Advanced Gene Therapy for Treatment of Cardiomyopathy and Respiratory Insufficiency in Duchenne Muscular Dystrophy
Abstract
The primary goal of this application is to develop and evaluate a novel therapeutic approach for the restoration of dystrophin levels in Duchenne Muscular Dystrophy (DMD) patients using recombinant adeno-associated virus (rAAV) vector-mediated gene transfer. More specifically, we propose to evaluate the clinical outcome of intrapleural administration of a Herpes Simplex virus type I System (HSV) production system-derived rAAV serotype 9 (rAAV9) vector encoding a codon-optimized mini dystrophin gene (miniDys) in the golden retriever muscular dystrophy (GRMD) model. This is a logical progression from the culmination of preclinical and clinical work done by our team in the field of gene therapy and myopathies. In particular, we have been able to show that rAAV-mediated gene transfer can result in significant therapeutic transgene expression in both the murine and canine models of muscular dystrophy, including DMD, which have led to current ongoing clinical trials. Furthermore, we demonstrated the superiority of rAAV serotype 9 to confer lasting and elevated gene expression in cardiac and skeletal muscles in murine, canine, and rhesus monkey models, suggesting the feasibility of using this vector system in the human population. This proposal comprises two specific aims. The first specific aim is to develop a clinically scalable and flexible platform of vector production based on the HSV system originally developed by Byrne et al. To-date, large-scale rAAV manufacturing using transfection of adherent cells is extremely cumbersome and time-consuming and generally impractical and unfeasible for large preclinical studies or clinical trials in patients with inherited myopathies. We believe the scalable HSV platform is required for generating sufficient amounts of highly pure and concentrated rAAV9-miniDys necessary for clinical trials.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2014
- Accession Number
- ADA613171
Entities
People
- Barry J. Byrne
Organizations
- University of Florida