Project 5 - Development of novel gene therapy strategies for treatment of autosomal dominant retinitis pigmentosa in a pig model

Treating the causative genetic defect of monogenic disease directly at the genomic level completely restores the original genetic constellation, providing hope for almost any inherited disease. Multiple aspects, however may influence the perspectives of such treatment.

First issue is the appropriate time point of treatment. Obviously, tissue shall not be damaged by secondary malformation that are difficult to revert. For this, we study the progress of retinitis pigmentosa on a pig model carrying a mono-allelic P347L mutation in the RHO gene. We will combine molecular, histological and physiological measurements on cohorts of RHO pigs during their first year of life, in comparison to littermate controls

Second issue is the definition of an appropriate gene editing approach. We will prioritize complete inactivation of the disease allele, but also approach the ultimate correction of the RHO gene. We will also put emphasis on the improving in vitro test systems as most of them dramatically overestimate the therapeutic capacity in vivo.

Finally, we aim at delivering gene editing tools into the eye of RHO pigs, as pre-clinical model for later translation into the clinics. This objective involves the packaging of promising gene editing tools into vectors that are capable to deliver them into the target cells of the retina, without affecting its structure or causing inflammatory reactions.

Our work program involves interaction with the other groups in FOR5621, specifically on the phenotype characterization in RHO pigs and on the delivery of gene editing compounds into the pig eye.