Abstract
Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene, leading to a progressive dystrophy characterized by chronic muscle fiber loss, fat replacement, and fibrosis. To correct the underlying histopathology and function, expression of full-length DYSF is required. Dual adeno-associated virus vectors have been developed, defined by a region of homology, to serve as a substrate for reconstitution of the full 6.5 kb dysferlin cDNA. Previous work studied the efficacy of this treatment through intramuscular and regional delivery routes. To maximize clinical efficacy, dysferlin-deficient mice were treated systemically to target all muscles through the vasculature for efficacy and safety studies. Mice were evaluated at multiple time points between 4 and 13 months post treatment for dysferlin expression and functional improvement using magnetic resonance imaging and magnetic resonance spectroscopy and membrane repair. A systemic dose of 6 × 1012 vector genomes resulted in widespread gene expression in the muscles. Treated muscles showed a significant decrease in central nucleation, collagen deposition, and improvement of membrane repair to wild-type levels. Treated gluteus muscles were significantly improved compared to placebo-treated muscles and were equivalent to wild type in volume, intra- and extramyocellular lipid accumulation, and fat percentage using magnetic resonance imaging and magnetic resonance spectroscopy. Dual-vector treatment allows for production of full-length functional dysferlin with no toxicity. This confirms previous safety data and validates translation of systemic gene delivery for dysferlinopathy patients.
Highlights
THERE IS NO CURE OR TREATMENT for dysferlinopathies, a group of related disorders with varying clinical manifestations caused by absent or mutant dysferlin (DYSF)
Treated muscles show a reduction in centralized nuclei to 70% through all time points (n = 3 per group; Fig. 1)
In addition to sarcolemmal expression, strong cytoplasmic expression of dysferlin is commonly noted in regenerating fibers in dystrophic patient biopsies[3,47] as well as following gene delivery
Summary
THERE IS NO CURE OR TREATMENT for dysferlinopathies, a group of related disorders with varying clinical manifestations caused by absent or mutant dysferlin (DYSF). There are two major clinical presentations of dysferlin deficiency. Limb girdle muscular dystrophy type 2B is one of the most common limb girdle muscular dystrophies in the United States, with worldwide reports of incidence of 1/100,000–1/ 200,000,2 while Miyoshi myopathy is a more limited distal lower extremity form of dysferlinopathy. Miyoshi myopathy often begins distally with atrophy of the gastrocnemius muscle and spreads over time to affect proximal muscles.[3] Regardless of where muscle weakness begins, the disease progresses to the majority of muscles in the trunk, all limb muscles, the diaphragm, and, in some cases,
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