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Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model

INTRODUCTION: Therapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate. We have developed two gene therapy strategies for the disease: mitochondrial-targeted and allotopic expressed and compared them in a mouse model of...

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Autores principales: Velmurugan, Sindhu, Chou, Tsung-Han, Eastwood, Jeremy D., Porciatti, Vittorio, Liu, Yuan, Hauswirth, William W., Guy, John, Yu, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10083341/
https://www.ncbi.nlm.nih.gov/pubmed/37051151
http://dx.doi.org/10.3389/fnins.2023.1119724
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author Velmurugan, Sindhu
Chou, Tsung-Han
Eastwood, Jeremy D.
Porciatti, Vittorio
Liu, Yuan
Hauswirth, William W.
Guy, John
Yu, Hong
author_facet Velmurugan, Sindhu
Chou, Tsung-Han
Eastwood, Jeremy D.
Porciatti, Vittorio
Liu, Yuan
Hauswirth, William W.
Guy, John
Yu, Hong
author_sort Velmurugan, Sindhu
collection PubMed
description INTRODUCTION: Therapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate. We have developed two gene therapy strategies for the disease: mitochondrial-targeted and allotopic expressed and compared them in a mouse model of LHON. METHODS: A LHON mouse model was generated by intravitreal injection of a mitochondrialtargeted Adeno-associated virus (AAV) carrying mutant human NADH dehydrogenase 4 gene (hND4/m.11778G>A) to induce retinal ganglion cell (RGC) degeneration and axon loss, the hallmark of the human disease. We then attempted to rescue those mice using a second intravitreal injection of either mitochondrial-targeted or allotopic expressed wildtype human ND4. The rescue of RGCs and their axons were assessed using serial pattern electroretinogram (PERG) and transmission electron microscopy. RESULTS: Compared to non-rescued LHON controls where PERG amplitude was much reduced, both strategies significantly preserved PERG amplitude over 15 months. However, the rescue effect was more marked with mitochondrial-targeted therapy than with allotopic therapy (p = 0.0128). Post-mortem analysis showed that mitochondrial-targeted human ND4 better preserved small axons that are preferentially lost in human LHON. CONCLUSIONS: These results in a pre-clinical mouse model of LHON suggest that mitochondrially-targeted AAV gene therapy, compared to allotopic AAV gene therapy, is more efficient in rescuing the LHON phenotype.
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spelling pubmed-100833412023-04-11 Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model Velmurugan, Sindhu Chou, Tsung-Han Eastwood, Jeremy D. Porciatti, Vittorio Liu, Yuan Hauswirth, William W. Guy, John Yu, Hong Front Neurosci Neuroscience INTRODUCTION: Therapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate. We have developed two gene therapy strategies for the disease: mitochondrial-targeted and allotopic expressed and compared them in a mouse model of LHON. METHODS: A LHON mouse model was generated by intravitreal injection of a mitochondrialtargeted Adeno-associated virus (AAV) carrying mutant human NADH dehydrogenase 4 gene (hND4/m.11778G>A) to induce retinal ganglion cell (RGC) degeneration and axon loss, the hallmark of the human disease. We then attempted to rescue those mice using a second intravitreal injection of either mitochondrial-targeted or allotopic expressed wildtype human ND4. The rescue of RGCs and their axons were assessed using serial pattern electroretinogram (PERG) and transmission electron microscopy. RESULTS: Compared to non-rescued LHON controls where PERG amplitude was much reduced, both strategies significantly preserved PERG amplitude over 15 months. However, the rescue effect was more marked with mitochondrial-targeted therapy than with allotopic therapy (p = 0.0128). Post-mortem analysis showed that mitochondrial-targeted human ND4 better preserved small axons that are preferentially lost in human LHON. CONCLUSIONS: These results in a pre-clinical mouse model of LHON suggest that mitochondrially-targeted AAV gene therapy, compared to allotopic AAV gene therapy, is more efficient in rescuing the LHON phenotype. Frontiers Media S.A. 2023-03-27 /pmc/articles/PMC10083341/ /pubmed/37051151 http://dx.doi.org/10.3389/fnins.2023.1119724 Text en Copyright © 2023 Velmurugan, Chou, Eastwood, Porciatti, Liu, Hauswirth, Guy and Yu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Velmurugan, Sindhu
Chou, Tsung-Han
Eastwood, Jeremy D.
Porciatti, Vittorio
Liu, Yuan
Hauswirth, William W.
Guy, John
Yu, Hong
Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model
title Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model
title_full Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model
title_fullStr Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model
title_full_unstemmed Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model
title_short Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model
title_sort comparison of different gene-therapy methods to treat leber hereditary optic neuropathy in a mouse model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10083341/
https://www.ncbi.nlm.nih.gov/pubmed/37051151
http://dx.doi.org/10.3389/fnins.2023.1119724
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