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Targeting Autophagy in nephropathic cystinosis

Dysregulation of the autophagic flux is a critical check point in the generation of renal injury in nephropathic cystinosis. In this proposal, we plan to study, in depth, the pathogenic mechanisms of renal cell autophagy and mitophagy (Objective 1). We also propose in Objective 2 to perform exon sequencing to evaluate for CLU and other autophagy pathway specific mutations in nephropathic cystinosis, and to interrogate the functional relevance of these mutations with respect to alteration in RPTE levels of iCLU and sCLU (based on our previous publication by Sansanwal et al, JASN, 2012). We will also reposition use of an FDA approved drug (currently used for cancer), an antisense-based drug Custirsen/OGX-011, which targets the translation initiation site of human CLU mRNA, and test the efficacy of this drug to rescue renal cell viability in nephropathic cystinosis in human RPTE patient cultures in the Sarwal Lab (Objective 3). Custirsen has entered into human clinical trials in prostate cancer and is well tolerated unlike cysteamine and valuable preclinical and clinical data exists on toxicity, safety, and human dosing. If Aim 2 is successful it could lead to rapid repositioning of Custirsen for renal salvage in a clinical trial in nephropathic cystinosis, at a fraction of the cost it would take to generate a new drug target for an orphan disease.