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AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1
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 regenerat...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013664/ https://www.ncbi.nlm.nih.gov/pubmed/33542455 http://dx.doi.org/10.1038/s41434-021-00231-3 |
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author | Ozes, Burcak Myers, Morgan Moss, Kyle Mckinney, Jennifer Ridgley, Alicia Chen, Lei Bai, Shasha Abrams, Charles K. Freidin, Mona M. Mendell, Jerry R. Sahenk, Zarife |
author_facet | Ozes, Burcak Myers, Morgan Moss, Kyle Mckinney, Jennifer Ridgley, Alicia Chen, Lei Bai, Shasha Abrams, Charles K. Freidin, Mona M. Mendell, Jerry R. Sahenk, Zarife |
author_sort | Ozes, Burcak |
collection | PubMed |
description | 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, Trembler(J) 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. |
format | Online Article Text |
id | pubmed-9013664 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90136642022-04-19 AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1 Ozes, Burcak Myers, Morgan Moss, Kyle Mckinney, Jennifer Ridgley, Alicia Chen, Lei Bai, Shasha Abrams, Charles K. Freidin, Mona M. Mendell, Jerry R. Sahenk, Zarife Gene Ther Article 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, Trembler(J) 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. Nature Publishing Group UK 2021-02-04 2022 /pmc/articles/PMC9013664/ /pubmed/33542455 http://dx.doi.org/10.1038/s41434-021-00231-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ozes, Burcak Myers, Morgan Moss, Kyle Mckinney, Jennifer Ridgley, Alicia Chen, Lei Bai, Shasha Abrams, Charles K. Freidin, Mona M. Mendell, Jerry R. Sahenk, Zarife AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1 |
title | AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1 |
title_full | AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1 |
title_fullStr | AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1 |
title_full_unstemmed | AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1 |
title_short | AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1 |
title_sort | aav1.nt-3 gene therapy for x-linked charcot–marie–tooth neuropathy type 1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013664/ https://www.ncbi.nlm.nih.gov/pubmed/33542455 http://dx.doi.org/10.1038/s41434-021-00231-3 |
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