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Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2021 May 05; Vol. 29 (5), pp. 1883-1902. Date of Electronic Publication: 2021 Jan 26. - Publication Year :
- 2021
-
Abstract
- Neonatal AAV9-gene therapy of the lysosomal enzyme galactosylceramidase (GALC) significantly ameliorates central and peripheral neuropathology, prolongs survival, and largely normalizes motor deficits in Twitcher mice. Despite these therapeutic milestones, new observations identified the presence of multiple small focal demyelinating areas in the brain after 6-8 months. These lesions are in stark contrast to the diffuse, global demyelination that affects the brain of naive Twitcher mice. Late-onset lesions exhibited lysosomal alterations with reduced expression of GALC and increased psychosine levels. Furthermore, we found that lesions were closely associated with the extravasation of plasma fibrinogen and activation of the fibrinogen-BMP-SMAD-GFAP gliotic response. Extravasation of fibrinogen correlated with tight junction disruptions of the vasculature within the lesioned areas. The lesions were surrounded by normal appearing white matter. Our study shows that the dysregulation of therapeutic GALC was likely driven by the exhaustion of therapeutic AAV episomal DNA within the lesions, paralleling the presence of proliferating oligodendrocyte progenitors and glia. We believe that this is the first demonstration of diminishing expression in vivo from an AAV gene therapy vector with detrimental effects in the brain of a lysosomal storage disease animal model. The development of this phenotype linking localized loss of GALC activity with relapsing neuropathology in the adult brain of neonatally AAV-gene therapy-treated Twitcher mice identifies and alerts to possible late-onset reductions of AAV efficacy, with implications to other genetic leukodystrophies.<br /> (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Animals, Newborn
Cells, Cultured
Dependovirus genetics
Disease Models, Animal
Female
Fibrinogen metabolism
Galactosylceramidase metabolism
Genetic Vectors administration & dosage
Leukodystrophy, Globoid Cell blood
Leukodystrophy, Globoid Cell genetics
Leukodystrophy, Globoid Cell therapy
Male
Mice
Recurrence
Galactosylceramidase genetics
Genetic Therapy methods
Leukodystrophy, Globoid Cell pathology
White Matter pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 29
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 33508430
- Full Text :
- https://doi.org/10.1016/j.ymthe.2021.01.026