A Neuron-Specific Gene Therapy Relieves Motor Deficits in Pompe Disease Mice
- 510 Downloads
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.
- 1.Hirschhorn R, Reuser A (2001) Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver C, Beaudet A, Sly W, Valle D (eds) The metabolic and molecular bases of inherited disease, vol III, 8th edn. McGraw-Hill, New York, pp. 3389–3420Google Scholar
- 3.Amalfitano A, McVie-Wylie AJ, Hu H, Dawson TL, Raben N, Plotz P, Chen YT (1999) Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-alpha-glucosidase. Proc Natl Acad Sci U S A 96(16):8861–8866CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Chien YH, Lee NC, Chen CA, Tsai FJ, Tsai WH, Shieh JY, Huang HJ, Hsu WC, Tsai TH, Hwu WL (2015) Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. J Pediatr 166 (4):985-991 e981-982. doi:10.1016/j.jpeds.2014.10.068Google Scholar
- 11.van Gelder CM, van Capelle CI, Ebbink BJ, Moor-van Nugteren I, van den Hout JM, Hakkesteegt MM, van Doorn PA, de Coo IF et al (2012) Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy. J Inherit Metab Dis 35(3):505–511CrossRefPubMedGoogle Scholar
- 16.Raben N, Nagaraju K, Lee E, Kessler P, Byrne B, Lee L, LaMarca M, King C et al (1998) Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J Biol Chem 273(30):19086–19092CrossRefPubMedGoogle Scholar
- 21.Khanna R, Flanagan JJ, Feng J, Soska R, Frascella M, Pellegrino LJ, Lun Y, Guillen D et al (2012) The pharmacological chaperone AT2220 increases recombinant human acid alpha-glucosidase uptake and glycogen reduction in a mouse model of Pompe disease. PLoS One 7(7):e40776CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Deacon RM (2013) Measuring the strength of mice. J Vis Exp (76)Google Scholar
- 33.Deacon RM (2013) Measuring motor coordination in mice. J Vis Exp (75):e2609Google Scholar