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Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis

There is emerging evidence that the misfolding of superoxide dismutase 1 (SOD1) may represent a common pathogenic event in both familial and sporadic amyotrophic lateral sclerosis (ALS). To reduce the burden of misfolded SOD1 species in the nervous system, we have tested a novel therapeutic approach...

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Autores principales: Patel, Priyanka, Kriz, Jasna, Gravel, Mathieu, Soucy, Geneviève, Bareil, Christine, Gravel, Claude, Julien, Jean-Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944333/
https://www.ncbi.nlm.nih.gov/pubmed/24394188
http://dx.doi.org/10.1038/mt.2013.239
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author Patel, Priyanka
Kriz, Jasna
Gravel, Mathieu
Soucy, Geneviève
Bareil, Christine
Gravel, Claude
Julien, Jean-Pierre
author_facet Patel, Priyanka
Kriz, Jasna
Gravel, Mathieu
Soucy, Geneviève
Bareil, Christine
Gravel, Claude
Julien, Jean-Pierre
author_sort Patel, Priyanka
collection PubMed
description There is emerging evidence that the misfolding of superoxide dismutase 1 (SOD1) may represent a common pathogenic event in both familial and sporadic amyotrophic lateral sclerosis (ALS). To reduce the burden of misfolded SOD1 species in the nervous system, we have tested a novel therapeutic approach based on adeno-associated virus (AAV)–mediated tonic expression of a DNA construct encoding a secretable single-chain fragment variable (scFv) antibody composed of the variable heavy and light chain regions of a monoclonal antibody (D3H5) binding specifically to misfolded SOD1. A single intrathecal injection of the AAV encoding the single-chain antibody in SOD1(G93A) mice at 45 days of age resulted in sustained expression of single-chain antibodies in the spinal cord, and it delayed disease onset and extension of life span by up to 28%, in direct correlation with scFv titers in the spinal cord. The treatment caused attenuation of neuronal stress signals and reduction in levels of misfolded SOD1 in the spinal cord of SOD1(G93A) mice. From these results, we propose that an immunotherapy based on intrathecal inoculation of AAV encoding a secretable scFv against misfolded SOD1 should be considered as potential treatment for ALS, especially for individuals carrying SOD1 mutations.
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spelling pubmed-39443332014-03-06 Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis Patel, Priyanka Kriz, Jasna Gravel, Mathieu Soucy, Geneviève Bareil, Christine Gravel, Claude Julien, Jean-Pierre Mol Ther Original Article There is emerging evidence that the misfolding of superoxide dismutase 1 (SOD1) may represent a common pathogenic event in both familial and sporadic amyotrophic lateral sclerosis (ALS). To reduce the burden of misfolded SOD1 species in the nervous system, we have tested a novel therapeutic approach based on adeno-associated virus (AAV)–mediated tonic expression of a DNA construct encoding a secretable single-chain fragment variable (scFv) antibody composed of the variable heavy and light chain regions of a monoclonal antibody (D3H5) binding specifically to misfolded SOD1. A single intrathecal injection of the AAV encoding the single-chain antibody in SOD1(G93A) mice at 45 days of age resulted in sustained expression of single-chain antibodies in the spinal cord, and it delayed disease onset and extension of life span by up to 28%, in direct correlation with scFv titers in the spinal cord. The treatment caused attenuation of neuronal stress signals and reduction in levels of misfolded SOD1 in the spinal cord of SOD1(G93A) mice. From these results, we propose that an immunotherapy based on intrathecal inoculation of AAV encoding a secretable scFv against misfolded SOD1 should be considered as potential treatment for ALS, especially for individuals carrying SOD1 mutations. Nature Publishing Group 2014-03 2014-01-07 /pmc/articles/PMC3944333/ /pubmed/24394188 http://dx.doi.org/10.1038/mt.2013.239 Text en Copyright © 2014 The American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Original Article
Patel, Priyanka
Kriz, Jasna
Gravel, Mathieu
Soucy, Geneviève
Bareil, Christine
Gravel, Claude
Julien, Jean-Pierre
Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis
title Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis
title_full Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis
title_fullStr Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis
title_full_unstemmed Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis
title_short Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis
title_sort adeno-associated virus–mediated delivery of a recombinant single-chain antibody against misfolded superoxide dismutase for treatment of amyotrophic lateral sclerosis
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944333/
https://www.ncbi.nlm.nih.gov/pubmed/24394188
http://dx.doi.org/10.1038/mt.2013.239
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