MICA: Pre-clinical studies on a novel prodrug delivery technology for cystinosis.

The rare genetic disease cystinosis affects approximately 1 in 200,000 births. It is characterized by accumulation of a waste product, cystine, in all cells and, if untreated, cystine crystals form, causing permanent organ damage and kidney failure, often death, by ten years of age. Cystinosis is currently treated with capsules of Cystagon or Procysbi, both of which contain the active agent cysteamine, which removes cystine and therefore delays disease progression. However, there are several problems with these medicines that lead to a large proportion of cystinosis patients missing doses: it has an intensely unpleasant taste and smell, which often cause nausea and vomiting during and after taking the capsules, and it can cause painful irritation, and even ulcer formation, in the gastrointestinal tract. Furthermore, most of the cysteamine is wasted when it is broken down by the body, converting some into unpleasant smells, which cause halitosis (bad breath) and pungent body odour. To maintain the correct levels of cysteamine in the blood, four daily doses of Cystagon are required, usually midnight, 6am, noon and 6pm - up to 24 capsules each day. To prevent the accumulation of cystine and organ damage, it is important that patients adhere strictly to the six hourly intake of Cystagon, despite disruption to sleep. The sustained release form Procysbi is taken twice per day, but is required in a similar high dose due to metabolic wastage, does not reduce the production of smelly metabolites and still causes stomach pains. Patients have to take several additional medicines every day to treat other symptoms; even small children can have four to six sets of medicine to take four times a day. Cystinosis patients have indicated that a medicine with less smell and taste, that doesn't cause stomach pains, is not required four times a day, and causes no halitosis and body odour would help them to maintain the dosage regimen. We have developed a new technology to deliver an inactive form of cysteamine, CF10, directly to cells. It is activated on the cell surface to release cysteamine that can pass immediately into cells, avoiding the problem of wastage due to metabolism. This should lead to smaller and less frequent doses, causing fewer side effects. A reduction in halitosis is also anticipated, as there will be less cysteamine in the blood and so less production of smelly products by metabolism. CF10 was also designed to have an improved taste and smell and to cause less gastric irritation. A wide range of experiments have been carried out and the results support progression of CF10 into pre-clinical development studies. If successful, these studies would support an application to the UK regulatory government agency MHRA for clinical trials approval for CF10.