PPMD Awards $329K to Researchers Looking to Better Understand Promising Duchenne Therapies

Kanneboyina Nagaraju, PhD, and his research team at Binghamton University, State University of New York will get a $329,000 Parent Project Muscular Dystrophy (PPMD) grant to study responses to differing treatments for Duchenne muscular dystrophy.

The researchers will focus on the role of the immune system on dystrophin restoration, resulting from exon skipping and gene therapy. Dystrophin is key for the strength of muscle fibers and protection from injury as muscles contract and relax.

Exon skipping and gene therapy are widely viewed as promising treatments for slowing Duchenne progression, while raising dystrophin levels. Nagaraju, of Binghamton’s School of Pharmacy and Pharmaceutical Sciences, seeks to discover their impact on human immune systems.

”For almost 25 years, PPMD has funded research aimed at treating Duchenne, and finally therapies like exon skipping and gene therapy are near term,” Abby Bronson, PPMD senior vice president of research strategy, said in a news release. “We believe there is great value in the work Dr. Nagaraju and his team are doing — work that could improve the post-treatment outcomes of these potential therapies.”

Treatments such as exon skipping and gene therapy call for shortened versions of the dystrophin protein to be produced within the muscles. Still, more understanding is needed on how much of the protein needs to be restored, and how the distribution process works.

Nagaraju will investigate the combination of exon skipping or gene therapy with an immunosuppressive treatment, using either Rituxan (rituximab) to block antibodies against the newly made dystrophin, Orencia (abatacept) to stop an anti-dystrophin response, or corticosteroids (prednisolone, vamorolone, or eplerenone) to test reductions in inflammatory and anti-dystrophin immune response.

The use of rituximab — currently approved for treating rheumatoid arthritis and non-Hodgkin’s lymphoma — in Duchenne aims to stop the immune response by restricting mouse B-cells, a key antibody-producing cell involved in immune response. The hope is that by blocking antibody production, dystrophin generation will be enhanced.

The researchers have the same hope — perhaps even greater — for abatacept, which helps to delay T-cell activation (and is also approved to treat rheumatoid arthritis). Instead of merely preventing antibody production, abatacept disrupts the immune response. That could have a major impact on raising dystrophin levels.

The extent to which the anti-inflammatory medications affect dystrophin restoration, in addition to inflammation, immune response modulation and muscle function, will also be examined.

”Long-term immunological consequences of dystrophin gene correction and gene replacement therapeutic strategies in Duchenne are currently unknown,” Nagaraju said. “This project will explore interventions that modulate inflammation and immune response after gene and exon skipping therapies.”

“Both exon skipping and gene therapies hold great promise as treatments for Duchenne. Like Dr. Nagaraju, PPMD believes that it is important to support those therapies with additional treatments that create a more favorable environment in the body and could improve their impact.” Bronson said.

Exondy’s 51 (eteplirsen), by Sarepta Therapeutics, was approved by the FDA in 2016 to treat Duchenne patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.

PPMD is a non-profit organization, focused on finding a cure for Duchenne, a disorder that progressively saps patients of their muscle strength.