A Neuron-Specific Gene Therapy Relieves Motor Deficits in Pompe Disease Mice
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In Pompe disease, deficient lysosomal acid α-glucosidase (GAA) activity causes glycogen accumulation in the muscles, which leads to weakness, cardiomyopathy, and respiratory failure. Although glycogen accumulation also occurs in the nervous system, the burden of neurological deficits in Pompe disease remains obscure. In this study, a neuron-specific gene therapy was administered to Pompe mice through intracerebroventricular injection of a viral vector carrying a neuron-specific promoter. The results revealed that gene therapy increased GAA activity and decreased glycogen content in the brain and spinal cord but not in the muscles of Pompe mice. Gene therapy only slightly increased the muscle strength of Pompe mice but substantially improved their performance on the rotarod, a test measuring motor coordination. Gene therapy also decreased astrogliosis and increased myelination in the brain and spinal cord of Pompe mice. Therefore, a neuron-specific treatment improved the motor coordination of Pompe mice by lowering glycogen accumulation, decreasing astrogliosis, and increasing myelination. These findings indicate that neurological deficits are responsible for a significant burden in Pompe disease.
KeywordsPompe disease Glycogen Gene therapy Adeno-associated viral vector Neuron-specific Enzyme replacement therapy
This work was funded by a grant from the Ministry of Science and Technology (103-2314-B-002-057-MY3) of Taiwan. The authors would like to thank the scientists from the Taiwan Mouse Clinic and the National Taiwan University Disease Animal Research Center, both of which are funded by the National Research Program for Biopharmaceuticals (NRPB), and doctor Kun-Ze Lee for the setting up of respiratory study. We thank Mika Ito and Naomi Takino (Jichi Medical University, Japan) for their help with the production of the AAV vectors.
Statement of Author Contributions
N.L, W.H., and Y.C. designed and conducted the study and performed statistical analysis. S.M. provided the AAVN vector. D.F., B.B., and L.T. supervised the immunohistochemistry and respiratory study. C.C, N.S., and K.C. performed the immunohistochemistry, functional study, and molecular studies. All authors participated in the manuscript preparation and approved the final version for submission.
Compliance with Ethical Standards
The authors have disclosed the potential conflicts of interest. The experimental procedures were approved and performed in accordance with the guidelines of the National Taiwan University College of Medicine and the College of Public Health Institutional Animal Care and Use Committee (IACUC No. 20120334). There is no human samples in this study and no inform consent is needed.
Conflict of Interest
S. M. owns equity in a gene therapy company (Gene Therapy Research Institution) that commercializes the use of AAV vectors for gene therapy applications. To the extent that the work in this manuscript increases the value of these commercial holdings, S. M. has a conflict of interest. No competing financial interests exist for other authors.
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