Activation of a molecular chaperone (sigma 1 receptor) in a murine model of autosomal dominant retinitis pigmentosa.

Abstract

Retinitis pigmentosa (RP) is a devastating group of inherited retinal diseases that leads to visual impairment and eventually complete blindness. Currently no cure or treatment exists for RP patients, thus research into prolonging the vision in these patients is imperative. Sigma 1 receptor (Sig1R) is a promising small molecule target that appears to have neuroprotective benefits in the retina of fast degenerating mouse models. However, it is not clear whether Sig1R activation can provide similar neuroprotective benefits in more slowly progressing RP models, which are more similar to human patients. In this study, we examined whether Sig1R activation can be neuroprotective (i.e. prolong vision) in a more slowly progressing mouse model of autosomal dominant retinitis pigmentosa, RhoP23H/+. Current studies in the field give a brief overview of the RhoP23H/+ degeneration, but do not give a complete characterization of disease progression. Aim 1 of this study sought to further characterize the degeneration of the RhoP23H/+ mouse using 3 in vivo methods, Optomotor Response (OMR), Electrophysiology (ERG), and Spectral Domain-Optical Coherence Tomography (SD-OCT). A slow retinal degeneration was observed in both male and female RhoP23H/+ mice when compared to WT. Visual acuity showed a gradual decline through 10 months. Interestingly, visual acuity was still detectible, albeit significantly reduced through 10 months in both male and female mutant mice. Females appeared to have significantly lower visual acuity than males. These RhoP23H/+ mice showed a gradual decline in scotopic and photopic responses. Aims 2 and 3 sought to investigate the neuroprotective benefits of Sig1R activation in the RhoP23H/+ mouse model. Mutant mice were treated with a high specificity Sig1R ligand (+)-pentazocine ((+)-PTZ) 3x/week and examined using OMR, ERG, SD-OCT. A significant retention of visual function was observed in both males and females at 10 months of age, with treated females retaining ~50% greater visual acuity than non-treated mutant females. Using ERG, significant retention of scotopic and photopic b-wave amplitudes were observed at 6 months in both male and female mice treated with (+)-PTZ. Further, in vivo analysis of ONL thickness revealed a significant retention in both male and female treated mice. Histological studies using retinal cryosections showed significant retention of IS/OS length (~50%), ONL thickness, and number of rows of PRC nuclei at 6 months in both male and female (+)-PTZ-treated mice. Interestingly, electron microscopy revealed preservation of OS discs in (+)-PTZ treated mutant mice. Taken collectively, the in vivo and in vitro data represent the first report of Sig1R activation rescuing visual function and structure in the RhoP23H/+ mouse model. These results are promising and lay the framework for future studies to investigate Sig1R as a potential therapeutic target in retinal degenerative disease.