Therapeutic Window of AAV-SIRT1 Gene Therapy in Mouse Models of Optic Nerve Degeneration.
4 affiliations
- 1Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA.
- 2F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- 3Center for Preventive Ophthalmology and Biostatistics, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 4Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
Abstract
Purpose
Optic neuropathies involve progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision deficits. While pretreatment with drugs or gene therapy that upregulate sirtuin 1 (SIRT1), an NAD⁺-dependent deacetylase, has shown neuroprotective effects, its effectiveness when administered after disease onset remains uncertain. We investigated whether adeno-associated virus (AAV)-mediated SIRT1 overexpression in RGCs can provide post-onset neuroprotection in preclinical models of optic neuropathy.Methods
RGC degeneration was induced in C57BL/6 mice (8-10/group) using two models: elevated intraocular pressure via intracameral magnetic microbeads (glaucoma model), and myelin oligodendrocyte glycoprotein immunization to induce optic neuritis in an experimental autoimmune encephalomyelitis (EAE model). Mice received intravitreal injections of either control AAV2 or AAV2-SIRT1, which drives SIRT1 expression under the γ-synuclein promoter. Treatment was delivered either 2 weeks before, at, or 1 week after disease onset. We assessed RGC survival and function by immunolabeled RGC counting and optokinetic response, respectively.Results
Intraocular pressure elevation and EAE induction reduced RGC counts and optokinetic response. In the glaucoma model, AAV2-SIRT1 administered before or after onset preserved visual function and increased RGC survival. In the EAE model, SIRT1 therapy significantly increased RGC survival at all time points, although visual function was not significantly improved.Conclusions
SIRT1 gene therapy confers robust RGC neuroprotection and potentially preserves visual function when delivered before or after disease onset in the models of ocular hypertension and optic neuritis.Translational relevance
Our study underscores the translational relevance of SIRT1-based interventions and suggests their potential to avert vision loss in optic neuropathies.
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BibTeX
@article{chaqour2026therapeutic,
title = {{Therapeutic Window of AAV-SIRT1 Gene Therapy in Mouse Models of Optic Nerve Degeneration.}},
author = {Brahim Chaqour and Jennifer C Pham and Jipeng Yue and Kimberly Dine and Fangming Jin and Gui-Shuang Ying and Jean Bennett and Kenneth S Shindler and Ahmara G Ross},
journal = {Translational vision science \& technology},
year = {2026},
month = oct,
doi = {10.1167/tvst.15.10.17},
url = {https://europepmc.org/article/MED/42872912},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Therapeutic Window of AAV-SIRT1 Gene Therapy in Mouse Models of Optic Nerve Degeneration.
AU - Brahim Chaqour
AU - Jennifer C Pham
AU - Jipeng Yue
AU - Kimberly Dine
AU - Fangming Jin
AU - Gui-Shuang Ying
AU - Jean Bennett
AU - Kenneth S Shindler
AU - Ahmara G Ross
PY - 2026
DA - 2026/10/01
JO - Translational vision science & technology
DO - 10.1167/tvst.15.10.17
UR - https://europepmc.org/article/MED/42872912
AB - Purpose Optic neuropathies involve progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision deficits. While pretreatment with drugs or gene therapy that upregulate sirtuin 1 (SIRT1), an NAD⁺-dependent deacetylase, has shown neuroprotective effects, its effectiveness when administered after disease onset remains uncertain. We investigated whether adeno-associated virus (AAV)-mediated SIRT1 overexpression in RGCs can provide post-onset neuroprotection in preclinical models of optic neuropathy.Methods RGC degeneration was induced in C57BL/6 mice (8-10/group) using two models: elevated intraocular pressure via intracameral magnetic microbeads (glaucoma model), and myelin oligodendrocyte glycoprotein immunization to induce optic neuritis in an experimental autoimmune encephalomyelitis (EAE model). Mice received intravitreal injections of either control AAV2 or AAV2-SIRT1, which drives SIRT1 expression under the γ-synuclein promoter. Treatment was delivered either 2 weeks before, at, or 1 week after disease onset. We assessed RGC survival and function by immunolabeled RGC counting and optokinetic response, respectively.Results Intraocular pressure elevation and EAE induction reduced RGC counts and optokinetic response. In the glaucoma model, AAV2-SIRT1 administered before or after onset preserved visual function and increased RGC survival. In the EAE model, SIRT1 therapy significantly increased RGC survival at all time points, although visual function was not significantly improved.Conclusions SIRT1 gene therapy confers robust RGC neuroprotection and potentially preserves visual function when delivered before or after disease onset in the models of ocular hypertension and optic neuritis.Translational relevance Our study underscores the translational relevance of SIRT1-based interventions and suggests their potential to avert vision loss in optic neuropathies.
SN - 2164-2591
ER -