Cystinosin deficient rats recapitulate the phenotype of nephropathic cystinosis

The lysosomal storage disease cystinosis is caused by mutations in CTNS, encoding a cystine transporter, and in its severest form leads to proximal tubule dysfunction followed by kidney failure. Patients receive the drug-based therapy cysteamine from diagnosis. However, despite long-term treatment, cysteamine only slows the progression of end-stage renal disease. Pre-clinical testing in cystinotic rodents is required to evaluate new therapies; however, the current models are sub-optimal. To solve this problem we generated a new cystinotic rat model using CRISPR/Cas9-mediated gene editing to disrupt exon 3 of Ctns and measured various parameters over a 12-month time-course.

Ctns-/- rats display hallmarks of cystinosis by 3-6 months of age as seen by a failure to thrive, excessive thirst and urination, cystine accumulation in tissues, corneal cystine crystals, a loss of Lrp2 in proximal tubules and immune cell infiltration. High levels of glucose, calcium, albumin and protein are excreted at 6-months of age, consistent with the onset of Fanconi syndrome, with a progressive diminution of urine urea and creatinine from 9-months of age, indicative of chronic kidney disease. The kidney histology and immunohistochemistry showed proximal tubule atrophy and glomerular damage as well as classic ‘swan neck’ lesions. Overall, Ctns-/- rats show a disease progression that more faithfully recapitulates nephropathic cystinosis than existing rodent models. The Ctns-/- rat provides an excellent new rodent model of nephropathic cystinosis that is ideally suited for conducting pre-clinical drug testing and a powerful tool to advance cystinosis research.