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Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers.
Mol Ther 2005; 11(1):48-56MT

Abstract

Pompe disease (type II glycogen storage disease) is an autosomal recessive disorder caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) leading to the accumulation of glycogen in the lysosomes primarily in cardiac and skeletal muscle. The recombinant human GAA (rhGAA) is currently in clinical trials for enzyme replacement therapy of Pompe disease. Both clinical data and the results of preclinical studies in our knockout model of this disease show that rhGAA is much more effective in resolving the cardiomyopathy than the skeletal muscle myopathy. By contrast, another form of human GAA--transgenic enzyme constitutively produced in liver and secreted into the bloodstream of knockout mice (Gaa-/-)--completely prevented both cardiac and skeletal muscle glycogen accumulation. In the experiments reported here, the transgenic enzyme was much less efficient when delivered to skeletal muscle after significant amounts of glycogen had already accumulated. Furthermore, the transgenic enzyme and the rhGAA have similar therapeutic effects, and both efficiently clear glycogen from cardiac muscle and type I muscle fibers, but not type II fibers. Low abundance of proteins involved in endocytosis and trafficking of lysosomal enzymes combined with increased autophagy in type II fibers may explain the resistance to therapy.

Authors+Show Affiliations

Arthritis and Rheumatism Branch, NIAMS, National Institutes of Health, 9000 Rockville Pike, Building 10/9N244, Bethesda, MD 20892, USA. rabenn@arb.niams.nih.govNo affiliation info availableNo affiliation info availableNo 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

Language

eng

PubMed ID

15585405

Citation

Raben, Nina, et al. "Replacing Acid Alpha-glucosidase in Pompe Disease: Recombinant and Transgenic Enzymes Are Equipotent, but Neither Completely Clears Glycogen From Type II Muscle Fibers." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 11, no. 1, 2005, pp. 48-56.
Raben N, Fukuda T, Gilbert AL, et al. Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers. Mol Ther. 2005;11(1):48-56.
Raben, N., Fukuda, T., Gilbert, A. L., de Jong, D., Thurberg, B. L., Mattaliano, R. J., ... Plotz, P. H. (2005). Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers. Molecular Therapy : the Journal of the American Society of Gene Therapy, 11(1), pp. 48-56.
Raben N, et al. Replacing Acid Alpha-glucosidase in Pompe Disease: Recombinant and Transgenic Enzymes Are Equipotent, but Neither Completely Clears Glycogen From Type II Muscle Fibers. Mol Ther. 2005;11(1):48-56. PubMed PMID: 15585405.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers. AU - Raben,Nina, AU - Fukuda,Tokiko, AU - Gilbert,Abigail L, AU - de Jong,Deborah, AU - Thurberg,Beth L, AU - Mattaliano,Robert J, AU - Meikle,Peter, AU - Hopwood,John J, AU - Nagashima,Kunio, AU - Nagaraju,Kanneboyina, AU - Plotz,Paul H, PY - 2004/07/19/received PY - 2004/09/02/accepted PY - 2004/12/9/pubmed PY - 2005/5/5/medline PY - 2004/12/9/entrez SP - 48 EP - 56 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 11 IS - 1 N2 - Pompe disease (type II glycogen storage disease) is an autosomal recessive disorder caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) leading to the accumulation of glycogen in the lysosomes primarily in cardiac and skeletal muscle. The recombinant human GAA (rhGAA) is currently in clinical trials for enzyme replacement therapy of Pompe disease. Both clinical data and the results of preclinical studies in our knockout model of this disease show that rhGAA is much more effective in resolving the cardiomyopathy than the skeletal muscle myopathy. By contrast, another form of human GAA--transgenic enzyme constitutively produced in liver and secreted into the bloodstream of knockout mice (Gaa-/-)--completely prevented both cardiac and skeletal muscle glycogen accumulation. In the experiments reported here, the transgenic enzyme was much less efficient when delivered to skeletal muscle after significant amounts of glycogen had already accumulated. Furthermore, the transgenic enzyme and the rhGAA have similar therapeutic effects, and both efficiently clear glycogen from cardiac muscle and type I muscle fibers, but not type II fibers. Low abundance of proteins involved in endocytosis and trafficking of lysosomal enzymes combined with increased autophagy in type II fibers may explain the resistance to therapy. SN - 1525-0016 UR - https://www.unboundmedicine.com/medline/citation/15585405/Replacing_acid_alpha_glucosidase_in_Pompe_disease:_recombinant_and_transgenic_enzymes_are_equipotent_but_neither_completely_clears_glycogen_from_type_II_muscle_fibers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(04)01468-6 DB - PRIME DP - Unbound Medicine ER -