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Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme.
Mol Ther 2002; 6(5):601-8MT

Abstract

Although many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal acid alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease. We have addressed the issue of reversibility of the disease in the Gaa(-/-) mouse model. We have made transgenic lines expressing human GAA in skeletal and cardiac muscle of Gaa(-/-) mice, and we turned the transgene on at different stages of disease progression by using a tetracycline-controllable system. We have demonstrated that levels of 20-30% of normal activity are indeed sufficient to clear glycogen in the heart of young Gaa(-/-) mice, but not in older mice with a considerably higher glycogen load. However, in skeletal muscle-a major organ affected in infantile and in milder, late-onset variants in humans-induction of GAA expression in young Gaa(-/-) mice to levels greatly exceeding wildtype values did not result in full phenotypic correction, and some muscle fibers showed little or no glycogen clearance. The results demonstrate that complete reversal of pathology in skeletal muscle or long-affected heart muscle will require much more enzyme than previously expected or a different approach.

Authors+Show Affiliations

Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. rabenn@arb.niams.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12409258

Citation

Raben, Nina, et al. "Glycogen Stored in Skeletal but Not in Cardiac Muscle in Acid Alpha-glucosidase Mutant (Pompe) Mice Is Highly Resistant to Transgene-encoded Human Enzyme." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 6, no. 5, 2002, pp. 601-8.
Raben N, Jatkar T, Lee A, et al. Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme. Mol Ther. 2002;6(5):601-8.
Raben, N., Jatkar, T., Lee, A., Lu, N., Dwivedi, S., Nagaraju, K., & Plotz, P. H. (2002). Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme. Molecular Therapy : the Journal of the American Society of Gene Therapy, 6(5), pp. 601-8.
Raben N, et al. Glycogen Stored in Skeletal but Not in Cardiac Muscle in Acid Alpha-glucosidase Mutant (Pompe) Mice Is Highly Resistant to Transgene-encoded Human Enzyme. Mol Ther. 2002;6(5):601-8. PubMed PMID: 12409258.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme. AU - Raben,Nina, AU - Jatkar,Tejas, AU - Lee,Alicia, AU - Lu,Nina, AU - Dwivedi,Sunita, AU - Nagaraju,Kanneboyina, AU - Plotz,Paul H, PY - 2002/11/1/pubmed PY - 2003/5/15/medline PY - 2002/11/1/entrez SP - 601 EP - 8 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 6 IS - 5 N2 - Although many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal acid alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease. We have addressed the issue of reversibility of the disease in the Gaa(-/-) mouse model. We have made transgenic lines expressing human GAA in skeletal and cardiac muscle of Gaa(-/-) mice, and we turned the transgene on at different stages of disease progression by using a tetracycline-controllable system. We have demonstrated that levels of 20-30% of normal activity are indeed sufficient to clear glycogen in the heart of young Gaa(-/-) mice, but not in older mice with a considerably higher glycogen load. However, in skeletal muscle-a major organ affected in infantile and in milder, late-onset variants in humans-induction of GAA expression in young Gaa(-/-) mice to levels greatly exceeding wildtype values did not result in full phenotypic correction, and some muscle fibers showed little or no glycogen clearance. The results demonstrate that complete reversal of pathology in skeletal muscle or long-affected heart muscle will require much more enzyme than previously expected or a different approach. SN - 1525-0016 UR - https://www.unboundmedicine.com/medline/citation/12409258/Glycogen_stored_in_skeletal_but_not_in_cardiac_muscle_in_acid_alpha_glucosidase_mutant__Pompe__mice_is_highly_resistant_to_transgene_encoded_human_enzyme_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525001602907161 DB - PRIME DP - Unbound Medicine ER -