Drug Profile

Cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene located on the short arm of chromosome 17 [1,2]. The CTNS gene encodes a lysosomal cystine transporter protein, cystinosin, which helps facilitate the efflux of cystine from lysosomes. The accumulation of the disulfide amino acid cystine within cellular lysosomes leads to the formation of cystine crystals in various tissues, including the kidney, thyroid, testis, pancreas, muscle, brain and eye [3]. This results in progressive dysfunction of multiple organs, leading to end-stage renal disease, diabetes, hypothyroidism, myopathy, and neurologic deterioration. Cystinosis is estimated to affect a total of approximately 600 children and adults in the USA [4]. Cystinosis appears in three phenotypic forms: infantile nephropathic, intermediate adolescent and benign adult, with the most severe type being the infantile form. While patients with cystinosis appear healthy at birth, progressive destruction of the proximal renal tubules soon results in renal Fanconi syndrome [5], which is characterized by increased urinary loss of water, essential electrolytes, minerals, glucose and proteins, as a result of failure of the renal tubules to reabsorb these substances. Rickets and growth retardation follow, and renal transplantation is generally required at an average age of 10 years [6]. Corneal cystine crystal accumulation is a common manifestation of all three types of cystinosis, which overlap to form a continuum of different degrees of severity. In vivo confocal microscopy and anterior segment optical coherence tomography studies reveal that the crystals are predominantly concentrated within the anterior corneal stroma [7]. The corneal cystine crystals present by 16 months of age and can result in severe photophobia, blepharospasm, recurrent current erosions and band keratopathy (Figure 1) [8–10]. Oral cysteamine bitartrate (Cystagon, Mylan Pharmaceuticals), f irst used in the treatment of cystinosis in 1976 and approved by the US FDA in 1994, reduces intralysosomal cystine concentrations, stabilizes renal function and prevents the development of extrarenal complications in patients with cystinosis [11–13]. However, the oral formulation has no noticeable effect on corneal crystal accumulation [14], most likely because the cornea lacks a vascular supply, resulting in inadequate corneal cysteamine concentrations Nancy Huynh1, William A Gahl2 and Rachel J Bishop*1