Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Nephropathic cystinosis is a severe, monogenic systemic disorder that presents early in life and leads to progressive organ damage, particularly affecting the kidneys. It is caused by mutations in the CTNS gene, which encodes the lysosomal transporter cystinosin, resulting in intralysosomal accumulation of cystine. Recent studies demonstrated that the loss of cystinosin is associated with disrupted autophagy dynamics, accumulation of distorted mitochondria, and increased oxidative stress, leading to abnormal proliferation and dysfunction of kidney cells. We discuss these molecular mechanisms driving nephropathic cystinosis. Further, we consider how unravelling molecular mechanisms supports the identification and development of new strategies for cystinosis by the use of small molecules, biologicals, and genetic rescue of the disease in vitro and in vivo. Nephropathic cystinosis is a severe, monogenic systemic disorder caused by mutations in the lysosomal cystine/proton cotransporter cystinosin and the leading cause of inherited renal Fanconi syndrome.Cysteamine efficiently depletes lysosomal cystine and improves clinical outcomes; however, it does not reverse established kidney failure.A multifaceted impact of cystinosin loss of function is observed in cystinosis pathology, involving increased oxidative stress, apoptosis, and impaired autophagy and energy metabolism.Several small molecules and biologics correcting non-transport functions of cystinosin are emerging and have been shown to be effective either alone or in combination with cysteamine.Hematopoietic stem cell transplantation and translational read-through drugs pose promising new treatment options.