Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1783703123002392576 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8175802 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT audouardemilie completecorrectionofbrainandspinalcordpathologyinmetachromaticleukodystrophymice AT ogervalentin completecorrectionofbrainandspinalcordpathologyinmetachromaticleukodystrophymice AT mehabeatrix completecorrectionofbrainandspinalcordpathologyinmetachromaticleukodystrophymice AT cartiernathalie completecorrectionofbrainandspinalcordpathologyinmetachromaticleukodystrophymice AT sevincaroline completecorrectionofbrainandspinalcordpathologyinmetachromaticleukodystrophymice AT piguetfrancoise completecorrectionofbrainandspinalcordpathologyinmetachromaticleukodystrophymice |