PHENOTYPIC CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL FOR LIMB-GIRDLE MUSCULAR DYSTROPHY 2i
Maricelli, Joseph William
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Muscular dystrophies are a subset of inherited neuromuscular diseases that are characterized by weakened muscle structure and muscle wasting. Treatment options for these diseases are limited to treating the symptoms and not the disease. However, recombinant adeno-associated virus (rAAV) vector gene therapies have become a promising area of study for potential cures. The benefits of rAAV therapy for muscular dystrophies are as follows: 1) a high tropism for skeletal and cardiac muscle among vector serotypes, 2) they allow for production of native protein or functional truncated to restore muscle function, 3) the use of muscle-specific promoters maintains vector specificity, and 4) there is no incorporation of the transgene into genomic DNA. Unfortunately, most gene therapy clinical trials do not complete all trial phases, wasting substantial time and money. This is due to limited animal models for the extensive subtypes of muscular dystrophy and variations in phenotypic presentation in animal and human pathology. Additionally, animal models are not sufficiently challenged or tested with assays that are translatable and non-invasive for human patients. The goal of this work was to isolate whole animal testing metrics for a novel limb-girdle muscular dystrophy 2i (LGMD2i) mouse model by recording gait analysis and exercise capacity. We found that the mice had myopathic gaits, dilated cardiomyopathy, impaired respiration, and sustained muscle damage with forced exercise. We then tested this rigorous exercise protocol on aged mice injected with an AAV serotype 6 gene therapy. Results indicate that the disease phenotype is ameliorated by the drug, preventing further muscle damage and decreased respiratory capacity caused by the exercise schedule. Overall, the studies have shown that systemic whole animal testing of dystrophic models provide useful assays for disease characterization. These assays can be used to challenge drug therapies, as demonstrated in the LGMD2i mice with the rAAV6 vector, to determine the efficacy of future clinical trials.