AAV.Dysferlin Dual Vector Gene Therapy as a Treatment for Dysferlinopathies

Louise Rodino-Klapac, PhD and Jerry R. Mendell, MD

The Research Institute at Nationwide Children's Hospital

Dr. Rodino-Klapac, PhD is an assistant professor in the Department of Pediatrics and Principle Investigator at the Center for Gene Therapy at Nationwide Children's Hospital. Jerry R. Mendell, MD is a Professor of Pediatrics and Neurology and Director of the Center for Gene therapy at the Research Institute at Nationwide Children's Hospital.

Past Projects

Objective: 
Our AAV.Dysferlin Dual Vector gene transfer project is a stepwise, milestone driven approach to bring an efficacious product with a proven safety profile to clinical trial for LGMD2B/MM.

This project is devoted to translating AAVrh.74.Dysferlin Dual Vector (DV) gene transfer to the clinic.  In this approach, two viral vectors are co-administered to reconstitute the full-length dysferlin gene.  This is mediated by a 1 kb region of homology between the two vectors.  The first phase of the project focused on completing the pre-clinical data necessary to support IND application and includes: long term assessment of dysferlin expression following dual vector delivery; definition of the minimum effective dose to achieve functional restoration in dysferlin deficient mice; and demonstration of efficient and sustained expression in non-human primates following intramuscular and vascular delivery of AAVrh.74.DYSF.DV.  In the second phase, these studies were formally presented to the FDA in a Pre-IND meeting and guidance was obtained for a formal toxicology/biodistribution study performed at a CRO.  As soon as the second phase is complete, we will submit an IND application for a Phase I intramuscular trial in LGMD2B/MM patients.  This first trial will primarily assess safety and expression efficacy.  The final goal for treatment will be systemic delivery to treat all muscle groups to achieve clinically meaningful results for LGMD2B/MM.