Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder that affects approximately 1:3500 to 1:5200 live male births caused by mutations in the X-linked DMD gene. DMD gene mutations result in absence of the dystrophin protein in muscle fibers, leading to myofiber necrosis, endomysial fibrosis, and fat replacement. It is a devastating disorder, leading to loss of ambulation by age 12, and historically to death by age 20. The psychological and socioeconomic effects on families are enormous; these include but are not limited to the costs of medical care, opportunity costs for career and work, and the psychological toll taken on parents and siblings. Our long-term goal is to develop a rAAVrh74.MCK.GALGT2 as a surrogate gene therapy that can provide significant clinical benefit to boys affected by DMD. Our objective in this project is to perform first-in-huma studies demonstrating the safety and expression of the vector following intramuscular injection, and our central hypothesis is that following intramuscular injection into the extensor digitorum brevis (EDB) muscle, CT antigen expression will be widely identifiable at the sarcolemmal membrane, and no significant inflammation will be seen. The rationale for this trial is that the demonstration of the safety of rAAVrh74.MCK.GALGT2 following intramuscular injection in the first-in-human context represents a necessary precursor to intravascular gene transfer studies targeting whole limbs, with the goal of preventing loss of ambulation, that are now in the planning stages.
Our specific aims are to 1) perform a first-in-human safety study of intramuscular gene transfer of rAAVrh74.MCK.GALGT2, and 2) assess the degree of and the effects of CT antigen expression in EDB muscles. The expected outcome of these aims will be to confirm the expression of GALGT2 from the rAAVrh74.MCK.GALGT2 vector for the first time in humans, consistent with our preclinical data in mice, dogs, and non-human-primates (NHPs), and similarly to show a lack of toxicity consistent with our preclinical results. The immediate impact of our work will be to provide preliminary data from humans that support our anticipated vascular delivery studies in humans; these are in the active planning stage, supported by additional extensive preclinical work in mice and in NHPs. Such vascular delivery would be expected to deliver significant clinically meaningful benefit to boys with DMD.
The psychological and socioeconomic effects of DMD on families are enormous. These include medical care costs, opportunity costs for career and work, and the psychological toll taken on parents and siblings. The development of a novel surrogate gene therapy that does not treat only one class of dystrophin mutations - and in fact may prove useful for other, non-dystrophinopathy muscular dystrophies - will have an immediate impact on patients and their families.