Cystinosis Clinical Trials

Cystinosis is a monogenic autosomal recessive lysosomal storage disease with complete penetrance, caused by a biallelic mutation in the CTNS gene (17p13.2) encoding cystinosin, a ubiquitous membrane protein whose role is to clear cystine into the cytosol. Its dysfunction in patients with cystinosis leads to systemic accumulation of cystine, an oxidised dimer of cysteines linked by a disulphide bridge, in the lysosomal space, and irreversible cellular dysfunction. Renal damage is at the forefront, with Fanconi syndrome (proximal tubulopathy) and chronic renal failure developing early in childhood/adolescence. There are also multi-systemic disorders, notably endocrine and ophthalmological. Cysteamine is an amino thiol which reduces the level of intra-lysosomal cystine by breaking the disulphide strands of cystine, giving two cysteines which complex with cysteamine to leave the lysosome. Since the late 1980s, there has been an immediate-release form of the drug, which has considerably improved overall patient survival despite having a major impact on quality of life. This improvement in survival has also led to the emergence of later complications that were not previously observed. This musculoskeletal complication (described in an international consensus in 2019), known as 'CMBD' for Cystinosis Metabolic Bone Disease, may be explained at least in part by an intrinsic defect in the osteoblast and osteoclast that contribute to the human bone phenotype. This intrinsic bone defect appears to be responsible for premature ageing. In order to identify potential future therapeutic targets for CMBD, it is essential to gain a better understanding of the underlying pathophysiological mechanisms. To better understand premature aging in extra-renal damage in cystinosis, it seems relevant to investigate energy metabolism dysfunction, particularly mitochondrial dysfunction.