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Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance.
Am J Hum Genet. 2007 Nov; 81(5):1042-9.AJ

Abstract

Pompe disease, which results from mutations in the gene encoding the glycogen-degrading lysosomal enzyme acid alpha -glucosidase (GAA) (also called "acid maltase"), causes death in early childhood related to glycogen accumulation in striated muscle and an accompanying infantile-onset cardiomyopathy. The efficacy of enzyme replacement therapy (ERT) with recombinant human GAA was demonstrated during clinical trials that prolonged subjects' overall survival, prolonged ventilator-free survival, and also improved cardiomyopathy, which led to broad-label approval by the U.S. Food and Drug Administration. Patients who lack any residual GAA expression and are deemed negative for cross-reacting immunologic material (CRIM) have a poor response to ERT. We previously showed that gene therapy with an adeno-associated virus (AAV) vector containing a liver-specific promoter elevated the GAA activity in plasma and prevented anti-GAA antibody formation in immunocompetent GAA-knockout mice for 18 wk, predicting that liver-specific expression of human GAA with the AAV vector would induce immune tolerance and enhance the efficacy of ERT. In this study, a very low number of AAV vector particles was administered before initiation of ERT, to prevent the antibody response in GAA-knockout mice. A robust antibody response was provoked in naive GAA-knockout mice by 6 wk after a challenge with human GAA and Freund's adjuvant; in contrast, administration of the AAV vector before the GAA challenge prevented the antibody response. Most compellingly, the antibody response was prevented by AAV vector administration during the 12 wk of ERT, and the efficacy of ERT was thereby enhanced. Thus, AAV vector-mediated gene therapy induced a tolerance to introduced GAA, and this strategy could enhance the efficacy of ERT in CRIM-negative patients with Pompe disease and in patients with other lysosomal storage diseases.

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 available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17924344

Citation

Sun, Baodong, et al. "Enhanced Response to Enzyme Replacement Therapy in Pompe Disease After the Induction of Immune Tolerance." American Journal of Human Genetics, vol. 81, no. 5, 2007, pp. 1042-9.
Sun B, Bird A, Young SP, et al. Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance. Am J Hum Genet. 2007;81(5):1042-9.
Sun, B., Bird, A., Young, S. P., Kishnani, P. S., Chen, Y. T., & Koeberl, D. D. (2007). Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance. American Journal of Human Genetics, 81(5), 1042-9.
Sun B, et al. Enhanced Response to Enzyme Replacement Therapy in Pompe Disease After the Induction of Immune Tolerance. Am J Hum Genet. 2007;81(5):1042-9. PubMed PMID: 17924344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance. AU - Sun,Baodong, AU - Bird,Andrew, AU - Young,Sarah P, AU - Kishnani,Priya S, AU - Chen,Y-T, AU - Koeberl,Dwight D, Y1 - 2007/09/21/ PY - 2007/05/17/received PY - 2007/07/27/accepted PY - 2007/10/10/pubmed PY - 2007/12/6/medline PY - 2007/10/10/entrez SP - 1042 EP - 9 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 81 IS - 5 N2 - Pompe disease, which results from mutations in the gene encoding the glycogen-degrading lysosomal enzyme acid alpha -glucosidase (GAA) (also called "acid maltase"), causes death in early childhood related to glycogen accumulation in striated muscle and an accompanying infantile-onset cardiomyopathy. The efficacy of enzyme replacement therapy (ERT) with recombinant human GAA was demonstrated during clinical trials that prolonged subjects' overall survival, prolonged ventilator-free survival, and also improved cardiomyopathy, which led to broad-label approval by the U.S. Food and Drug Administration. Patients who lack any residual GAA expression and are deemed negative for cross-reacting immunologic material (CRIM) have a poor response to ERT. We previously showed that gene therapy with an adeno-associated virus (AAV) vector containing a liver-specific promoter elevated the GAA activity in plasma and prevented anti-GAA antibody formation in immunocompetent GAA-knockout mice for 18 wk, predicting that liver-specific expression of human GAA with the AAV vector would induce immune tolerance and enhance the efficacy of ERT. In this study, a very low number of AAV vector particles was administered before initiation of ERT, to prevent the antibody response in GAA-knockout mice. A robust antibody response was provoked in naive GAA-knockout mice by 6 wk after a challenge with human GAA and Freund's adjuvant; in contrast, administration of the AAV vector before the GAA challenge prevented the antibody response. Most compellingly, the antibody response was prevented by AAV vector administration during the 12 wk of ERT, and the efficacy of ERT was thereby enhanced. Thus, AAV vector-mediated gene therapy induced a tolerance to introduced GAA, and this strategy could enhance the efficacy of ERT in CRIM-negative patients with Pompe disease and in patients with other lysosomal storage diseases. SN - 0002-9297 UR - https://www.unboundmedicine.com/medline/citation/17924344/Enhanced_response_to_enzyme_replacement_therapy_in_Pompe_disease_after_the_induction_of_immune_tolerance_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63878-6 DB - PRIME DP - Unbound Medicine ER -