Cystinosis is an autosomal recessively inherited disease which is caused by a mutation in cystinosin. This is a transport protein localized in the lysosome, needed for the transport of cystine from the lysosome. In a way that is not yet understood this leads to Fanconi syndrome and later - at the age of about 9 - to renal insuffiency along with increased damage to other organs, particularly the thyroidal gland and the eye (cornea, retina). Therapy with cysteamine, which lowers the concentration of cystine in the lysosomal compartment, only has a retarding effect on the occurrence of symptoms. Aim of this study is to arrive at a better treatment of cystinosis.
The first part of the research aims at a more effective treatment with cysteamine. Probably the present dosage of 4 times a day is insufficient. The cystine concentration will be monitored during 24 hours in the granulocyte, lymphocyte and, if possible, monocyte. A concentration in the heterozygote range over 24 hours should be strived after. This is not reached with the present scheme. Since it is assumed that the increased cystine concentration in the lysosome leads to a lower ATP production, the mitochondrial function will be tested in granulocyte, lymphocyte and fibroblasts and the result will be related to the cystine concentration.
Insight into the pathogenesis will be obtained by studying isolated human proximal tubulus cells. The present opinion is that cystine storage in the proximal tubulus lowers the production of ATP in the cell and thus disturbs the active transport of a.o. glucose, amino acids and sodium. In the stage of ATP depletion the cells gives signals leading to interstitial damage of the kidney (our opinion). These tubulus cells will be obtained from the urine of patients or from human kidney tissue. The tubulus cells from human kidney tissue will be loaded with cystine. Also here the mitochondrial function will be tested, and additionally selected vasoactive substances, chemokines and cytokines will be measured on expression / production in the search for an explanation of the interstitial fibrosis in cystinosis patients. A better treatment strategy may result from this. |
