Retinitis pigmentosa (RP; 268000), affecting 30,000 to 40,000 people in France, are part of a large group of orphan diseases yet without available therapies. It is a group of very heterogeneous diseases with the common characteristics with the consistent loss of peripheral vision. In patient suffering from RP, rod photoreceptors, responsible for night vision degenerate by apoptosis. As a consequence, the first clinic feature is night blindness (a fuzy vision during the light to dark transition) and a visual field narrowing form the periphery. The visual field is narrowing to the point that the remaining vision is tubular, as seeing through a narrow tube.

cone-enriched cultures

Most often, cone photoreceptors get touched. Cone photoreceptors are responsible not only colour vision but most importantly high contrast vision, visual acuity and all the vision in normal light environment. During the natural history of the disease, the central vision is reduced to blindness. The first symptoms appear usually during childhood (between 10 and 20 year).The evolution of the disease occurs in general during 20 to 30 years. At 60, the vision is inferior to 1/10 (blindness). Cone are also affected in a polygenic ageing disease Aged-related Macular Degeneration (AMD).
Among the corrective therapy approaches now envisioned, gene therapy has only a restrict potential since it is selective, while the neuroprotective approach are broadly applicable but non-selective. The fact that more than 100 different RP genes have been identified, is a challenge for the development of corrective gene therapy approaches.
The scientific approach at Inserm Unit592 - University Pierre and Marie Curie in Paris derives from the analysis of events leading to secondary cone degeneration, in order to develop novel strategies aimed at limiting their loss. The observation that cone degeneration follows that of rods led us to formulate the hypothesis of a trophic signalling from rods to cones. The transplantation of sheets of rod photoreceptors into the eye of a mouse model of retinitis pigmentosa was done when all rods have degenerated but before at the onset of of cone loss. The grafting was shown to slow down cone degeneration by half.

The Inserm Unit592 - University Pierre and Marie Curie has undertaken a systematic strategy to identify and characterize endogenous cone viability factors using an expression cloning approach. This research has already led to the identification of a novel protein, Rod-derived Cone Viability Factor (RdCVF) secreted and expressed specifically by rods (608791).

Cell counting

The sequencing of a normalized mouse retinal library by the Génoscope at Evry should optimize the screening by expression cloning using a bioinformatics analyses.

The identification of RdCVF is a key step toward the therapeutic goal as well as it opens many new perspectives. The potential use of RdCVF for therapy is large since the expression of the protein is not affected by the primary genetic defect. RdCVF delivery might even be performed at late stage in the disease since 95% cone loss compatible with a correct orientation and discrimination performance and 50% cone loss compatible with acuity of 20/20 (normal acuity).
The clinical extension of that research will be performed within the future Institut de la Vision (Paris XV-XX).