Abstract P3049: Exploring The Therapeutic Potential Of Aav-mediated Restoration Of Col6a2 In A Mouse Model Of Ullrich Muscular Dystrophy

Abstract

Ullrich muscular dystrophy is a genetic disease characterized by joint contractures and muscle weakness which leads to loss of ambulation and respiratory insufficiency early in life. This disease is caused by mutations in any of the three major genes of collagen VI - Col6a1, Col6a2, or Col6a3. Together, these three genes are required to generate a complex quaternary protein assembly that is secreted to help form the basement membrane. Currently there is no cure or greater treatment for Ullrich muscular dystrophy although 2 of the genes (Col6a1, Col6a2) are within the size limit of adeno-associated virus (AAV) and could be addressed by gene therapy. However, it is unclear what cell type in muscle generates the bulk of Collagen VI during development, or if it could be replaced at a later time by gene therapy from expression in myofibers or from fibroblasts. Given that mutations in the Col6a2 gene are the most common cause of Ullrich muscular dystrophy, here we generated Col6a2 gene deleted (Col6a2 -/- ) mice which showed the anticipated histopathologic evidence of dystrophic disease as young adults. Adult mice were then subject to retro-orbital injection of MyoAAV-Col6a2, which resulted in robust expression of Col6a2 within the myofibers of all skeletal muscles analyzed (and heart), although this was ineffective in restoring the collagen VI complex within the basement membrane. Further characterization into the effects of Col6a2 re-expression from the myofibers versus the fibroblasts in these gene targeted mice is underway with the goal of defining a combinatorial (with Col6a1 and Col6a3) or cell type restricted infection protocol to successfully achieve full restoration of Collagen VI in muscle.