Liver depot gene therapy for Pompe disease.

Gene therapy for Pompe disease has advanced to early phase clinical trials, based upon proof-of-concept data indicating that gene therapy could surpass the benefits of the current standard of care, enzyme replacement therapy (ERT). ERT requires frequent infusions of large quantities of recombinant human acid α-glucosidase (GAA), whereas gene therapy involves a single infusion of a vector that stably transduces tissues to continuously produce GAA. Liver-specific expression of GAA with an adeno-associated virus (AAV) vector established stable GAA secretion from the liver accompanied by receptor-mediated uptake of GAA, which corrected the deficiency of GAA and cleared the majority of accumulated glycogen in the heart and skeletal muscle. Liver depot gene therapy was equivalent to ERT at a dose of the AAV vector that could be administered in an early phase clinical trial. Furthermore, high-level expression of GAA has decreased glycogen stored in the brain. A unique advantage of liver-specific expression stems from the induction of immune tolerance to GAA following AAV vector administration, thereby suppressing anti-GAA antibodies that otherwise interfere with efficacy. A Phase I clinical trial of AAV vector-mediated liver depot gene therapy has been initiated based upon promising preclinical data (NCT03533673). Overall, gene therapy promises to address limits of currently available ERT, if clinical translation currently underway is successful.