Use of Human Induced Pluripotent Stem Cells and Kidney Organoids To Develop a Cysteamine/mTOR Inhibition Combination Therapy for Cystinosis

In its severest form, the lysosomal storage disease cystinosis is characterized by accumulation of cystine; renal proximal tubule dysfunction; and kidney failure. Research has also implicated cystinosin in modulating the mammalian target of rapamycin (mTOR) complex 1 pathway. Use of the cystine-depleting drug cysteamine, the sole treatment option for cystinosis, only slows disease progression. The authors developed induced pluripotent stem cell and kidney organoid models of cystinosis that exhibit elevated cystine levels, enlarged lysosomes, increased apoptosis, and defective basal autophagy. Although the latter is not rescued by cysteamine treatment, mTOR inhibition with everolimus was able to restore basal autophagy to levels of healthy controls. Dual treatment of everolimus and cysteamine rescued all of the observed cystinotic phenotypes in the models, suggesting that a combination therapy may improve outcomes in patients with cystinosis.