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Therapeutic Benefit of Autophagy Modulation in Pompe Disease.

Molecular therapy : the journal of the American Society of Gene Therapy (2018-05-29)
Jeong-A Lim, Baodong Sun, Rosa Puertollano, Nina Raben
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Ubiquitin Antibody, Lys63-Specific, clone Apu3, rabbit monoclonal, clone Apu3, from rabbit
Sigma-Aldrich
Anti-LC3B antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
InnoZyme Calpain 1/2 Activity Assay Kit
Sigma-Aldrich
Anti-Puromycin Antibody, clone 12D10, clone 12D10, from mouse