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Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effe...

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Autores principales: Audouard, Emilie, Oger, Valentin, Meha, Béatrix, Cartier, Nathalie, Sevin, Caroline, Piguet, Françoise
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175802/
https://www.ncbi.nlm.nih.gov/pubmed/34093126
http://dx.doi.org/10.3389/fnmol.2021.677895
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author Audouard, Emilie
Oger, Valentin
Meha, Béatrix
Cartier, Nathalie
Sevin, Caroline
Piguet, Françoise
author_facet Audouard, Emilie
Oger, Valentin
Meha, Béatrix
Cartier, Nathalie
Sevin, Caroline
Piguet, Françoise
author_sort Audouard, Emilie
collection PubMed
description Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.
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spelling pubmed-81758022021-06-05 Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice Audouard, Emilie Oger, Valentin Meha, Béatrix Cartier, Nathalie Sevin, Caroline Piguet, Françoise Front Mol Neurosci Neuroscience Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD. Frontiers Media S.A. 2021-05-21 /pmc/articles/PMC8175802/ /pubmed/34093126 http://dx.doi.org/10.3389/fnmol.2021.677895 Text en Copyright © 2021 Audouard, Oger, Meha, Cartier, Sevin and Piguet. 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
Audouard, Emilie
Oger, Valentin
Meha, Béatrix
Cartier, Nathalie
Sevin, Caroline
Piguet, Françoise
Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
title Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
title_full Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
title_fullStr Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
title_full_unstemmed Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
title_short Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
title_sort complete correction of brain and spinal cord pathology in metachromatic leukodystrophy mice
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175802/
https://www.ncbi.nlm.nih.gov/pubmed/34093126
http://dx.doi.org/10.3389/fnmol.2021.677895
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