Research Scientist I-Stem corbeil-Essonnes, Ile-de-France, France
Abstract: Alström syndrome (AS) is a rare syndromic monogenic recessive disorder characterized by hearing and vision loss, obesity, type 2 diabetes mellitus, dilated cardiomyopathy and progressive renal dysfunction. Visual symptoms develop within a few weeks after birth, progressively leading to blindness. Currently, no cure is available. ALMS1 gene is responsible of this disorder. The protein coded by this gene localizes at the centrosome and within the basal bodies of ciliated cells and has suggested roles in intraciliary transport, cell migration, extracellular matrix production, and in endosomal trafficking. Our work aims to model visual symptoms in a human cell model of AS with the goal to understand molecular mechanisms underlying AS and to identify novel therapeutic targets. To this end, we generated different human induced pluripotent cells (hiPSC) lines using CRISPR/Cas9 base editing approaches to induce selected non-sense mutations within ALMS1’s sequence. The different cell lines obtained were qualified to confirm their pluripotency. The lines were then differentiated into retinal organoids to assess the consequence of gene mutations. All ALMS1 mutated hiPSC differentiated into retinal organoids lost photoreceptors compared to isogenic wild type controls after 150 days in culture, recapitulating photoreceptor loss in AS patients. Future work on these retinal organoids will allow deciphering molecular mechanisms involved in this photoreceptor loss in order to identify a molecular target suitable for drug testing.
Funding Source: I-Stem is part of the Biotherapies Institute for Rare Diseases supported by the Association Française contre les Myopathies-Téléthon. This work was funded by Retina FRANCE.
