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Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease.
Hum Gene Ther. 2012 May; 23(5):460-72.HG

Abstract

Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression might best be combined with nonhepatic expression, achieving the benefits of ubiquitous expression in addition to evading deleterious immune responses.

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

Language

eng

PubMed ID

22260439

Citation

Zhang, Ping, et al. "Immunodominant Liver-specific Expression Suppresses Transgene-directed Immune Responses in Murine Pompe Disease." Human Gene Therapy, vol. 23, no. 5, 2012, pp. 460-72.
Zhang P, Sun B, Osada T, et al. Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease. Hum Gene Ther. 2012;23(5):460-72.
Zhang, P., Sun, B., Osada, T., Rodriguiz, R., Yang, X. Y., Luo, X., Kemper, A. R., Clay, T. M., & Koeberl, D. D. (2012). Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease. Human Gene Therapy, 23(5), 460-72. https://doi.org/10.1089/hum.2011.063
Zhang P, et al. Immunodominant Liver-specific Expression Suppresses Transgene-directed Immune Responses in Murine Pompe Disease. Hum Gene Ther. 2012;23(5):460-72. PubMed PMID: 22260439.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease. AU - Zhang,Ping, AU - Sun,Baodong, AU - Osada,Takuya, AU - Rodriguiz,Ramona, AU - Yang,Xiao Yi, AU - Luo,Xiaoyan, AU - Kemper,Alex R, AU - Clay,Timothy M, AU - Koeberl,Dwight D, Y1 - 2012/03/29/ PY - 2012/1/21/entrez PY - 2012/1/21/pubmed PY - 2012/10/6/medline SP - 460 EP - 72 JF - Human gene therapy JO - Hum. Gene Ther. VL - 23 IS - 5 N2 - Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression might best be combined with nonhepatic expression, achieving the benefits of ubiquitous expression in addition to evading deleterious immune responses. SN - 1557-7422 UR - https://www.unboundmedicine.com/medline/citation/22260439/Immunodominant_liver_specific_expression_suppresses_transgene_directed_immune_responses_in_murine_pompe_disease_ L2 - https://www.liebertpub.com/doi/full/10.1089/hum.2011.063?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -