Gene therapy in the Retinal Degeneration Slow model of retinitis pigmentosa

Abstract

Human blinding disorders are often initiated by hereditary mutations that insult rod and/or cone photoreceptors and cause subsequent cellular death. Generally, the disease phenotype can be predicted from the specific mutation as many photoreceptor genes are specific to rods or cones; however certain genes, such as Retinal Degeneration Slow (RDS), are expressed in both cell types and cause different forms of retinal disease affecting rods, cones, or both photoreceptors. RDS is a transmembrane glycoprotein critical for photoreceptor outer segment disc morphogenesis, structural maintenance, and renewal. Studies using animal models with Rds mutations provide valuable insight into Rds gene function and regulation; and a better understanding of the physiology, pathology, and underlying degenerative mechanisms of inherited retinal disease. Furthermore, these models are an excellent tool in the process of developing therapeutic interventions for the treatment of inherited retinal degenerations. In this paper, we review these topics with particular focus on the use of rds models in gene therapy.

Fig. 70

IRBP nanoparticles can drive persistent and elevated transgene expression in the WT Retina. WT mice were injected at P5 (a, b) or P2 (c) with IRBP nanoparticles. At various timepoints whole eyes were harvested and processed for qRT-PCR using Rds primers (a) or immunohistochemistry using mAB 3B6-green (specific for transferred/transgenic RDS) or RDS-CT polyclonal antibody-red (for endogenous RDS) with DAPI counterstain-blue (b–d). (a) Nanoparticle injection results in Rds message levels several fold higher than in uninjected contralateral control eyes. Levels remain elevated to PI-30. (b) Transferred RDS is detected at PI-2 in the nascent OS layer and co-localizes with the endogenous RDS at all timepoints examined. When nanoparticles are injected at P2, transferred protein is detected prior to the onset of endogenous RDS (c) although in stable transgenic mice generated using the same construct as the nanoparticle, transgenic RDS is not detectable until P12 (equivalent to PI-7) (d). Scale bar, 20 μm