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In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease
Published on: December 20, 2017
Therapeutic Benefit of Autophagy Modulation in Pompe Disease
Jeong-A Lim1, Baodong Sun2, Rosa Puertollano3
1Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
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.
Insights
Combination therapy is crucial for lysosomal storage disorders like Pompe disease. Inhibiting autophagy via TSC knockdown shows promise in reversing muscle damage and improving enzyme replacement therapy efficacy.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Lysosomal storage disorders, such as Pompe disease, present complex pathogenic cascades requiring multifaceted therapeutic strategies.
- Enzyme replacement therapy (ERT) is the standard for Pompe disease but often shows limited efficacy due to massive autophagic buildup in muscle.
- This autophagic buildup impedes glycogen clearance and contributes to poor patient outcomes.
Purpose of the Study:
- To investigate novel therapeutic strategies for Pompe disease by targeting autophagic buildup.
- To evaluate the efficacy of genetic autophagy suppression and AAV-mediated TSC knockdown in enhancing ERT outcomes.
- To determine if established autophagic buildup can be reversed, not just prevented.
Main Methods:
- Utilized a mouse model of Pompe disease (glycogen storage disease type II).
- Explored two distinct approaches: genetic suppression of autophagy and adeno-associated virus (AAV)-mediated knockdown of TSC.
- Assessed outcomes including autophagic buildup, muscle force, glycogen levels, protein aggregation, oxidative stress, and muscle atrophy.
Main Results:
- Genetic suppression of autophagy reduced autophagic buildup and improved muscle function but caused adverse effects like protein aggregation and oxidative stress.
- AAV-mediated TSC knockdown upregulated mTOR, inhibited autophagy, reversed muscle atrophy, and enhanced cellular clearance with ERT.
- This approach demonstrated the potential to reverse existing autophagic buildup.
Conclusions:
- Targeting autophagy is a viable strategy to enhance ERT efficacy in Pompe disease.
- AAV-mediated TSC knockdown offers a promising therapeutic avenue by reversing autophagic buildup and mitigating disease pathology.
- This research highlights the potential for reversing established cellular damage in lysosomal storage disorders.
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