Résumé
IntroductionHuman induced pluripotent stem cell (iPSC)-derived models have revolutionized disease modelling for inherited retinal disorders (IRDs). iPSC-derived retinal pigment epithelium (RPE) is a morphologically characteristic monolayer that also reproduces the functions of this tissue in the eye. iPSC-derived retinal organoids contain an outer layer of photoreceptors complete with outer segment-like structures protruding from the surface. Thus, iPSC-derived RPE or organoids generated from the somatic cells of an IRD individual provide a window directly into the patient’s retina that can yield unexpected discoveries. Moreover, variants in the same IRD gene can give rise to distinct clinical forms and patient-specific iPSC-derived models are sensitive enough to allow the identification of mutation-specific or disease-specific phenotypes. Lastly, such models are valuable for testing the efficacy of different therapies to reverse the disease phenotype.ObjectivesTo illustrate these features by two notable examples.MethodsFirstly, we generated iPSC-derived RPE from individuals carrying variants in RLBP1 and affected with the different associated clinical subtypes, Retinitis punctata albescens, Bothnia dystrophy and Newfoundland rod-cone dystrophy. Secondly, we generated iPSC-derived retinal organoids from individuals carrying variants in USH2A and affected with isolated retinitis pigmentosa (RP) or Usher syndrome (USH), which associates RP with hearing loss.ResultsIn the RLBP1-associated iPSC-derived RPE, we identified pathophysiological markers that served as pertinent therapeutic read-outs to evaluate gene replacement therapy. Unexpectedly, we identified a previously unsuspected smaller CRALBP isoform that is naturally and differentially expressed in both human and murine retina. In the USH2A-associated retinal organoids, we identified distinct retinal RP and USH phenotypes that were validated by isogenic-corrected controls. In particular, USH organoids showed a striking and unexpected cone phenotype that was confirmed clinically.ConclusionTaken together, this work further demonstrates the power of iPSC-derived modelling and the unexpected advances that can be made towards understanding retinal function and dysfunction.