Delivery of Full Length Dystrophin to Muscle Cells for DMD Gene Therapy

PROJECT SUMMARY Project Title: Delivery of Full Length Dystrophin to Muscle Cells for DMD Gene Therapy Organization: GigaMune Inc. PI: David Johnson, Ph.D. Duchenne’s muscular dystrophy (DMD) is a severe, incurable, X-linked recessive disorder resulting in chronic muscle wasting caused by any of rt7,000 mutations in the dystrophin gene. Wheelchair dependency typically starts around 12 years, assisted ventilation is generally required by 20 years, and life expectancy is about 27 years. Unfortunately, dystrophin is very large, comprising 3,685 amino acids and an mRNA of 14kb, complicating delivery of complete dystrophin via adeno-associated virus (AAV), which is limited by a strict payload limit of 5kb. The ideal gene therapy for DMD would be long-term replacement of the complete dystrophin protein. One option other than AAV would be lentivirus (LV), which has been used to deliver full-length dystrophin in vitro. GigaMune has developed a novel next-generation LV platform (GigaLentiTM) for in vivo delivery of any gene to any cell in vivo. The basis of GigaLentiTM is an abrogated fusogenic pseudotype which leverages cell-surface targeting by an antibody fragment (scFv) for highly efficient, cell type-specific gene delivery. We have engineered GigaLentiTM to specifically deliver gene payloads to T and B cells in vitro, but we have not yet engineered muscle-specific LVs. The Specific Aim of this Phase I SBIR project is to use in vitro models to develop a novel lentiviral technology for efficient and specific delivery of the full-length dystrophin gene to muscle cells for modulation of DMD.