Liver depot gene therapy for Pompe disease

Annals of Translational Medicine
Priya S Kishnani, Dwight D Koeberl

Abstract

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 gen...Continue Reading

Citations

Sep 24, 2020·Biomolecules·Naresh K Meena, Nina Raben
Dec 23, 2020·International Journal of Molecular Sciences·Aitana Almodóvar-PayáTomàs Pinós
Aug 11, 2020·Molecular Therapy. Methods & Clinical Development·Giuseppa PirasH Bobby Gaspar
Aug 11, 2020·Molecular Therapy. Methods & Clinical Development·Makiko YasudaThomas Wechsler
Jan 23, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jamie L ShirleyRoland W Herzog
Jan 8, 2020·Molecular Therapy. Methods & Clinical Development·Sang-Oh HanDwight D Koeberl

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