RD-CURE

Bringing Gene Supplementation Therapy for Inherited PDE6A- and CNGA3-associated Retinopathies into Clinical Practice

01.10.2016 bis 31.12.2017

The goal of the RD-CURE project is to develop and establish supplemental gene therapy for i) CNGA3-linked achromatopsia and ii) PDE6A-associated retinal dystrophies including first phase I/II safety and efficacy trials in human patients.
The Consortium initiated its work on the project in October 2012. In a joint effort, the partners of the Consortium were able to initiate crucial steps along the path and already accomplished several important milestones in the last 42 months (see Fig. 1 and Table 1). Main steps in the preparation phase of the CNGA3 gene therapy study were i) the generation and validation of the final humanized vector construct, ii) the GMP-grade vector production, iii) the preclinical toxicology and biodistribution study in non-human primates, and iv) the recruitment, diagnostic genotyping and clinical phenotyping of a considerable number of patients with CNGA3-linked achromatopsia. 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. The first patient was treated on November 11, 2016. At the time being all patients from the first dose group have successfully undergone surgery and the Data Monitoring Committee approved continuation of the trial with the second dose group. The last patient of this trial is expected to undergo surgery at the edge of funding period (FP) 2/3.
In parallel, the consortium successfully advanced the clinical translation of gene therapy for PDE6A-associated retinal dystrophies. A novel murine R562W knockin model was generated and a variety of mutant lines were characterized with respect to onset and course of retinal degeneration. Following the initial proof-of-concept gene therapy in mice in the Tsang group we generated a ‘humanized’ AAV8-hPDE6A vector and could show biological activity and transgene expression in the Pde6a:D670G mouse mutant which has now been selected as the primary target for preclinical therapy studies. The GMP production of the vector has been initiated and product lots used for the toxicology/biodistribution study and the clinical trial are expected to be delivered in July 2016 and January 2017, respectively. In addition, despite the low prevalence of PDE6A-linked RP patients in our population, a total of 27 patients with mutations in PDE6A could be enrolled in the pre-trial clinical phenotyping study. New collaborations with clinical and genetic centers in Europe are currently negotiated in order to further increase the number of patients eligible for the gene therapeutic trial.