Towards personalized medicine in ophthalmology: a new therapeutic approach combining PARP-inhibition and AAV-mediated gene replacement improves vision in advanced stages of retinal neurodegeneration

15.08.2017 bis 14.08.2020

The combined therapeutic approach outlines a new strategy for a personalized treatment and requires deep insight and knowledge about the major properties and key players leading and guiding the pathological process that is unique for a mutation. This is of particular relevance for Retinitis Pigmentosa (RP), a genetically heterogeneous group of retinal hereditary diseases causing photoreceptor cell death, thus resulting in progressive visual field constriction and finally complete blindness. Despite the advancing genetic knowledge, to date, no effective cure is available for this disease in human patients. Although in genetic diseases, specific restoration of gene function would seem like an ideal therapeutic target, in clinical ophthalmologic practice, the genetic heterogeneity and often late diagnosis of RP could be a drawback for this particular approach. Thus, there’s a need for the development of mutation-independent therapeutic strategies that are applicable regardless of the primary genetic defect. In this context, our proposal provides a new combination of therapeutic approaches for RP animal models by using a mutation-independent treatment with PARP-inhibitors or AAV-siRNA-PARP (neuroprotection) to (1) open the therapeutic window for AAV-based gene delivery (gene replacement) and to (2) restore the function of the mutated protein at more advanced stages of degeneration. Based on our findings from Objective 1, we will study the therapeutic efficacy of a new innovative approach combining PARP inhibition followed by an AAV-mediated gene delivery (Objective 5). In Objective 2, we plan to figure out the endpoint for a curative AAV-mediated treatment defined by the causative mutation properties and related molecular mechanisms. In Objectives 3 and 4, the most effective concentration of a PARP inhibitor (drugs or AAV-siRNA-PARP vector) will be evaluated indicating the optimal point of halting photoreceptor cell death. In Objective 5, the most exciting and promising part, we aim at addressing to different issues combining results based on Objectives 1-4. The five objectives will be translated into the practical work by five work packages; the neuroprotection including in vitro and in vivo treatments as well all project related immunhistological, biochemical investigations and assays will be performed by Dr. Sahaboglu Tekgöz. The treatment by rAAV-mediated gene and investigations in vivo by using non-invasive diagnostic techniques on different animal models for RP will be performed by Dr. Mühlfriedel. In terms of the outcome, comparison and interaction of experimental data, all objectives are closely related and give reason to expect two benefits: a) delay in photoreceptor degeneration including cone photoreceptor survival for lifetime and b) restoration of protein function and morphology at more advanced stages when the point of “no return” is exceeded.