Audentes is developing AT982 for the treatment of Pompe disease.
Pompe Disease is a rare, inherited disorder characterized by severe, progressive muscle weakness and respiratory impairment. It is caused by mutations in the gene that encodes an enzyme called acid alpha-glucosidase, also known as GAA, which is needed by the body to break down glycogen – a stored form of sugar used for energy. Pompe Disease affects approximately one in every 40,000 births.
The goal of gene therapy for Pompe disease is long-term expression of acid alpha glucosidase after administration of a vector carrying the GAA gene. Increased levels of acid alpha-glucosidase are expected to produce improvement in symptoms related to the disease. Multiple studies have demonstrated encouraging results for the treatment of Pompe after delivery of the acid alpha-glucosidase gene using adeno-associated virus.
Systemic administration of adeno-associated virus to deliver acid alpha-glucosidase in GAA-deficient mice demonstrated significant increases of GAA activity in cardiac and skeletal muscle, which led to improved diaphragm contractile strength, reduced cardiac glycogen, reduced left ventricular mass, and improved ejection fraction. (Byrne et al, Human Molecular Genetics, 2011, Vol 20, Review Issue 1).
In addition, a recent study in a mouse model of Pompe disease compared the effects of a single systemic injection of AT982 (AAV-GAA) to bi-monthly injections of recombinant human GAA (ERT) over a three-month period. Improvements in diaphragmatic contractile and cardiac function were observed in both treatment groups at three months post-injection compared with untreated animals, while breathing frequency and expiratory time were significantly improved in AAV-GAA treated animals but not in ERT treated animals. In addition, glycogen deposition was significantly elevated in untreated and ERT animals, but not in AAV-GAA treated animals at three months post treatment. (Falk, et. al., Molecular Therapy – Methods and Clinical Development (2015) 2, 15007).