Therapeutic Benefit of Autophagy Modulation in Pompe Disease.
Abstract
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.
Type
Journal articlePermalink
https://hdl.handle.net/10161/17191Published Version (Please cite this version)
10.1016/j.ymthe.2018.04.025Publication Info
Lim, Jeong-A; Sun, Baodong; Puertollano, Rosa; & Raben, Nina (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 https://hdl.handle.net/10161/17191.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
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 studie

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