could receive and replace the missing gene function. That’s a big advantage,” Chief Executive Officer Ken Mills said.

REGENXBIO’s DMD asset is a gene therapy approach dubbed RGX-202. DMD is caused by mutations in the DMD gene, which encodes for dystrophin, a protein involved in muscle cell structure and signaling pathways. Without that dystrophin, the muscles throughout the body become progressively weaker. Eventually, DMD patients lose their mobility and require assistance breathing before the disease leads to an early death. RGX-202 is designed to deliver a novel microdystrophin transgene, which includes an extended coding region of the C-Terminal (CT) domain found in naturally occurring dystrophin.

As the company noted, the CT domain’s presence has been shown to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in previous animal studies. RGX-202 is designed to use the company’s NAV AAV8 vector and a well-characterized muscle-specific promoter called Spc5-12 that supports the delivery and targeted expression of genes throughout skeletal and heart muscle.

The three current treatments on the market, two from Sarepta Therapeutics and one from NS Pharma that was recently approved, are all exon-skipping treatments, meaning the therapies allow for a skipping of the exons that cause the mutation.

REGENXBIO Chief Scientific Officer Olivier Danos said new treatment options for patients with DMD has been a goal for the gene therapy field for many years. Since he joined REGENXBIO in 2017, Danos has been developing this gene therapy candidate using the company’s proprietary AAV8 vector.

By focusing on including the C-Terminal Domain of dystrophin, he said that might “bolster the key cell-signaling pathways and muscle membrane integrity,” which should lead to improved muscle strength and resistance. In preclinical research conducted by the company, Danos said they have seen a good efficacy and safety level.

Although RGX-202 was only recently announced, Mills anticipates the asset will enter the clinic later this year. The company is putting together its Investigational New Drug-enabling package. The hope is that gene therapy will show clinical benefits that change the disease’s course and improve the treated boys’ lives. Danos added the company is “fine-tuning” the structure of the clinical trial.

“We’re excited because we think we’re bringing something forward that’s a real scientific advancement,” Mills said.

Although the program has yet to enter the clinic, Mills said REGENXBIO is already focusing on manufacturing needs for gene therapy. He said the company has commercial-ready manufacturing capabilities in Rockville and aims to “get ahead of the curve” as quickly as possible.

“There’s a great unmet need and a sense of urgency,” Mills said.

In addition to DMD, REGENXBIO is also taking aim at other rare diseases. Among the diseases, the company will aim its AAV technology at are Hurler Syndrome, a rare lysosomal storage disease and the most severe form of mucopolysaccharidosis type 1, as well as Hunter Syndrome, a genetic disease where the body does not have enough of enzyme iduronate 2-sulfatase. The company is also developing a gene therapy for Batten disease, a rare genetic disorder caused by a mutation in the gene responsible for making tripeptidyl peptidase.

REGENXBIO has already made its mark in gene therapy and treating rare diseases. Zolgensma, a gene therapy for spinal muscular atrophy, a progressive neuromuscular disease caused by a mutation in the SMN1 gene that Novartis markets, uses technology developed by REGENXBIO. Novartis isn’t the only company that has licensed the company’s NAV technology. Pfizer, Rocket Pharmaceuticals, and Ultragenyx have also harnessed the company’s technology in their own drug development efforts.

“We’re part of this ecosystem no matter what. Zolgensma does not exist without REGENXBIO technology. We expect to win with our own pipeline, and we expect to win through our partner’s pipeline,” Mills said.

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Alex Keown is a freelance journalist who writes about a variety of subjects including the pharma, biotech, and life science industries. Prior to freelancing, Alex has served as a staff writer and editor for several publications.