Résumé :
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Communication n° 579 Pompe disease is an autosomal recessive neuromuscular disorder of lysosomal glycogen metabolism resulting from deficiency of the enzyme acid alpha-glycosidase (GAA). A GAA knockout mouse model has been generated in which the mice demonstrate similar biochemical and pathological changes as seen in the human disease (N. Raben, NIH). We have utilized this model to investigate the underlying mechanisms of disease progression and to assess the efficacy of enzyme replacement therapy (ERT) with respect to age. Previously, we have demonstrated that the cardiac and skeletal muscle tissue of 12 month old mice do not clear glycogen as efficiently as the tissues of 3 month old mice following treatment with recombinant human GAA (rhGAA). Several avenues of investigation have been pursued in an attempt to identify the mechanisms underlying the apparent skeletal muscle resistance to ERT observed in older Pompe mice. This resistance does not appear related to the antibody response generated against rhGAA or to the post-dose motor activity status of the animals. Not surprisingly, histological analysis of muscle sections indicates a higher degree of lysosomal rupture and elevated levels of extra-lysosomal glycogen in the tissues of the older mice. However, a significant portion of the stored glycogen was still membrane bound suggesting that the substrate should have been accessible to rhGAA. Gene expression analysis of selected muscle tissues demonstrated differential expression of multiple genes between the different ages of mice, as well as in response to ERT. The relevance and implications of the differential pathology, tissue targeting and gene expression differences as a function of age in mice will be discussed.
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