Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 418, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aam6375
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Funding
- Genethon
- French Muscular Dystrophy Association (AFM)
- European Union [667751, 658712]
- European Research Council [617432]
- ASTRE (Action de soutien a la technologie et a la recherche en Esssonne)
- NIH [R01-HL092096, F32-HL119059]
- American Liver Foundation
- Stanford Dean's Fellowship
- NIH from National Center for Research Resources (NCRR) [S10-OD01058001-A1]
- Fonds pour le Rayonnement de la Recherche, Universite d'Evry
- Marie Curie Actions (MSCA) [658712] Funding Source: Marie Curie Actions (MSCA)
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Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid a-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. 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. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa(-/-)) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa(-/-) mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector-mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.
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