Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.
Animals
Ataxia
/ genetics
Central Nervous System Diseases
/ genetics
Dependovirus
/ genetics
Disease Models, Animal
Female
Genetic Therapy
Genetic Vectors
/ administration & dosage
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Mitochondrial Diseases
/ genetics
Phosphate Transport Proteins
/ physiology
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
13 03 2020
13 03 2020
Historique:
received:
22
08
2019
revised:
10
11
2019
accepted:
11
11
2019
pubmed:
17
1
2020
medline:
4
6
2021
entrez:
17
1
2020
Statut:
ppublish
Résumé
Mitochondrial disorders are the result of nuclear and mitochondrial DNA mutations that affect multiple organs, with the central and peripheral nervous system often affected. Currently, there is no cure for mitochondrial disorders. Currently, gene therapy offers a novel approach for treating monogenetic disorders, including nuclear genes associated with mitochondrial disorders. We utilized a mouse model carrying a knockout of the mitochondrial fusion-fission-related gene solute carrier family 25 member 46 (Slc25a46) and treated them with neurotrophic AAV-PHP.B vector carrying the mouse Slc25a46 coding sequence. Thereafter, we used immunofluorescence staining and western blot to test the transduction efficiency of this vector. Toluidine blue staining and electronic microscopy were utilized to assess the morphology of optic and sciatic nerves following treatment, and the morphology and respiratory chain activity of mitochondria within these tissues were determined as well. The adeno-associated virus (AAV) vector effectively transduced in the cerebrum, cerebellum, heart, liver and sciatic nerves. AAV-Slc25a46 treatment was able to rescue the premature death in the mutant mice (Slc25a46-/-). The treatment-improved electronic conductivity of the peripheral nerves increased mobility and restored mitochondrial complex activities. Most notably, mitochondrial morphology inside the tissues of both the central and peripheral nervous systems was normalized, and the neurodegeneration, chronic neuroinflammation and loss of Purkinje cell dendrites observed within the mutant mice were alleviated. Overall, our study shows that AAV-PHP.B's neurotrophic properties are plausible for treating conditions where the central nervous system is affected, such as many mitochondrial diseases, and that AAV-Slc25a46 could be a novel approach for treating SLC25A46-related mitochondrial disorders.
Identifiants
pubmed: 31943007
pii: 5701563
doi: 10.1093/hmg/ddz277
pmc: PMC7068115
doi:
Substances chimiques
Phosphate Transport Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
649-661Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR064551
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY026609
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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