Intra-CSF AAV9 and AAVrh10 Administration in Nonhuman Primates: Promising Routes and Vectors for Which Neurological Diseases?
AAV
central nervous system
gene therapy
intra-CSF
intracerebroventricular delivery
intrathecal delivery
motor neurons
muscle
neurons
nonhuman primate
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:
12 Jun 2020
12 Jun 2020
Historique:
received:
10
03
2020
accepted:
02
04
2020
entrez:
2
5
2020
pubmed:
2
5
2020
medline:
2
5
2020
Statut:
epublish
Résumé
The identification of the most efficient method for whole central nervous system targeting that is translatable to humans and the safest route of adeno-associated virus (AAV) administration is a major concern for future applications in clinics. Additionally, as many AAV serotypes were identified for gene introduction into the brain and the spinal cord, another key to human gene-therapy success is to determine the most efficient serotype. In this study, we compared lumbar intrathecal administration through catheter implantation and intracerebroventricular administration in the cynomolgus macaque. We also evaluated and compared two AAV serotypes that are currently used in clinical trials: AAV9 and AAVrh10. We demonstrated that AAV9 lumbar intrathecal delivery using a catheter achieved consistent transgene expression in the motor neurons of the spinal cord and in the neurons/glial cells of several brain regions, whereas AAV9 intracerebroventricular delivery led to a consistent transgene expression in the brain. In contrast, AAVrh10 lumbar intrathecal delivery led to rare motor neuron targeting. Finally, we found that AAV9 efficiently targets respiratory and skeletal muscles after injection into the cerebrospinal fluid (CSF), which represents an outstanding new property that can be useful for the treatment of diseases affecting both the central nervous system and muscle.
Identifiants
pubmed: 32355866
doi: 10.1016/j.omtm.2020.04.001
pii: S2329-0501(20)30061-9
pmc: PMC7184633
doi:
Types de publication
Journal Article
Langues
eng
Pagination
771-784Informations de copyright
© 2020.
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