Preservation of retinal structure and function in two mouse models of inherited retinal degeneration by ONL1204, an inhibitor of the Fas receptor.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
08 Aug 2024
08 Aug 2024
Historique:
received:
15
04
2024
accepted:
01
08
2024
revised:
30
07
2024
medline:
9
8
2024
pubmed:
9
8
2024
entrez:
8
8
2024
Statut:
epublish
Résumé
Due to the large number of genes and mutations that result in inherited retinal degenerations (IRD), there has been a paucity of therapeutic options for these patients. There is a large unmet need for therapeutic approaches targeting shared pathophysiologic pathways in a mutation-independent manner. The Fas receptor is a major activator and regulator of retinal cell death and inflammation in a variety of ocular diseases. We previously reported the activation of Fas-mediated photoreceptor (PR) cell death in two different IRD mouse models, rd10 and P23H, and demonstrated the protective effect of genetic Fas inhibition. The purpose of this study was to examine the effects of pharmacologic inhibition of Fas in these two models by intravitreal injection with a small peptide inhibitor of the Fas receptor, ONL1204. A single intravitreal injection of ONL1204 was given to one eye of rd10 mice at P14. Two intravitreal injections of ONL1204 were given to the P23H mice, once at P14 and again at 2-months of age. The fellow eyes were injected with vehicle alone. Fas activation, rate of PR cell death, retinal function, and the activation of immune cells in the retina were evaluated. In both rd10 and P23H mice, ONL1204 treatment resulted in decreased number of TUNEL (+) PRs, decreased caspase 8 activity, enhanced photoreceptor cell counts, and improved visual function compared with vehicle treated fellow eyes. Treatment with ONL1204 also reduced immune cell activation in the retinas of both rd10 and P23H mice. The protective effect of pharmacologic inhibition of Fas by ONL1204 in two distinct mouse models of retinal degeneration suggests that targeting this common pathophysiologic mechanism of cell death and inflammation represents a potential therapeutic approach to preserve the retina in patients with IRD, regardless of the genetic underpinning.
Identifiants
pubmed: 39117629
doi: 10.1038/s41419-024-06970-6
pii: 10.1038/s41419-024-06970-6
doi:
Substances chimiques
fas Receptor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
576Subventions
Organisme : NEI NIH HHS
ID : R01 EY020823
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : P30EY-07003
Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : P30EY007003
Organisme : NEI NIH HHS
ID : R01 EY020823
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : P30EY007003
Organisme : NEI NIH HHS
ID : R01 EY020823
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : P30EY007003
Informations de copyright
© 2024. The Author(s).
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