This proposal intends to advance the regional delivery of a chimeric adeno-associated virus (rAAV)-based, highly-truncated dystrophin (minidystrophin) gene therapy for the treatment of Duchenes Muscular Dystrophy (DMD). Experiments focus on completing preclinical studies required to initiate, the also proposed, FDA recommended Phase Ib bridging study. The proposed Phase Ib investigates regional gene delivery to the lower extremities of DMD patients. More specifically, the studies herein evaluate vector delivery (transduction potential) and expression profiles achieved using blood vessel-mediated, regional, isolated lower limb infusion (ILP) in large animal models [the Golden Retriever Muscular Dystrophy model (GRMD) and non-human primates (NHP)]. The GRMD model offers the additional potential to investigate the efficacy of rAAV- minidystrophin in ameliorating the nearest pathological counterpart of DMD. Our preliminary Phase 1 data indicate rAAV-minidystrophin is well tolerated and mediates expression levels as high as 2.5 transgene copies/diploid genome when directly injected in the bicep. Additionally, initial investigations of tranvascular limb delivery in GRMD and NHP demonstrate widespread transduction potential, and sustained high levels of gene expression. These data cumulatively allude to the positive outcomes expected from the proposed preclinical studies on which the jointly proposed Phase Ib trial is contingent. A positive outcome of rAAV-minidystrophin in Phase 1b clinical trials is expected to immediately impact DMD patients by supporting Phase II clinical trials of regional limb delivery of rAAV-minidystrophin. More importantly advancing a gene therapy for DMD offers the significant potential for prolonged ambulation, increased exercise capacity, and reduced disease progression to a currently incurable population whose treatments remain palliative. In recognition of this potential and in light of the preliminary studies including an Interim DSMB/IDMC Phase Ia trial report, Asklepios Biopharmaceutical has been awarded an MDA TRAC grant funding 50% of the proposed studies. This proposal intends to advance the regional delivery of a gene therapy for the treatment of Duchenes Muscular Dystrophy (DMD). Experiments focus on completing preclinical studies in large animal models that are required to initiate, the also proposed and FDA recommended, Phase Ib bridging study that involves regional gene delivery to the lower extremities of DMD patients. Advancing a gene therapy for DMD offers the significant potential for improved quality of life to a currently incurable population whose treatments remain palliative.
