Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease.
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2010-11
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BACKGROUND: Lysosomal storage disorders such as Pompe disease can be more effectively treated, if immune tolerance to enzyme or gene replacement therapy can be achieved. Alternatively, immune responses against acid α-glucosidase (GAA) might be evaded in Pompe disease through muscle-specific expression of GAA with adeno-associated virus (AAV) vectors. METHODS: An AAV vector containing the MHCK7 regulatory cassette to drive muscle-specific GAA expression was administered to GAA knockout (KO) mice, immune tolerant GAA-KO mice and mannose-6-phosphate deficient GAA-KO mice. GAA activity and glycogen content were analyzed in striated muscle to determine biochemical efficacy. RESULTS: The biochemical efficacy from GAA expression was slightly reduced in GAA-KO mice, as demonstrated by higher residual glycogen content in skeletal muscles. Next, immune tolerance to GAA was induced in GAA-KO mice by co-administration of a second AAV vector encoding liver-specific GAA along with the AAV vector encoding muscle-specific GAA. Antibody formation was prevented by liver-specific GAA, and the biochemical efficacy of GAA expression was improved in the absence of antibodies, as demonstrated by significantly reduced glycogen content in the diaphragm. Efficacy was reduced in old GAA-KO mice despite the absence of antibodies. The greatest impact upon gene therapy was observed in GAA-KO mice lacking the mannose-6-phosphate receptor in muscle. The clearance of stored glycogen was markedly impaired despite high GAA expression in receptor-deficient Pompe disease mice. CONCLUSIONS: Overall, antibody formation had a subtle effect upon efficacy, whereas the absence of mannose-6-phosphate receptors markedly impaired muscle-targeted gene therapy in murine Pompe disease.
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Sun, Baodong, Songtao Li, Andrew Bird, Haiqing Yi, Alex Kemper, Beth L Thurberg and Dwight D Koeberl (2010). Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease. J Gene Med, 12(11). pp. 881–891. 10.1002/jgm.1511 Retrieved from https://hdl.handle.net/10161/15091.
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Baodong Sun
My overall research interests are finding effective treatment for human glycogen storage diseases (GSDs) and other inherited metabolic disorders. My current research focuses on identification of novel therapeutic targets and development of effective therapies for GSD II (Pompe disease), GSD III (Cori disease), and GSD IV (Andersen disease) using cellular and animal disease models. The main therapeutic approaches we are using in our pre-clinical studies include protein/enzyme therapy, AAV-mediated gene therapy, and substrate reduction therapy with small molecule drugs.
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