Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection.
Journal
Gene therapy
ISSN: 1476-5462
Titre abrégé: Gene Ther
Pays: England
ID NLM: 9421525
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
12
06
2024
accepted:
11
10
2024
revised:
10
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
aheadofprint
Résumé
Gene augmentation therapy is a promising treatment for incurable, blinding inherited retinal diseases, and intravitreal delivery is being studied as a safe alternative to subretinal injections. Adeno-Associated Viruses (AAV) are commonly-used vectors for ocular gene augmentation therapy. Naturally occurring pre-operative exposure and infection with AAV could result in presence of neutralizing antibodies (NAB's) in patients' serum, and may affect the safety and efficacy of treatment. Our aim was to characterize the humoral response against AAV pre- and post-intravitreal delivery of AAV2.7m8 vectors in a naturally-occurring sheep model of CNGA3 achromatopsia. Serial serum neutralization assays were performed to screen sheep for pre-exiting anti-AAV2 NAB's, and to assess the effect of intravitreal AAV2.7m8 injection on post-operative NAB titers and intraocular inflammation in sheep. The effect of viral dose and transgene type were also assessed. Serological screening revealed pre-operative seropositivity in 21.4% of animals, with age being a risk factor for the presence of anti-AAV2 NAB's. NAB titers increased following intravitreal AAV administration in the majority of sheep. There was no significant difference in the degree of post-operative serum neutralization between pre-operatively seronegative sheep and those with pre-existing antibodies. However, only sheep with pre-existing antibodies presented with signs of post-operative inflammation. We conclude that pre-existing anti-AAV2 NAB's do not affect the level of post-operative NAB titers; however, they increase the risk of post-operative ocular inflammation. Our results could have implications for the management of AAV-mediated ocular gene therapies, a technology being increasingly studied and used in patients.
Identifiants
pubmed: 39472677
doi: 10.1038/s41434-024-00495-5
pii: 10.1038/s41434-024-00495-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Ministry of Health, State of Israel (Ministry of Health)
ID : 3-0000-15068
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Organisme : Israel Science Foundation (ISF)
ID : 1257/15
Informations de copyright
© 2024. The Author(s).
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