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.

Wolfram syndrome is a rare form of diabetes and neurodegeneration, and a target for the International Rare Diseases Research Consortium (IRDiRC) goal of developing new treatments for rare diseases. The prognosis is poor as most patients die prematurely with severe neurological disabilities such as bulbar dysfunction and organic brain syndrome. There is no cure, and no treatment that will arrest or delay the progress of the disease. We are developing a novel, repurposed drug therapy suitable for the management of patients worldwide with Wolfram syndrome by promoting cell survival via increased p21cip1 expression and reduced apoptosis, leading to an overall improvement in patient relevant outcome measures. To date we have: (1) identified the cell cycle regulator p21cip1 as a therapeutic target; (2) undertaken a drug screen and identified sodium valproate (SV) as a regulator of p21cip1 expression, and reduced endoplasmic reticulum stress and apoptosis markers; (3) have applied for and gained EMA and FDA Orphan Drug Designation for SV for the treatment of Wolfram syndrome; (4) received EMA protocol assistance and engaged closely with patient groups to design a pivotal clinical trial with patient relevant endpoints. We now seek further funding to allow progression of the project according to a defined translational and commercialization strategy encompassed within a business plan that includes: (1) undertaking an efficacy study of SV to delay or prevent progression of neurodegeneration and glucose intolerance in a mouse model of Wolfram syndrome; (2) undertaking a clinical trial to assess safety and tolerability of SV in patients with Wolfram syndrome; (3) reaching technical readiness for a future pivotal clinical trial to form the basis of an EU application for marketing authorization. This will move the technology along the translational pathway towards adoption as the recommended treatment in the clinic.

Patient impact: The diagnosis of Wolfram syndrome is devastating for the affected person and their family or carers, as it virtually guarantees progressive sensory, motor, autonomic and mental faculty loss, followed by premature death. We surveyed 48 affected people from 4 national patient support groups and asked them to rank the most important symptoms they would like a treatment to address. Vision ranked highest, closely followed by balance, bladder and diabetes. The impact of health on preserved sight, the most treasured of our senses, cannot be overstated. The programme of work planned in this application will allow us to provide information on the effectiveness of sodium valproate in preventing or slowing down the progression of Wolfram syndrome complications in an animal model; the safety of valproate treatment in Wolfram patients; and an estimate of the size of the benefit for patients. This will provide robust evidence for the design of the definitive Pivotal Clinical Trial of sodium valproate in Wolfram syndrome. We have assured our proposal by including efficacy measures closely aligned to Patient Relevant Outcome Measures (PROMS) that the EMA Protocol Assistance committee have informed us should be the primary clinical endpoints of a future efficacy trial.
NHS and wider health care and social services community: rare diseases collectively affect up to 1 in 17 or 6% of the UK population. The management of rare diseases and their complications, consumes a significant part of the NHS budget. Wolfram syndrome require a resource cost out of all proportion to the numbers of patients affected. These resource costs include education support services, devices for low vision, insulin and medical devices for its administration, provision of catheters, surgery for neuropathic bladder, mental health services, and complex care services for eventual bulbar palsy. A repurposed medicine to prevent or delay the progression of Wolfram syndrome would have significant economic impact on the provision of long term health care for these patients. Patients would have a reduced direct and indirect cost of treatment, and reduced need for multiple hospital appointments. NHS England would benefit because patient management costs will be reduced. There would be an additional economic impact due to a reduction in time away from education or employment, and reduction in travel costs. Reductions in the long term welfare costs of patients who would normally develop severe vision impairment would also be significant, as will the saving of taxable income of those who would remain fit to work.
Biomedical industry and economic impact: Our aims are aligned with industry needs in terms of identification and exploitation of repurposed therapeutic targets. It also maps on to the UK Government's strategy for life sciences, which aims to make the UK a world-leading place for life sciences investment. Highlighting novel uses for existing therapies used for other indications will impact across other sectors as opportunities for other applications of this platform technology (for instance, other endoplasmic reticulum stress diseases) may become apparent throughout the lifetime of the project. Enhanced UK competitiveness and prosperity would result through international commercialization and exploitation alongside the UK Government's NIHR Translational Research Collaboration for Rare Diseases programme to build national capacity in rare diseases.
Academia impact: The identification of a repurposed drug targeting the cell cycle has already raised significant interest in the field of rare diseases. We will continue to report our discoveries, both in the context of our technology development, and in the new understanding of disease processes generated by our studies. Researchers working on other rare diseases will benefit from discovery of a validated repurposed drug and the associated step change in our capabilities to address this devastating disease