Regardless, it is clear there is an unmet need for therapy aimed at delaying and potentially aborting the cell death associated with loss of vision.Īny primary insult to the visual tract or secondary deficits due to inflammation, demyelination, compression, or structural effects of the surrounding tissue can lead to RGC death and visual decline. Mechanisms such as vascular and inflammatory mediators of RGC death have been implicated in perpetuating the process of RGC death, however the true pathophysiology is likely direct cell death. The damage occurs at the level of axons, disrupting critical connections needed to maintain retinal ganglion cell (RGC) function. Although this type of injury can occur in any age group, most TON occurs in young males under the age of 18, resulting in a range of visual outcomes from unaffected to substantial vision loss. The irreversible effects of traumatic optic neuropathy (TON) can result from direct impulse or indirectly by shearing or stretch of the optic nerve. This study expands our understanding of SIRT1 mediated neuroprotection in the context of compressive or traumatic optic neuropathy, making it a strong therapeutic candidate for testing in all optic neuropathies. Over-expression of SIRT1 through AAV-mediated gene transduction suggests a RGC selective component of neuro-protection using the ONC model. RGC-selective expression of SIRT1 offers a targeted therapy for an animal model with significant ganglion cell loss. Intravitreal delivery of AAV7m8-SNCG.SIRT1 mediated significant preservation of the OKR and RGC survival compared to AAV7m8-SNCG.eGFP controls, an effect not seen with the AAV2 vector. Animals modeling ONC demonstrated reduced visual acuity compared to controls. The AAV7m8-SNCG.SIRT1 vector showed 44% transduction efficiency for RGCs compared with 25% ( P > 0.05) by AAV2-CAG.SIRT1, and AAV7m8-SNCG.SIRT1 drives expression selectively in RGCs in vivo. Retina and optic nerves were harvested to investigate RGC survival by immunolabeling. Visual function was examined by optokinetic response (OKR) for 7 days following ONC. Cohorts of C57Bl/6J mice received intravitreal injection of experimental or control AAVs using either a ganglion cell promoter or a constitutive promoter and ONC was performed. We hypothesized that AAV-mediated overexpression of SIRT1 in RGCs reduces RGC loss, thereby preserving visual function. We investigated the neuroprotective potential of RGC-selective SIRT1 gene therapy in the optic nerve crush (ONC) model. The exact mechanism of loss is not known, prior evidence suggests this is through oxidative stress to either neighboring cells or RGC specifically. SIRT1 prevents retinal ganglion cell (RGC) loss in models of optic neuropathy following pharmacologic activation or genetic overexpression.
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