PhD defence: Investigating the pathophysiology and potential therapeutic approaches for nephropathic cystinosis

Nephropathic cystinosis is an autosomal recessive monogenic kidney disorder characterized by lysosomal accumulation of cystine throughout the body, causing organ damage, particularly the kidneys. This is due to pathogenic mutations in the CTNS gene, which encodes for the lysosomal cystine transporter cystinosin, transporting cystine from the lysosome into the cytoplasm.

Patients with nephropathic cystinosis usually develop symptoms of renal Fanconi syndrome, and if not treated, progress to end stage renal disease within the first 12 years of life. The mainstay for cystinosis treatment is life-long therapy with cysteamine, a cystine depleting agent. Although cysteamine efficiently lowers lysosomal cystine levels and improves some clinical outcomes, it does not reverse the established renal Fanconi syndrome and cannot prevent the loss in renal function. This suggests involvement of complex pathophysiological processes in disease progression that may not be directly related to cystine overload.

Therefore, this thesis aimed to investigate the disease pathophysiology and to find new potential therapeutic interventions that could replace or compliment cysteamine therapy for patients with cystinosis.