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Modulation of glycogen synthesis by RNA interference: towards a new therapeutic approach for glycogenosis type II.
Hum Mol Genet. 2008 Dec 15; 17(24):3876-86.HM

Abstract

Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by defects in the acid alpha-glucosidase gene, which leads to lysosomal glycogen accumulation and enlargement of the lysosomes mainly in cardiac and muscle tissues, resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severely affected patients. Enzyme replacement therapy has already proven to be beneficial in this disease, but correction of pathology in skeletal muscle still remains a challenge. As substrate deprivation was successfully used to improve the phenotype in other lysosomal storage disorders, we explore here a novel therapeutic approach for GSDII based on a modulation of muscle glycogen synthesis. Short hairpin ribonucleic acids (shRNAs) targeted to the two major enzymes involved in glycogen synthesis, i.e. glycogenin (shGYG) and glycogen synthase (shGYS), were selected. C2C12 cells and primary myoblasts from GSDII mice were stably transduced with lentiviral vectors expressing both the shRNAs and the enhanced green fluorescent protein (EGFP) reporter gene. Efficient and specific inhibition of GYG and GYS was associated not only with a decrease in cytoplasmic and lysosomal glycogen accumulation in transduced cells, but also with a strong reduction in the lysosomal size, as demonstrated by confocal microscopy analysis. A single intramuscular injection of recombinant AAV-1 (adeno-associated virus-1) vectors expressing shGYS into newborn GSDII mice led to a significant reduction in glycogen accumulation, demonstrating the in vivo therapeutic efficiency. These data offer new perspectives for the treatment of GSDII and could be relevant to other muscle glycogenoses.

Authors+Show Affiliations

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

18782850

Citation

Douillard-Guilloux, Gaelle, et al. "Modulation of Glycogen Synthesis By RNA Interference: Towards a New Therapeutic Approach for Glycogenosis Type II." Human Molecular Genetics, vol. 17, no. 24, 2008, pp. 3876-86.
Douillard-Guilloux G, Raben N, Takikita S, et al. Modulation of glycogen synthesis by RNA interference: towards a new therapeutic approach for glycogenosis type II. Hum Mol Genet. 2008;17(24):3876-86.
Douillard-Guilloux, G., Raben, N., Takikita, S., Batista, L., Caillaud, C., & Richard, E. (2008). Modulation of glycogen synthesis by RNA interference: towards a new therapeutic approach for glycogenosis type II. Human Molecular Genetics, 17(24), 3876-86. https://doi.org/10.1093/hmg/ddn290
Douillard-Guilloux G, et al. Modulation of Glycogen Synthesis By RNA Interference: Towards a New Therapeutic Approach for Glycogenosis Type II. Hum Mol Genet. 2008 Dec 15;17(24):3876-86. PubMed PMID: 18782850.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of glycogen synthesis by RNA interference: towards a new therapeutic approach for glycogenosis type II. AU - Douillard-Guilloux,Gaelle, AU - Raben,Nina, AU - Takikita,Shoichi, AU - Batista,Lionel, AU - Caillaud,Catherine, AU - Richard,Emmanuel, Y1 - 2008/09/09/ PY - 2008/9/11/pubmed PY - 2009/7/17/medline PY - 2008/9/11/entrez SP - 3876 EP - 86 JF - Human molecular genetics JO - Hum Mol Genet VL - 17 IS - 24 N2 - Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by defects in the acid alpha-glucosidase gene, which leads to lysosomal glycogen accumulation and enlargement of the lysosomes mainly in cardiac and muscle tissues, resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severely affected patients. Enzyme replacement therapy has already proven to be beneficial in this disease, but correction of pathology in skeletal muscle still remains a challenge. As substrate deprivation was successfully used to improve the phenotype in other lysosomal storage disorders, we explore here a novel therapeutic approach for GSDII based on a modulation of muscle glycogen synthesis. Short hairpin ribonucleic acids (shRNAs) targeted to the two major enzymes involved in glycogen synthesis, i.e. glycogenin (shGYG) and glycogen synthase (shGYS), were selected. C2C12 cells and primary myoblasts from GSDII mice were stably transduced with lentiviral vectors expressing both the shRNAs and the enhanced green fluorescent protein (EGFP) reporter gene. Efficient and specific inhibition of GYG and GYS was associated not only with a decrease in cytoplasmic and lysosomal glycogen accumulation in transduced cells, but also with a strong reduction in the lysosomal size, as demonstrated by confocal microscopy analysis. A single intramuscular injection of recombinant AAV-1 (adeno-associated virus-1) vectors expressing shGYS into newborn GSDII mice led to a significant reduction in glycogen accumulation, demonstrating the in vivo therapeutic efficiency. These data offer new perspectives for the treatment of GSDII and could be relevant to other muscle glycogenoses. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/18782850/Modulation_of_glycogen_synthesis_by_RNA_interference:_towards_a_new_therapeutic_approach_for_glycogenosis_type_II_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddn290 DB - PRIME DP - Unbound Medicine ER -