Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders.
achromatopsia
intravitreal delivery
novel AAV
retina
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
09 04 2021
09 04 2021
Historique:
revised:
14
01
2021
received:
03
09
2020
accepted:
15
01
2021
pubmed:
23
2
2021
medline:
26
10
2021
entrez:
22
2
2021
Statut:
ppublish
Résumé
Gene therapy using recombinant adeno-associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful targeting of photoreceptors still relies on subretinal vector delivery, which detaches the retina and harbours substantial risks of collateral damage, often without achieving widespread photoreceptor transduction. Herein, we report the development of novel engineered rAAV vectors that enable efficient targeting of photoreceptors via less invasive intravitreal administration. A unique in vivo selection procedure was performed, where an AAV2-based peptide-display library was intravenously administered in mice, followed by isolation of vector DNA from target cells after only 24 h. This stringent selection yielded novel vectors, termed AAV2.GL and AAV2.NN, which mediate widespread and high-level retinal transduction after intravitreal injection in mice, dogs and non-human primates. Importantly, both vectors efficiently transduce photoreceptors in human retinal explant cultures. As proof-of-concept, intravitreal Cnga3 delivery using AAV2.GL lead to cone-specific expression of Cnga3 protein and rescued photopic cone responses in the Cnga3
Identifiants
pubmed: 33616280
doi: 10.15252/emmm.202013392
pmc: PMC8033523
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13392Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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