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Cell-based evaluation of small molecules for treatment of Pompe disease

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center




  • A Gustafson
  • W Westbroek
  • J Marugan
  • J Xiao
  • W Zheng
  • A Velayati
  • E Goldin
  • E Sidranksy


Pompe disease is a recessive lysosomal storage disorder caused by dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA), which metabolizes glycogen. Mutations impair the breakdown of glycogen, and cause storage in lysosomes. Cardiac and skeletal muscles are affected, causing impaired breathing and mobility. Over 100 disease-causing mutations are known, some of which retain some enzymatic activity, but are not trafficked to lysosomes. Instead the misfolded GAA undergoes proteosome-mediated breakdown. Enzyme replacement therapy with Myozyme® improves clinical outcome, but the treatment remains expensive and does not reverse all symptoms. Small molecules which aid in protein folding could provide an alternate therapeutic strategy. We identified several promising non-inhibitory compounds for GAA folding from a chemical compound library using in vitro assays. We optimized an in vivo cell-based immune-fluorescence assay for further evaluation of GAA translocation. Co-localization of GAA and the lysosomal marker Cathepsin-D was assessed with confocal microscopy. Control fibroblasts showed GAA staining in the lysosomes, while Pompe fibroblasts lacked this signal. However, after six days of chemical compound treatment, the expression level and translocation of GAA to lysosomes in Pompe cells was comparable to control cells. These promising small molecules merit further evaluation as a potential new therapy for Pompe disease.

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