Research project nephropathic cystinosis

Exploiting new therapeutic strategies for treating nephropathic cystinosis

Dysfunction of epithelial cells lining proximal tubules (PT) of the kidney characterizes nephropathic cystinosis-a recessively inherited disorder caused by inactivating mutations in the CTNS gene that encodes the ubiquitous lysosome cystine transporter cystinosin (CTNS).

Using animal and cell-based models, we have recently observed that CTNS loss-of-function leads to endolysosome alterations, resulting in defective autophagic clearance of mitochondria and increasing oxidative stress which, in turn, impairs proximal tubule cell differentiation.

The mechanism/s linking CTNS deficiency with endolysosome defects remains unknown, preventing the development of disease-modifying therapies.

Based on recent insights supporting a key role of phosphoinositide (PI) in ensuring lysosome identity, we investigate whether: (i) the functional loss of CTNS might perturb endolysosome-based cellular degradative capacity by impairing PIs homeostasis; and (ii) manipulation of PIs metabolism might rescue lysosome-autophagy degradative pathways, ameliorating proximal tubule function in nephropathic cystinosis.