Amelioration of Muscle and Nerve Pathology in LAMA2 Muscular Dystrophy by AAV9-Mini-Agrin

LAMA2-related muscular dystrophy (LAMA2 MD) is the most common and fatal form of early-onset congenital muscular dystrophies. Due to the large size of the laminin alpha 2 cDNA and heterotrimeric structure of the protein, it is challenging to develop a gene-replacement therapy. Our group has developed a novel adeno-associated viral (AAV) vector carrying the mini-agrin, which is a non-homologous functional substitute for the mutated laminin alpha 2. A significant therapeutic effect in skeletal muscle was observed in our previous study using AAV serotype 1 (AAV1). In this investigation, we examined AAV9 vector, which has more widespread transduction than AAV1, to determine if the therapeutic effects could be further improved. As expected, AAV9-mini-agrin treatment offered enhanced therapeutic effects over the previously used AAV1mini-agrin in extending mouse lifespan and improvement of muscle pathology. Additionally, overexpression of mini-agrin in peripheral nerves of dyw/dyw mice partially amended nerve pathology as evidenced by improved motor function and sensorimotor processing, partial restoration of myelination, partial restoration of basement membrane via EM examination, as well as decreased regeneration of Schwann cells. In conclusion, our studies indicate that overexpression of mini-agrin into dyw/dyw mice offers profound therapeutic effects in both skeletal muscle and nervous system.