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Characterization of AAV-mediated dorsal root ganglionopathy

Recent studies in non-human primates administered recombinant adeno-associated viruses (rAAVs) have shown lesions in the dorsal root ganglia (DRG) of unknown pathogenesis. In this study, rAAV9s manufactured using different purification methods alongside a non-expressing Null AAV9 vector was administ...

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Autores principales: Buss, Nicholas, Lanigan, Lisa, Zeller, Jillynne, Cissell, Derek, Metea, Monica, Adams, Eric, Higgins, Mikayla, Kim, Kwi Hye, Budzynski, Ewa, Yang, Lin, Liu, Ye, Butt, Mark, Danos, Olivier, Fiscella, Michele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851102/
https://www.ncbi.nlm.nih.gov/pubmed/35229008
http://dx.doi.org/10.1016/j.omtm.2022.01.013
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author Buss, Nicholas
Lanigan, Lisa
Zeller, Jillynne
Cissell, Derek
Metea, Monica
Adams, Eric
Higgins, Mikayla
Kim, Kwi Hye
Budzynski, Ewa
Yang, Lin
Liu, Ye
Butt, Mark
Danos, Olivier
Fiscella, Michele
author_facet Buss, Nicholas
Lanigan, Lisa
Zeller, Jillynne
Cissell, Derek
Metea, Monica
Adams, Eric
Higgins, Mikayla
Kim, Kwi Hye
Budzynski, Ewa
Yang, Lin
Liu, Ye
Butt, Mark
Danos, Olivier
Fiscella, Michele
author_sort Buss, Nicholas
collection PubMed
description Recent studies in non-human primates administered recombinant adeno-associated viruses (rAAVs) have shown lesions in the dorsal root ganglia (DRG) of unknown pathogenesis. In this study, rAAV9s manufactured using different purification methods alongside a non-expressing Null AAV9 vector was administered to groups of cynomolgus monkeys followed by neuropathological evaluation after 4 weeks. Lesions, including neuronal degeneration, increased cellularity, and nerve fiber degeneration, were observed in the DRG, regardless of purification methods. Animals did not develop any neurological signs throughout the study, and there was no loss of function observed in neuro-electrophysiological endpoints or clear effects on intraepidermal nerve fiber density. However, magnetic resonance imaging (MRI) of animals with axonopathy showed an increase in short tau inversion recovery (STIR) intensity and decrease in fractional anisotropy. In animals administered the Null AAV9 vector, DRG lesions were not observed despite vector DNA being detected in the DRG at levels equivalent to or greater than rAAV9-treated animals. This study further supports that DRG toxicity is associated with transgene overexpression in DRGs, with particular sensitivity at the lumbar and lumbosacral level. The data from this study also showed that the nerve fiber degeneration did not correlate with any functional effect on nerve conduction but was detectable by MRI.
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spelling pubmed-88511022022-02-27 Characterization of AAV-mediated dorsal root ganglionopathy Buss, Nicholas Lanigan, Lisa Zeller, Jillynne Cissell, Derek Metea, Monica Adams, Eric Higgins, Mikayla Kim, Kwi Hye Budzynski, Ewa Yang, Lin Liu, Ye Butt, Mark Danos, Olivier Fiscella, Michele Mol Ther Methods Clin Dev Original Article Recent studies in non-human primates administered recombinant adeno-associated viruses (rAAVs) have shown lesions in the dorsal root ganglia (DRG) of unknown pathogenesis. In this study, rAAV9s manufactured using different purification methods alongside a non-expressing Null AAV9 vector was administered to groups of cynomolgus monkeys followed by neuropathological evaluation after 4 weeks. Lesions, including neuronal degeneration, increased cellularity, and nerve fiber degeneration, were observed in the DRG, regardless of purification methods. Animals did not develop any neurological signs throughout the study, and there was no loss of function observed in neuro-electrophysiological endpoints or clear effects on intraepidermal nerve fiber density. However, magnetic resonance imaging (MRI) of animals with axonopathy showed an increase in short tau inversion recovery (STIR) intensity and decrease in fractional anisotropy. In animals administered the Null AAV9 vector, DRG lesions were not observed despite vector DNA being detected in the DRG at levels equivalent to or greater than rAAV9-treated animals. This study further supports that DRG toxicity is associated with transgene overexpression in DRGs, with particular sensitivity at the lumbar and lumbosacral level. The data from this study also showed that the nerve fiber degeneration did not correlate with any functional effect on nerve conduction but was detectable by MRI. American Society of Gene & Cell Therapy 2022-02-01 /pmc/articles/PMC8851102/ /pubmed/35229008 http://dx.doi.org/10.1016/j.omtm.2022.01.013 Text en © 2022 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
Buss, Nicholas
Lanigan, Lisa
Zeller, Jillynne
Cissell, Derek
Metea, Monica
Adams, Eric
Higgins, Mikayla
Kim, Kwi Hye
Budzynski, Ewa
Yang, Lin
Liu, Ye
Butt, Mark
Danos, Olivier
Fiscella, Michele
Characterization of AAV-mediated dorsal root ganglionopathy
title Characterization of AAV-mediated dorsal root ganglionopathy
title_full Characterization of AAV-mediated dorsal root ganglionopathy
title_fullStr Characterization of AAV-mediated dorsal root ganglionopathy
title_full_unstemmed Characterization of AAV-mediated dorsal root ganglionopathy
title_short Characterization of AAV-mediated dorsal root ganglionopathy
title_sort characterization of aav-mediated dorsal root ganglionopathy
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851102/
https://www.ncbi.nlm.nih.gov/pubmed/35229008
http://dx.doi.org/10.1016/j.omtm.2022.01.013
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