AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1
| Autor: | Jerry R. Mendell, Alicia Ridgley, Kyle Moss, Shasha Bai, Lei Chen, Morgan Myers, Mona M. Freidin, Burcak Ozes, Jennifer L. McKinney, Charles K. Abrams, Zarife Sahenk |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
Schwann cell Gene delivery Biology Connexins Nerve conduction velocity Mice Myelin Gastrocnemius muscle Charcot-Marie-Tooth Disease Internal medicine Genetics medicine Animals Humans Axon Autocrine signalling Molecular Biology Mice Knockout Genetic Therapy Axons Nerve Regeneration Compound muscle action potential medicine.anatomical_structure Endocrinology Mutation Molecular Medicine Schwann Cells |
| Zdroj: | Gene Therapy. 29:127-137 |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | X-linked Charcot-Marie-Tooth neuropathy (CMTX) is caused by mutations in the gene encoding Gap Junction Protein Beta-1 (GJB1)/Connexin32 (Cx32) in Schwann cells. Neurotrophin-3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. Improvements in these parameters have been shown previously in a CMT1 model, TremblerJ mouse, with NT-3 gene transfer therapy. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of 3-month-old Cx32 knockout (KO) mice. Measurable levels of NT-3 were found in the serum at 6-month post gene delivery. The outcome measures included functional, electrophysiological and histological assessments. At 9-months of age, NT-3 treated mice showed no functional decline with normalized compound muscle action potential amplitudes. Myelin thickness and nerve conduction velocity significantly improved compared with untreated cohort. A normalization toward age-matched wildtype histopathological parameters included increased number of Schmidt-Lanterman incisures, and muscle fiber diameter. Collectively, these findings suggest a translational application to CMTX1. |
| Databáze: | OpenAIRE |
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