Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease.
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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.
Disease Models, Animal
Gene Expression Regulation
Glycogen Storage Disease Type II
Receptor, IGF Type 2
Published Version (Please cite this version)10.1002/jgm.1511
Publication InfoBird, A; Kemper, Alex Randall; Koeberl, Dwight D; Li, S; Sun, Baodong; Thurberg, BL; & Yi, Haiqing (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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Professor of Pediatrics
My research focuses on improving the quality of care that children receive by strengthening the linkages between primary care, specialty care, and public health services. I study a wide array of conditions to address this research focus, with special concentration on vision impairment and genetically determined conditions such as inborn errors of metabolism. In addition, juvenile idiopathic arthritis has been added as an area of concentration. I provide mentorship to trainees and faculty
Professor of Pediatrics
The focus of our research has been the development of gene therapy with adeno-associated virus (AAV) vectors, most recently by genome editing with CRISPR/Cas9. We have developed gene therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD) and phenylketonuria (PKU). 1) GSD type Ia: Glucose-6-phosphatase (G6Pase) deficient animals provide models for developing new therapy for GSD type Ia, although early mortality complicates research with both
Associate Professor of Pediatrics
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 studie
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