Characterization of AAV-mediated dorsal root ganglionopathy.
AAV
AAV9
DRG
MRI
axonopathy
cynomolgus monkey
toxicity
Journal
Molecular therapy. Methods & clinical development
ISSN: 2329-0501
Titre abrégé: Mol Ther Methods Clin Dev
Pays: United States
ID NLM: 101624857
Informations de publication
Date de publication:
10 Mar 2022
10 Mar 2022
Historique:
received:
30
11
2021
accepted:
27
01
2022
entrez:
1
3
2022
pubmed:
2
3
2022
medline:
2
3
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35229008
doi: 10.1016/j.omtm.2022.01.013
pii: S2329-0501(22)00014-6
pmc: PMC8851102
doi:
Types de publication
Journal Article
Langues
eng
Pagination
342-354Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
N.B., M.H., K.H.K., E.B., L.Y., Y.L., O.D., and M.F. are currently employees of REGENXBIO Inc. L.L. was an employee of StageBio at the time of study and is currently an employee of Charles River Laboratories; D.C. is currently an employee of Invicro, A Konica Minolta Company; M.M. is an employee of Preclinical Electrophysiology Consulting, LLC; J.Z. and E.A. were employees of Northern Biomedical Research at the time of study; and M.B. is an employee of StageBio.
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