Silencing gene therapy for mutant membrane, secretory, and lipid proteins in retinitis pigmentosa (RP).

A mutation in retinal photoreceptor-specific proteins causes nearly 50% of retinitis pigmentosa (RP) cases; the other 50% is called sporadic RP, the etiology of which is unknown. To alleviate RP development, gene therapies, including insertion of a wild type gene or replacement of mutant genes, have been conducted in animal models. The result was not always satisfactory. We found that a mutant misfolded rhodopsin induces endoplasmic reticulum (ER) stress and that the resultant unfolded protein response (UPR) induces apoptosis in the retinal photoreceptor cells in transgenic S334ter rats. The levels of mutant misfolded rhodopsin, not those of normal rhodopsin appear to control disease development. Since mutant misfolded rhodopsin induces ER stress, it is essential to eliminate even minute levels of the mutant misfolded rhodopsin from retinal photoreceptor cells. We speculate that a complete elimination of mutant rhodopsin is more important than an insertion of a normal gene. Here, we propose a silencing gene therapy for complete elimination of mutant unfolded rhodopsin from photoreceptor cells. To achieve this therapy, custom synthesized double-stranded small interfering (si)RNAs will be used to silence the mutant rhodopsin mRNA. The silencing gene therapy will be applicable to many inherited diseases caused by ER stress induced by mutant membrane, secretory, and lipid proteins.