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Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of alpha-glucosidase in Pompe disease.
J Gene Med 2009; 11(4):279-87JG

Abstract

BACKGROUND

Glycogen storage disease type II (GSDII) or Pompe disease is an inherited disease of glycogen metabolism caused by a lack of functional lysosomal acid alpha-glucosidase (GAA). Affected individuals store glycogen in lysosomes resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe form. Even if enzyme replacement therapy (ERT) has already proven some efficacy, its results remain heterogeneous in skeletal muscle, especially in cross reactive immunological material (CRIM)-negative patients. We investigated for the first time the use of hematopoietic stem cell (HSC) gene therapy in a murine model of GSDII.

METHODS

Deficient HSC were transduced with a lentiviral vector expressing human GAA or enhanced green fluorescent protein (GFP) under the control of the retroviral MND promoter and transplanted into lethally irradiated GSDII mice. Animals were then subjected to an ERT protocol for 5 weeks and monitored for metabolic correction and GAA-induced immune reaction.

RESULTS

GAA was expressed as a correctly processed protein, allowing a complete enzymatic correction in transduced deficient cells without toxicity. Seventeen weeks after transplantation, a partial restoration of the GAA enzymatic activity was observed in bone marrow and peripheral blood cells of GSDII mice, allowing a significant glycogen clearance in skeletal muscle. ERT induced a robust antibody response in GFP-transplanted mice, whereas no immune reaction could be detected in GAA-transplanted mice.

CONCLUSIONS

Lentiviral vector-mediated HSC gene therapy leads to a partial metabolic correction and induces a tolerance to ERT in GSDII mice. This strategy could enhance the efficacy of ERT in CRIM-negative Pompe patients.

Authors+Show Affiliations

Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.No 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

19263466

Citation

Douillard-Guilloux, Gaëlle, et al. "Partial Phenotypic Correction and Immune Tolerance Induction to Enzyme Replacement Therapy After Hematopoietic Stem Cell Gene Transfer of Alpha-glucosidase in Pompe Disease." The Journal of Gene Medicine, vol. 11, no. 4, 2009, pp. 279-87.
Douillard-Guilloux G, Richard E, Batista L, et al. Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of alpha-glucosidase in Pompe disease. J Gene Med. 2009;11(4):279-87.
Douillard-Guilloux, G., Richard, E., Batista, L., & Caillaud, C. (2009). Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of alpha-glucosidase in Pompe disease. The Journal of Gene Medicine, 11(4), pp. 279-87. doi:10.1002/jgm.1305.
Douillard-Guilloux G, et al. Partial Phenotypic Correction and Immune Tolerance Induction to Enzyme Replacement Therapy After Hematopoietic Stem Cell Gene Transfer of Alpha-glucosidase in Pompe Disease. J Gene Med. 2009;11(4):279-87. PubMed PMID: 19263466.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of alpha-glucosidase in Pompe disease. AU - Douillard-Guilloux,Gaëlle, AU - Richard,Emmanuel, AU - Batista,Lionel, AU - Caillaud,Catherine, PY - 2009/3/6/entrez PY - 2009/3/6/pubmed PY - 2009/5/28/medline SP - 279 EP - 87 JF - The journal of gene medicine JO - J Gene Med VL - 11 IS - 4 N2 - BACKGROUND: Glycogen storage disease type II (GSDII) or Pompe disease is an inherited disease of glycogen metabolism caused by a lack of functional lysosomal acid alpha-glucosidase (GAA). Affected individuals store glycogen in lysosomes resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe form. Even if enzyme replacement therapy (ERT) has already proven some efficacy, its results remain heterogeneous in skeletal muscle, especially in cross reactive immunological material (CRIM)-negative patients. We investigated for the first time the use of hematopoietic stem cell (HSC) gene therapy in a murine model of GSDII. METHODS: Deficient HSC were transduced with a lentiviral vector expressing human GAA or enhanced green fluorescent protein (GFP) under the control of the retroviral MND promoter and transplanted into lethally irradiated GSDII mice. Animals were then subjected to an ERT protocol for 5 weeks and monitored for metabolic correction and GAA-induced immune reaction. RESULTS: GAA was expressed as a correctly processed protein, allowing a complete enzymatic correction in transduced deficient cells without toxicity. Seventeen weeks after transplantation, a partial restoration of the GAA enzymatic activity was observed in bone marrow and peripheral blood cells of GSDII mice, allowing a significant glycogen clearance in skeletal muscle. ERT induced a robust antibody response in GFP-transplanted mice, whereas no immune reaction could be detected in GAA-transplanted mice. CONCLUSIONS: Lentiviral vector-mediated HSC gene therapy leads to a partial metabolic correction and induces a tolerance to ERT in GSDII mice. This strategy could enhance the efficacy of ERT in CRIM-negative Pompe patients. SN - 1521-2254 UR - https://www.unboundmedicine.com/medline/citation/19263466/Partial_phenotypic_correction_and_immune_tolerance_induction_to_enzyme_replacement_therapy_after_hematopoietic_stem_cell_gene_transfer_of_alpha_glucosidase_in_Pompe_disease_ L2 - https://doi.org/10.1002/jgm.1305 DB - PRIME DP - Unbound Medicine ER -