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Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II.
Mol Ther. 2006 Dec; 14(6):822-30.MT

Abstract

Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid alpha-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative signal peptide could increase the secretion of GAA from transduced cells and enhance the receptor-mediated uptake of GAA in striated muscle. The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold. Receptor-mediated uptake of secreted, chimeric GAA corrected cultured GSD-II patient cells. High-level hGAA was sustained in the plasma of GSD-II mice for 24 weeks following administration of an AAV2/8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain. Administration of only 1 x 10(10) vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3 x 10(10) vector particles increased GAA activity and reduced glycogen content in the heart, diaphragm, and quadriceps. Furthermore, an AAV2/2 vector encoding chimeric GAA produced secreted hGAA for >12 weeks in the majority of treated GSD-II mice. Thus, chimeric, highly secreted GAA enhanced the efficacy of AAV vector-mediated gene therapy in GSD-II mice.

Authors+Show Affiliations

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16987711

Citation

Sun, Baodong, et al. "Enhanced Efficacy of an AAV Vector Encoding Chimeric, Highly Secreted Acid Alpha-glucosidase in Glycogen Storage Disease Type II." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 14, no. 6, 2006, pp. 822-30.
Sun B, Zhang H, Benjamin DK, et al. Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II. Mol Ther. 2006;14(6):822-30.
Sun, B., Zhang, H., Benjamin, D. K., Brown, T., Bird, A., Young, S. P., McVie-Wylie, A., Chen, Y. T., & Koeberl, D. D. (2006). Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II. Molecular Therapy : the Journal of the American Society of Gene Therapy, 14(6), 822-30.
Sun B, et al. Enhanced Efficacy of an AAV Vector Encoding Chimeric, Highly Secreted Acid Alpha-glucosidase in Glycogen Storage Disease Type II. Mol Ther. 2006;14(6):822-30. PubMed PMID: 16987711.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II. AU - Sun,Baodong, AU - Zhang,Haoyue, AU - Benjamin,Daniel K,Jr AU - Brown,Talmage, AU - Bird,Andrew, AU - Young,Sarah P, AU - McVie-Wylie,Alison, AU - Chen,Y-T, AU - Koeberl,Dwight D, Y1 - 2006/09/20/ PY - 2006/01/25/received PY - 2006/07/28/revised PY - 2006/08/11/accepted PY - 2006/9/22/pubmed PY - 2007/1/31/medline PY - 2006/9/22/entrez SP - 822 EP - 30 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 14 IS - 6 N2 - Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid alpha-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative signal peptide could increase the secretion of GAA from transduced cells and enhance the receptor-mediated uptake of GAA in striated muscle. The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold. Receptor-mediated uptake of secreted, chimeric GAA corrected cultured GSD-II patient cells. High-level hGAA was sustained in the plasma of GSD-II mice for 24 weeks following administration of an AAV2/8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain. Administration of only 1 x 10(10) vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3 x 10(10) vector particles increased GAA activity and reduced glycogen content in the heart, diaphragm, and quadriceps. Furthermore, an AAV2/2 vector encoding chimeric GAA produced secreted hGAA for >12 weeks in the majority of treated GSD-II mice. Thus, chimeric, highly secreted GAA enhanced the efficacy of AAV vector-mediated gene therapy in GSD-II mice. SN - 1525-0016 UR - https://www.unboundmedicine.com/medline/citation/16987711/Enhanced_efficacy_of_an_AAV_vector_encoding_chimeric_highly_secreted_acid_alpha_glucosidase_in_glycogen_storage_disease_type_II_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(06)01485-7 DB - PRIME DP - Unbound Medicine ER -