Development of a novel repurposed drug treatment for the neurodegeneration and diabetes in Wolfram syndrome

每17个英国人中就有一个人患有一种罕见的疾病。有6000多种罕见疾病，其中许多会导致过早死亡，而且几乎都无法治愈。Wolfram综合征是一种罕见的疾病，会导致儿童糖尿病和失明。这些孩子长大后会患上耳聋、失去对膀胱的控制、失去平衡，常常还会患上严重的抑郁症。死亡在中年是很常见的，由脑细胞死亡引起的呼吸困难导致的大脑萎缩。照顾受影响的人的唯一方法是治疗并发症：没有治愈方法，也没有任何治疗方法来防止或减缓疾病的发展。我们的目标是开发一种治疗方法，防止或延缓疾病恶化。我们相信，这样的治疗将为受影响的人提供更长、更好的生活质量。我们开发了一种Wolfram综合征的细胞模型，并用它来筛选可以治疗这种疾病的药物。其中之一，丙戊酸钠，可以减少我们的Wolfram细胞模型中的细胞死亡。丙戊酸钠是一个非常有趣的候选药物，因为它已经被用于治疗儿童癫痫几十年了。我们知道它对癫痫儿童是安全的。我们已经知道丙戊酸盐可以改善Wolfram综合征小鼠模型的糖尿病。在这个项目中，我们首先建议证明丙戊酸钠对Wolfram综合征小鼠模型是有效的。我们会给一半的小鼠服用丙戊酸盐，给另一半服用假药。我们将测量使用丙戊酸盐或假药治疗的Wolfram小鼠的大脑大小、视神经大小、糖尿病和平衡。我们将研究用丙戊酸盐治疗的Wolfram小鼠与用假药物治疗的小鼠相比，疾病的进展是否被预防或减缓。如果我们证明丙戊酸盐对我们的Wolfram小鼠有效，那么我们将研究丙戊酸钠对患有Wolfram综合征的儿童和成人的作用。我们需要证明丙戊酸钠对钨患者是安全的和耐受性的。我们将邀请18名患有Wolfram综合征的儿童和成年人参加。我们将征求成年人的书面同意，儿童的同意和他们的父母的同意。我们会让一个人一次服用丙戊酸钠片剂，检查安全性，然后再让下一个人服用。我们将在癫痫的推荐剂量范围内逐步增加丙戊酸盐的剂量。每增加一次剂量，我们都会进行安全检查。我们将要求人们服用丙戊酸钠12个月。我们预计18名儿童和成人中至少有16人会耐受丙戊酸钠。我们还将探索有效性；我们将通过在丙戊酸盐治疗开始前和治疗12个月后测量视力、糖尿病、平衡和脑大小来实现这一点。我们已经知道这种疾病在不治疗的情况下恶化的速度有多快。我们希望通过丙戊酸盐治疗来证明这种疾病不会恶化，或者恶化得更慢。这项研究将表明丙戊酸钠在阻止Wolfram综合征小鼠病情恶化方面是如何有效的。我们将展示丙戊酸钠对患有Wolfram综合征的儿童和成人是多么安全。我们将对丙戊酸钠在预防疾病恶化方面的效果进行估计。这将为一个新的项目提供证据，该项目将进行丙戊酸钠与假药的黄金标准临床试验；并使丙戊酸盐可供所有Wolfram患者使用。

One in 17 of the UK population suffers from a rare disease. There are over 6,000 rare diseases, many of which cause early death, and almost all have no cure. Wolfram syndrome is a rare disease that causes diabetes and blindness in children. These children grow up to develop deafness, loss of bladder control, loss of balance, and often severe depression. Death is common in mid life from breathing difficulties caused by death of brain cells and resulting brain shrinkage. The only way to look after affected people is to treat the complications: there is no cure, and no treatment to prevent or slow down the progression of the disease. Our goal is to develop a treatment that will prevent or delay the disease getting worse. We believe such a treatment will offer longer, better quality lives for affected people. We have developed a cell model of Wolfram syndrome, and used it to screen for drugs that can treat the disease. One of these, sodium valproate, reduces cell death in our cell model of Wolfram. Sodium valproate is a really interesting candidate as it has been used for decades to treat epilepsy in children. We know it is safe in children with epilepsy. We already know that valproate improves the diabetes in a mouse model of Wolfram syndrome. In this project we first propose to show that sodium valproate is effective in a mouse model of Wolfram syndrome. We will give valproate to half the mice, and dummy drug to the other half. We will measure brain size, optic nerve size, diabetes, and balance in Wolfram mice treated with valproate or dummy drug. We will study whether the disease progression is prevented or slowed in Wolfram mice treated with valproate compared with mice treated with dummy drug. If we show that valproate is effective in our Wolfram mice, we will then study sodium valproate in children and adults with Wolfram syndrome. We need to show that sodium valproate is safe and tolerated in people with Wolfram. We will invite 18 children and adults to take part, who have Wolfram syndrome. We will ask for written consent from adults, assent from children and consent from their parents. We will ask one person at a time to take sodium valproate tablets, check for safety, then the next person. We will gradually increase the dose of valproate within the recommended dose range for epilepsy. At each dose increase we will do safety checks. We will ask people to take sodium valproate for 12 months. We expect that at least 16 of the 18 children and adults will tolerate sodium valproate. We will also explore effectiveness; we will do that by measuring vision, diabetes, balance, and brain size before starting valproate treatment, and after 12 months of treatment. We already know how quickly the disease gets worse with no treatment. We hope to show that the disease stops getting worse, or gets worse more slowly, with valproate treatment.This study will show how effective is sodium valproate in stopping the disease getting worse in mice with Wolfram syndrome. We will show how safe is sodium valproate in children and adults with Wolfram syndrome. We will have an estimate of how effective is sodium valproate in preventing the disease getting worse. This will give us the evidence for a new project to do a Gold Standard Clinical Trial of sodium valproate compared with dummy drug; and make valproate available to all patients with Wolfram.