Pompe disease is an autosomal recessive disorder that leads to a deficiency of the enzyme acid α-glucosidase (GAA). The GAA enzyme gene is located on chromosome 17 (17q25.3). More than 300 mutations of the gene have been described so far. Classic infantile-onset Pompe disease develops when neither of the two alleles produce functioning enzyme. Late-onset forms of Pompe disease develop when there is partial deficiency in GAA production.
This pathology is the consequence of the accumulation of lysosomal glycogen. This default leads to the accumulation of material in lysosomes and ultimately tissue damage. Although all individuals with Pompe disease share the underlying GAA enzyme deficiency, variability in enzyme activity leads to a broad spectrum of illness. Enzyme replacement therapy is available for Pompe disease, however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle.
Genethon develops transgenes encoding GAA that could be expressed and secreted by hepatocytes. Using adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes, gene transfer rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in a mouse model of the disease.