Reduction of Autophagic Accumulation in Pompe Disease Mouse Model Following Gene Therapy.

ABSTRACT

BACKGROUND: Pompe disease is a fatal neuromuscular disorder caused by a deficiency in acid α-glucosidase, an enzyme responsible for glycogen degradation in the lysosome. Currently, the only approved treatment for Pompe disease is enzyme replacement therapy (ERT), which increases patient survival, but does not fully correct the skeletal muscle pathology. Skeletal muscle pathology is not corrected with ERT because low cation-independent mannose-6-phosphate receptor abundance and autophagic accumulation inhibits the enzyme from reaching the lysosome. Thus, a therapy that more efficiently targets skeletal muscle pathology, such as adeno-associated virus (AAV), is needed for Pompe disease. OBJECTIVE: The goal of this project was to deliver a rAAV9-coGAA vector driven by a tissue restrictive promoter will efficiently transduce skeletal muscle and correct autophagic accumulation. METHODS: Thus, rAAV9-coGAA was intravenously delivered at three doses to 12-week old Gaa-/- mice. 1 month after injection, skeletal muscles were biochemically and histologically analyzed for autophagy-related markers. RESULTS: At the highest dose, GAA enzyme activity and vacuolization scores achieved therapeutic levels. In addition, resolution of autophagosome (AP) accumulation was seen by immunofluorescence and western blot analysis of autophagy-related proteins. Finally, mice treated at birth demonstrated persistence of GAA expression and resolution of lysosomes and APs compared to those treated at 3 months. CONCLUSION: In conclusion, a single systemic injection of rAAV9-coGAA ameliorates vacuolar accumulation and prevents autophagic dysregulation.