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Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116612/ https://www.ncbi.nlm.nih.gov/pubmed/33508430 http://dx.doi.org/10.1016/j.ymthe.2021.01.026 |
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author | Heller, Gregory J. Marshall, Michael S. Issa, Yazan Marshall, Jeffrey N. Nguyen, Duc Rue, Emily Pathmasiri, Koralege C. Domowicz, Miriam S. van Breemen, Richard B. Tai, Leon M. Cologna, Stephanie M. Crocker, Stephen J. Givogri, Maria I. Sands, Mark S. Bongarzone, Ernesto R. |
author_facet | Heller, Gregory J. Marshall, Michael S. Issa, Yazan Marshall, Jeffrey N. Nguyen, Duc Rue, Emily Pathmasiri, Koralege C. Domowicz, Miriam S. van Breemen, Richard B. Tai, Leon M. Cologna, Stephanie M. Crocker, Stephen J. Givogri, Maria I. Sands, Mark S. Bongarzone, Ernesto R. |
author_sort | Heller, Gregory J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8116612 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-81166122022-05-05 Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease Heller, Gregory J. Marshall, Michael S. Issa, Yazan Marshall, Jeffrey N. Nguyen, Duc Rue, Emily Pathmasiri, Koralege C. Domowicz, Miriam S. van Breemen, Richard B. Tai, Leon M. Cologna, Stephanie M. Crocker, Stephen J. Givogri, Maria I. Sands, Mark S. Bongarzone, Ernesto R. Mol Ther Original Article 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. American Society of Gene & Cell Therapy 2021-05-05 2021-01-26 /pmc/articles/PMC8116612/ /pubmed/33508430 http://dx.doi.org/10.1016/j.ymthe.2021.01.026 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Heller, Gregory J. Marshall, Michael S. Issa, Yazan Marshall, Jeffrey N. Nguyen, Duc Rue, Emily Pathmasiri, Koralege C. Domowicz, Miriam S. van Breemen, Richard B. Tai, Leon M. Cologna, Stephanie M. Crocker, Stephen J. Givogri, Maria I. Sands, Mark S. Bongarzone, Ernesto R. Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease |
title | Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease |
title_full | Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease |
title_fullStr | Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease |
title_full_unstemmed | Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease |
title_short | Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease |
title_sort | waning efficacy in a long-term aav-mediated gene therapy study in the murine model of krabbe disease |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116612/ https://www.ncbi.nlm.nih.gov/pubmed/33508430 http://dx.doi.org/10.1016/j.ymthe.2021.01.026 |
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