Therapeutic Benefit of Autophagy Modulation in Pompe Disease.

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The complexity of the pathogenic cascade in lysosomal storage disorders suggests that combination therapy will be needed to target various aspects of pathogenesis. The standard of care for Pompe disease (glycogen storage disease type II), a deficiency of lysosomal acid alpha glucosidase, is enzyme replacement therapy (ERT). Many patients have poor outcomes due to limited efficacy of the drug in clearing muscle glycogen stores. The resistance to therapy is linked to massive autophagic buildup in the diseased muscle. We have explored two strategies to address the problem. Genetic suppression of autophagy in muscle of knockout mice resulted in the removal of autophagic buildup, increase in muscle force, decrease in glycogen level, and near-complete clearance of lysosomal glycogen following ERT. However, this approach leads to accumulation of ubiquitinated proteins, oxidative stress, and exacerbation of muscle atrophy. Another approach involves AAV-mediated TSC knockdown in knockout muscle leading to upregulation of mTOR, inhibition of autophagy, reversal of atrophy, and efficient cellular clearance on ERT. Importantly, this approach reveals the possibility of reversing already established autophagic buildup, rather than preventing its development.





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Lim, Jeong-A, Baodong Sun, Rosa Puertollano and Nina Raben (2018). Therapeutic Benefit of Autophagy Modulation in Pompe Disease. Molecular therapy : the journal of the American Society of Gene Therapy. 10.1016/j.ymthe.2018.04.025 Retrieved from

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Baodong Sun

Associate Professor in Pediatrics

My overall research interests are finding effective treatment for human glycogen storage diseases (GSDs) and other inherited metabolic disorders. My current research focuses on identification of novel therapeutic targets and development of effective therapies for GSD II (Pompe disease), GSD III (Cori disease), and GSD IV (Andersen disease) using cellular and animal disease models. The main therapeutic approaches we are using in our pre-clinical studies include protein/enzyme therapy, AAV-mediated gene therapy, and substrate reduction therapy with small molecule drugs.

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