Cell-Specific Expression of Human SIRT1 by Gene Therapy Reduces Retinal Ganglion Cell Loss Induced by Elevated Intraocular Pressure.

SIRT1 prevents retinal ganglion cell (RGC) loss in several acute and subacute optic neuropathy models following pharmacologic activation or genetic overexpression. We hypothesized that adeno-associated virus (AAV)-mediated overexpression of SIRT1 in RGCs in a chronic ocular hypertension model can reduce RGC loss, thereby preserving visual function by sustained therapeutic effect. A control vector AAV-eGFP and therapeutic vector AAV-SIRT1 were constructed and optimized for transduction efficiency. A magnetic microbead mouse model of ocular hypertension was optimized to induce a time-dependent and chronic loss of visual function and RGC degeneration. Mice received intravitreal injection of control or therapeutic AAV in which a codon-optimized human SIRT1 expression is driven by a RGC selective promoter. Intraocular pressure (IOP) was measured, and visual function was examined by optokinetic response (OKR) weekly for 49 days following microbead injection. Visual function, RGC survival, and axon numbers were compared among control and therapeutic AAV-treated animals. AAV-eGFP and AAV-SIRT1 showed transduction efficiency of ~ 40%. AAV-SIRT1 maintains the transduction of SIRT1 over time and is selectively expressed in RGCs. Intravitreal injections of AAV-SIRT1 in a glaucoma model preserved visual function, increased RGC survival, and reduced axonal degeneration compared with the control construct. Over-expression of SIRT1 through AAV-mediated gene transduction indicates a RGC-selective component of neuroprotection in multiple models of acute optic nerve degeneration. Results here show a neuroprotective effect of RGC-selective gene therapy in a chronic glaucoma model characterized by sustained elevation of IOP and subsequent RGC loss. Results suggest that this strategy may be an effective therapeutic approach for treating glaucoma, and warrants evaluation for the treatment of other chronic neurodegenerative diseases.