PPMD is excited to award Dr. Kanneboyina Nagaraju and his team at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences a $329,000 grant to continue his work examining the immune response to the production of new dystrophin protein, resulting from exon skipping and gene therapy treatments. This is an important next step in our exploration of both gene therapy and exon skipping as potential treatments for Duchenne.

This grant was made possible, in part, thanks to your contribution to PPMD’s Gene Therapy Initiative over the last two years!

Duchenne is caused by a change in the dystrophin gene. Without dystrophin, muscles are not able to function or repair themselves properly. While there is currently no cure for Duchenne, both exon skipping and gene therapy are being pursued as potential treatments that may slow the progression of Duchenne, while increasing dystrophin levels. Dr. Nagaraju hopes to understand the effect these treatments may have on the body’s immune system.

“For almost 25 years, PPMD has funded research aimed at treating Duchenne and finally therapies like exon skipping and gene therapy are near term. Now we need to look ahead to optimize the effectiveness of these promising new therapies,” according to Abby Bronson, PPMD’s Senior Vice President of Research Strategy. “We believe there is great value in the work Dr. Nagaraju and his team are doing – work that could improve the post-treatment outcome of these potential therapies.”

Dystrophin restoration in people with Duchenne has been the focus of a number of treatments in recent years. Treatments that have emerged include exon skipping and gene therapy, which aim to restore production of dystrophin.

Through these treatments, truncated versions of the dystrophin protein can be expressed within the muscle. Further investigation into the mechanisms that influence both the distribution and the extent of dystrophin restoration will be key to optimizing these treatments. While not currently well understood, one proposed influencer of treatment effectiveness is the body’s immune response to the production of new dystrophin protein.

To better understand the role of the immune system on dystrophin restoration, Dr. Nagaraju will explore the combination of exon skipping or micro-dystrophin gene therapy with an immunosuppressive treatment, using one of the following drugs:

• Treatment with rituximab to block antibodies to newly produced dystrophin.
• Treatment with abatacept CTLA4ig to halt an anti-dystrophin immune response.
• Treatment with either prednisolone, vamorolone, or eplerenone to test the respective reduction in inflammatory and anti-dystrophin immune response.

Rituximab is currently an FDA-approved drug for use in Rheumatoid Arthritis and non-Hodgkin’s lymphoma. This off-label use would seek to suppress the immune response via inhibition of mouse B-cells, one of the two main cell types involved in the immune response. B-cells produce antibodies, which act as signals to the immune system. By preventing antibody production against the newly expressed dystrophin, the amount of dystrophin generated in muscle and resulting muscle function may be improved.

Like rituximab, abatacept is an FDA-approved drug for Rheumatoid Arthritis. Abatacept helps to prevent activation of T-cells, the other main cell type involved in the immune response. By disrupting the immune response through T-cell inhibition, rather than just preventing antibody production, abatacept has the potential to have greater effect on increasing dystrophin expression than rituximab.

The last series of experiments will investigate three different anti-inflammatory drugs: prednisolone, vamorolone, and eplerenone. Their impact on dystrophin restoration after treatment will be evaluated. Each drug’s effect on inflammation, immune response modulation, and muscle function will be compared.

“Long-term immunological consequences of dystrophin gene correction and gene replacement therapeutic strategies in Duchenne are currently unknown,” said Dr. Nagaraju. “This project will explore interventions that modulate inflammation and immune response after gene and exon skipping therapies. I am really excited that PPMD recognized the merits of the studies proposed in this grant.”

Bronson adds, “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.”