Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina

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DESCRIPTION (provided by applicant): Neurodegenerative eye diseases such as glaucoma cause blindness in a large population in the USA, yet effective treatments are lacking. The ultimate goal of this project is to develop new methods for rescue of retinal neurodegeneration by exploiting a unique endogenous neuroprotective agent, the σ1R chaperone, whose anti-apoptotic properties are being uncovered. Our in vivo studies suggest that the σ1R is ROS (reactive oxygen species)-suppressing and is protective against retinal degeneration in ganglion cells as well as in photoreceptors. This project represents the first study to test the efficacy of the σ1R-mediated retinal neuroprotection by σ1R gene therapy, by overexpressing the σ1R in stem cell-derived photoreceptors to enhance their post-transplantation survival, and by using the sigma-1 receptor knock model (σ1ko) combined with the chronic DBA/2J glaucoma model or rd10 model. In Specific Aim 1, we will examine the impact of the absence of the σ1R for the viability of ganglion cells and photoreceptors in vivo in the DBA/2J model of glaucoma and the rd10 model of RP, respectively. Since we have discovered that ganglion cells of the σ1ko mice are more susceptible to retinal degeneration than the wild type in an acute model, we will further test our finding using a new model crossed with the σ1ko and the chronic glaucoma model of DBA/2J. We will also extend our investigation into a neuroprotective role of the σ1R in retinal photoreceptors, which has yet to be defined, in a new model that we have generated by crossing σ1ko and rd10. Retinal ROS levels will be compared in the presence and absence of the σ1R in these models. In Specific Aim 2, we will test σ1R gene therapy for rescue of retinal degeneration using lentiviruses. To increase the σ1R abundance in the retina, we will transduce the rd10 mouse photoreceptors with lentiviruses harboring the σ1R gene and the Opsin promoter using a technique of subretinal injection. Retinal functions of the transgenic eye overexpressing the σ1R will be compared to that injected with the σ1R-negative mock virus. In Specific Aim 3, we will explore the neuroprotective effect of the σ1R on the post-transplantation survival of stem cell-derived photoreceptors. In stem cell therapy, elevated oxidative stress due to the death of rods, which are active major consumers of oxygen in the retina, imposes detrimental threat to the survival of transplanted photoreceptors. We will overexpress the σ1R in human embryonic stem cell-derived photoreceptors to enhance their survival after transplantation into the rd10 retina. The pro-survival effect of the σ1R on transplanted photoreceptors will be assessed in comparison to the control transplant cells that are transduced with the σ1R-negative mock virus. Ultimately, our finding will lead to new σ1R-targeted therapeutic strategies for rescue of the devastating retinal neurodegenerative diseases.