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
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
Conclusion: In conclusion, a single systemic injection of rAAV9-coGAA ameliorates vacuolar
accumulation and prevents autophagic dysregulation.