The University of Auckland
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Cystinosin deficient rats recapitulate the phenotype of nephropathic cystinosis

Version 5 2022-05-03, 22:14
Version 4 2022-05-03, 22:12
Version 3 2022-05-02, 00:13
Version 2 2022-02-10, 21:39
Version 1 2022-02-09, 02:25
posted on 2022-05-03, 22:14 authored by Jennifer HollywoodJennifer Hollywood, Prasanna KallingappaPrasanna Kallingappa, Pang Yuk CheungPang Yuk Cheung, Renita MartisRenita Martis, Sree SreebhavanSree Sreebhavan, Robert 'AtiolaRobert 'Atiola, Aparajita ChatterjeeAparajita Chatterjee, Emma BuckelsEmma Buckels, Brya MatthewsBrya Matthews, Paula LewisPaula Lewis, Alan DavidsonAlan Davidson

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.



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