RHORCOD

Rod-cone dystrophies (RCD) are a heterogeneous group of retinal disorders affecting primarily rod (involved in dim light vision) then cone (involved in day light, detailed and coloured vision) photoreceptor cells eventually leading to blindness. There is no current treatment of the disease although different axes in therapeutic research are developed including gene therapy, neuroprotection or retinal prostheses. Over 180 different genes have been implicated to date in these degenerative disorders and mutations in RHO are the most common in particular in dominant forms of the disease. To develop therapeutic strategies a better understanding of the disease is required through correlation between phenotype and genotype and precise characterization of rod and cone kinetics of degeneration. To achieve this, harmonization of phenotypic techniques among specialists, development of novel precise phenotypic strategies in both human and animal models that can then be used to assess novel treatment, as well as the constitution of phenotypically and genotypically well-characterized cohort of patients from different ethnic background are essential. This is what the RHORCOD project was intended to fulfil gathering 6 groups composed of clinicians and scientits expert in inherited retinal diseases, their phenotypic assessment as well as retinal physiopathology. Our main goal was to more precisely document cone photoreceptors in RCD both in humans and animal models. In order to obtain a genetically more homogeneous group, dominant RCD with mutations in RHO and autosomal recessive RCD with mutation in PDE6A and PDE6B were selected. Indeed, both genes are specifically expressed in rod and not cone photorecteptor with promising development on cone neuroprotection in this genetic group with trophic factor such as RdCVF.

The main achievement of our project was to be able to screen a large European and Israeli cohorts of patients among the clinical centers involved in the projet and collect one of the largest group of families with autosomal dominant RCD with rhodopsin mutation: 50 families were included in the project gathering 150 subjects all together. The p.Pro257Leu mutation was the most common mutation present in more than 31% of cases. Four novel mutations were also identified and their pathogenic mechanism is under investigation. This large screening also revealed that RHO mutations are a rare cause of RCD in the Israeli population compared to Europe. In addition 5 families were identified with PDE6A mutations and 11 with PDE6B in Paris. All patients were reviewed once a year with minimum tests harmonized among all clinical centres in order to precisely document their phenotype with assessment of visual function and structure in a homogenized way. Each centre included their data in their local registry and a common database was established based on the minimum protocol (http://rhorcod.genoret.org/) by the German partners. This assessment revealed that not all cases of RCD with mutation on gene specifically expressed in rod photoreceptors had typical form with preservation of macular function but some had true macular involvement in the mid stage of the disease especially in case of RHO mutation located at the C-terminus of the protein. Mutations in the N-terminus of the protein, which represent a smaller percentage of families, had less severe disease (manuscript in preparation). Specific protocols were developed in some centres for a more precise phenotypic assessment: these include adaptive optics (Parisian centre), colour contrast sensitivity (Parisian and German centre) and neuroimaging including functional MRI (Portuguese centre). The registry, the common database and the additional tests will serve basis for future clinical trials including those aiming at cone photoreceptor neuroprotection. In addition, knowledge was gain on animal models of the disease, namely the P23H rat, model of mutant rhodopsin and on the rd10 mice. Iron chelator and antioxydants hold promises and data on apoptotic mechanisms involved in photoreceptor degeneration in these models may identify additional therapeutic targets.