It is clear that to improve the lives of cystinosis patients there needs to be: 1) better variants of cysteamine that are more tolerable to increase patient compliance and 2) alternative therapies targeting other pathways such as autophagy which are likely to play a role in the kidney failure, but are not corrected by cysteamine alone. In this proposal we will address both of these issues by testing the hypothesis that a CF10/Everolimus combination therapy provides a more effective treatment for cystinosis in a novel rat model of cystinosis that we have previously developed. Specifically, we will determine if this new drug treatment has the potential to minimise the unpleasant side-effects seen with cysteamine, reduce the frequency and level of dosing, and determine if it is more effective at slowing, and potentially stopping the decline in kidney function. To achieve this, we will make use of a new rat model of cystinosis (Hollywood et al., manuscript in revision) that we have developed that has a phenotype that closely resembles the progression of the human disease, and is therefore much more suitable for this study than existing mouse models.
We propose the following objectives:
Objective 1: Compare the pharmacokinetics and cystine depleting activity of CF10 to cysteamine in Ctns-/- rats when delivered via jelly pill.
Objective 2: Assess the long-term therapeutic effectiveness of CF10 on renal function in Ctns-/- rats.
Objective 3: Evaluate CF10 and Everolimus drug-drug interactions in cystinotic rats.
Objective 4: Assess the effects of a CF10 and Everolimus combination treatment on the renal defects in Ctns-/- rats.
