Pompe disease (PD) is caused by the deficiency of the lysosomal enzyme acid α-glucosidase (GAA), resulting in systemic pathological glycogen accumulation. PD can present with cardiac, skeletal muscle, and central nervous system manifestations, as a continuum of phenotypes among two main forms: classical infantile-onset PD (IOPD) and late-onset PD (LOPD). IOPD is caused by severe GAA deficiency and presents at birth with cardiac hypertrophy, muscle hypotonia, and severe respiratory impairment, leading to premature death, if not treated. LOPD is characterized by levels of residual GAA activity up to ∼20% of normal and presents both in children and adults with a varied severity of muscle weakness and motor and respiratory deficit. Enzyme replacement therapy (ERT), based on repeated intravenous (i.v.) infusions of recombinant human GAA (rhGAA), represents the only available treatment for PD. Upon more than 10 years from its launch, it is becoming evident that ERT can extend the life span of IOPD and stabilize disease progression in LOPD; however, it does not represent a cure for PD. The limited uptake of the enzyme in key affected tissues and the high immunogenicity of rhGAA are some of the hurdles that limit ERT efficacy. GAA gene transfer with adeno-associated virus (AAV) vectors has been shown to reduce glycogen storage and improve the PD phenotype in preclinical studies following different approaches. Here, we present an overview of the different gene therapy approaches for PD, focusing on in vivo gene transfer with AAV vectors and discussing the potential opportunities and challenges in developing safe and effective gene therapies for the disease. Based on emerging safety and efficacy data from clinical trials for other protein deficiencies, in vivo gene therapy with AAV vectors appears to have the potential to provide a therapeutically relevant, stable source of GAA enzyme, which could be highly beneficial in PD.
Keywords: AAV; GAA; Pompe; gene therapy.