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

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.