Cysteamine treatment for cystinosis Implications beyond cystine depletion

The aim of this thesis was to investigate the effects of the drug cysteamine in cystinosis, besides its cystine-depleting properties. Cysteamine is currently the only available drug for the orphan disease cystinosis, but it has been tested for numerous other indications troughout the years (chapter 1.1).In cystinosis, cysteamine has been used to lower intracellular cystine levels since 1976. The administration of cysteaminein cystinosis patients from an early age delays the progression of the disease, postpones the need for dialysis and renal transplantation and can prevent extra-renal symptoms. Besides these known properties of cysteamine, the drug also has other effects. The compliance with cysteamine therapy is hampered by the induction of halitosis. It was discovered that halitosis is caused by the metabolism of cysteamine into methanethiol and dimethylsulphide (chapter 2.1). Recently,a new enteric-coated formulation of cysteamine that can be administeredtwo times per day, instead of four times per day, was developed. Breathmeasurements revealed that the area under the curve of exhaled dimethylsulphide is lower after ingestion of the enteric-coated formula, compared to the normal formulation of cysteamine (chapter 2.2). Inthe past years, several cystinosis patients, most of whom were treated with high doses of cysteamine, were reported to develop side effects that had not been reported previously. These include skin symptoms (bruise-like lesions, striae), severe muscular and skeletal pains and neurological abnormalities. Skin biopsies of the skin lesions showed reactive angioendotheliomatosis and alterations of collagen fiber calibre (chapter 3.1). A study was conducted to investigate the pathogenesis behind those side effects, and it was found that all patients with cysteaminetoxicity suffered from copper deficiency. Since both copper deficiency and cysteamine can interfere with collagen cross-link formation, it is believed that copper deficiency played a pivotal role in the development of collagen abnormalities in these patients (chapter 3.2). Next, it was investigated whether cysteamine could have a direct effect on microvascular endothelial cells, and could cause angioendotheliomatosis. Itwas discovered that the administration of cysteamine to microvascular endothelial cells during 24 hours resulted in increased cell viability and proliferation, if cysteamine was refreshed every 6 hours (thus mimicking the in vivo situation) (chapter 3.3). Since cystinosis patients are increasingly surviving into adulthood, questions regarding fertility have become increasingly important. Cysteamine administration diminishes cystine accumulation in the gonads, thus improving gonadal function. Since over the years a few female cystinosis patients have given birth, but none of the male patients have fathered a child, we focussed on male cystinosis patients to study fertility status. Unexpectedly, we found azoospermia in all patients that were studied, including those that had been treated with cysteamine from an early age (chapter 4.1). In order to further investigate the origin of azoospermia in male cystinosis patients, a study was performed in Ctns-/- (knockout) mice. However,these mice displayed a normal fertility and histology of testes and epididymis was unchanged despite pronounced cystine accumulation in the testes (chapter 4.2).status: publishe