Bringing Gene Supplementation Therapy for PDE6A- and CNGA3-associated Retinopathies into Clinical Practice: A joint Tübingen-München Project

The prevalence of inherited retinal degeneration is about 1:4 000, i.e. more than 1 million people worldwide are affected by these rare blinding diseases. Degenerative retinal diseases are caused by mutations in a vast number of different genes. Since symptomatic treatment is unavailable, great hopes are placed on gene therapy. In humans, most gene therapeutic concepts are currently only used in clinical studies.

The Centre for Ophthalmology in Tübingen has pooled its expertise in clinical and basic research and, in cooperation with partners from the Ludwig Maximilian University in Munich, has successfully raised research funds to bring gene therapy from the laboratory to the clinic.

The "RD-Cure" project is funded by the Tistou & Charlotte Kerstan Foundation.

The goal of the RD-CURE project is to develop and establish supplemental gene therapy for:

• Study 1: Patients with mutations in the CNGA3 gene responsible for a form of autosomal recessive Achromatopsia
• Study 2: Patients with mutations in the PDE6A gene responsible for a form of autosomal recessive Retinitis pigmentosa.

In both studies a so-called AAV vector based gene replacement therapy is applied, i.e. a functional copy of the causative gene, which is mutated, is introduced into the cells of the retina. Recombinant adeno-associated viruses are used to transfer the therapeutic genes.

The Consortium initiated its work on the project in October 2012. Within the CNGA3 gene therapy study a humanized AAV-hCNGA3 vector was generated that was used for GMP-grade vector production. This vector was assessed in a preclinical toxicology and biodistribution study in non-human primates. In parallel, we recruited 36 patients with CNGA3-linked Achromatopsia that underwent diagnostic genotyping and clinical phenotyping within a CNGA3-linked Achromatopsia natural history study. The joint effort of all workpackages enabled the successful submission and final approval of the CNGA3 phase I/II dose escalation trial by the national regulatory authority and the local ethics committee in September 2015 (ClinicalTrials.gov Identifier: NCT02610582). The first patient was treated in November 2015 and the last patient in December 2016. The outcome of the study is currently being evaluated.

In parallel, the consortium successfully advanced the clinical translation of gene therapy for PDE6A-associated retinal dystrophies. A variety of mutant mouse lines were characterized with respect to onset and course of retinal degeneration. A ‘humanized’ AAV8-hPDE6A vector was generated and after subretinal injection could show biological activity and transgene expression in Pde6a mouse mutants. The GMP production of the vector has been initiated and product lots used for the toxicology and biodistribution studies. In addition, despite the low prevalence of PDE6A-linked RP patients in our population, a total of 55 patients with mutations in PDE6A could be enrolled in the pre-trial clinical phenotyping study, many of which were recruited through our clinical and genetic collaboration partners all over Europe. Treatment of the first patient is aimed for in 2019.