Modeling and treatment of retinal dystophies with iPS cells – eyePS

Current neurodegenerative models derived from human induced pluripotent stem (iPS) cells have the capacity to recapitulate cellular and molecular processes leading to the disease, creating novel avenues to model and understand the pathological development / pathobiology. Regarding retinal disorders, iPS cell technology is particularly attractive for inherited retinal dystrophies such as retinitis pigmentosa (RP) that affect more than 1.5 million people worldwide. While retinas of small-animal models of RP can be used to study some aspects of the disease pathology, they do not have all the features of the human disease. Thus, patient-specific iPS-derived retinal cells can be used to explore the molecular and cellular mechanisms of specific genetic mutations.
We are ambitioning to create RP-specific iPS cell lines to investigate the mechanisms by which mutations in the ubiquitous splicing factor PRPF31 cause retinal degeneration. No animal model can recapitulate the retinal disease, mediated by the mutation in PRPF31. To understand the PRPF31 pathogenicity and determine what specific retinal cell type is affected, we have derived iPS cells from PRPF31 patients carrying to types of mutations.
Based on the robust retinal differentiation protocol developed by partner 1, we will study the phenotype of both photoreceptors and retinal pigmented epithelial cells differentiated from these mutated iPS cells. Due to the biological function of PRPF31, we plan to determine if mutations in this splicing factor can cause RP via the generation of abnormally expressed and/or spliced transcripts in retinal cells by performing whole transcriptome analysis (RNA-Seq). Finally, we will develop a "gene augmentation therapy" approach (using simple genome editing) in iPS cells carrying PRPF31 mutations to reverse the retinal phenotype. These iPS cell models will be of major interests for pre-clinical studies and the design of new therapeutic strategies.