Therapeutic Window of AAV-SIRT1 Gene Therapy in Mouse Models of Optic Nerve Degeneration.

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.