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

这种罕见的遗传性疾病胱氨酸病的发病率约为20万分之一。它的特点是废物胱氨酸在所有细胞中积累，如果不治疗，胱氨酸晶体形成，造成永久性器官损伤和肾衰竭，通常在10岁时死亡。胱氨酸病目前用Cystagon或Procysbi胶囊治疗，这两种胶囊都含有活性物质半胱氨酸，可以去除胱氨酸，从而延缓疾病进展。然而，这些药物有几个问题，导致很大一部分胱氨酸病患者错过了剂量：它有一种非常令人不快的味道和气味，经常在服用胶囊期间和之后引起恶心和呕吐，它会引起胃肠道疼痛刺激，甚至溃疡形成。此外，大部分半胱胺在被身体分解时被浪费了，其中一些转化为令人不快的气味，导致口臭和刺鼻的体味。为了维持血液中正确的半胱胺水平，每天需要服用四次Cystagon，通常是午夜、早上6点、中午和下午6点，每天最多服用24粒胶囊。为了防止胱氨酸的积累和器官损伤，重要的是患者严格遵守每6小时摄入Cystagon，尽管睡眠受到干扰。Procysbi的缓释形式每天服用两次，但由于代谢浪费，需要类似的高剂量，不能减少臭味代谢物的产生，仍然会引起胃痛。患者必须每天服用几种额外的药物来治疗其他症状；即使是小孩子也可以每天服用四次，每次四到六套药。胱氨酸病患者表示，一种气味和味道更少、不会引起胃痛、不需要一天服用四次、不会引起口臭和体味的药物会帮助他们维持服药方案。我们已经开发了一种新技术，可以将半胱胺的一种非活性形式CF10直接输送到细胞中。它在细胞表面被激活，释放可以立即进入细胞的半胱胺，避免了新陈代谢造成的浪费问题。这将导致更小和更少的剂量，造成更少的副作用。预计口臭也会减少，因为血液中的半胱胺会减少，新陈代谢产生的臭味也会减少。CF10还被设计成具有更好的味道和气味，并减少对胃的刺激。开展了广泛的实验，结果支持CF10进入临床前开发研究。如果成功，这些研究将支持向英国监管机构MHRA申请CF10的临床试验批准。

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.