Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa

摘要

Deficiencies in rod-specific cyclic guanosine monophosphate (cGMP) phosphodiesterase-6 (PDE6) are the third most common cause of autosomal recessive retinitis pigmentosa (RP). Previously, viral gene therapy approaches on pre-clinical models with mutations in PDE6 have demonstrated that the photoreceptor cell survival and visual function can be rescued when the gene therapy virus is delivered into the subretinal space before the onset of disease. However, no studies have currently been published that analyze rescue effects after disease onset, a time when human RP patients are diagnosed by a clinician and would receive the treatment. We utilized the AAV2/8(Y733F)-Rho-Pde6(alpha) gene therapy virus and injected it into a pre-clinical model of RP with a mutation within the alpha subunit of PDE6: Pde6(alpha)~(D670G). These mice were previously shown to have long-term photoreceptor cell rescue when this gene therapy virus was delivered before the onset of disease. Now, we have determined that subretinal transduction of this rod-specific transgene at post-natal day (P) 2, when approximately half of the photoreceptor cells have undergone degeneration, is more efficient in rescuing cone than rod photoreceptor function long term. Therefore, AAV2/8(Y733F)-Rho-Pde6(alpha) is an effective gene therapy treatment that can be utilized in the clinical setting, in human patients who have lost portions of their peripheral visual field and are in the mid-stage of disease when they first present to an eye-care professional.