Investigating the pathophysiology and potential therapeutic approaches for nephropathic cystinosis

Abstract

Nephropathic cystinosis is a severe monogenetic systemic disorder that presents itself early in life and leads to progressive organ damage, particularly the kidneys. It is caused by mutations in the CTNS gene, encoding the lysosomal transporter cystinosin, resulting in intralysosomal accumulation of cystine throughout the body. Over the last decades, our understanding of cystinosis pathology has greatly extended beyond cystine accumulation. Recent studies based on in vitro and in vivo cystinosis models 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. Regardless of the observed cellular defects associated with the disease, the mechanism linking cystinosin loss and epithelial dysfunction remains largely unknown. In this review, we describe in detail the novel insights on the molecular mechanisms driving nephropathic cystinosis as well as the link between cystinosin loss and the cellular defects. Further, recent studies on genetic rescue of the disease, in vitro and in vivo are discussed. This information should aid in developing new therapeutic strategies for cystinosis.