Trials in the United States
Researchers at Washington University School of Medicine in St. Louis are launching a new clinical trial to assess the safety of a drug treatment for patients with the rare disease Wolfram syndrome.
Wolfram syndrome affects about one in every 500,000 people worldwide. Many of those patients die prematurely from the disease. Patients with Wolfram syndrome typically develop diabetes at a very young age and require insulin injections several times each day. The disorder also causes hearing loss, vision problems and difficulty with balance.
Although doctors treat patients’ symptoms, there have not been any therapies that slow the syndrome’s progress.
However, researchers at Washington University School of Medicine soon will test a drug treatment in 24 patients who have the genetic disorder.
The scientists previously reported in the Proceedings of the National Academy of Sciences that the drug, dantrolene — a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity — prevents the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome and in brain cells differentiated from skin samples taken from patients with the illness.
“Nobody has ever tested dantrolene in patients with Wolfram syndrome, so our first and most important objective is to make sure it’s safe,” said principal investigator Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine. “I am very hopeful, however. The major question that I get from every patient I see is, ‘Is there any treatment?’ And until now, I’ve had to say no. With any luck, perhaps this study can help change that.”
In the mouse studies, and in experiments with brain cells made from a patient’s own stem cells, Urano previously found that dantrolene prevented death of brain cells and insulin-secreting beta cells.
Urano’s team plans to study 12 adult and 12 pediatric patients over nine months. All of the participants will undergo extensive testing before they begin taking the medication and after having taken the drug for six months. The researchers will closely monitor patients’ vision and brain function, as well as the function of their remaining insulin-secreting beta cells.
To be eligible for the study, all patients must be able to travel to the Washington University Medical Campus for testing and medication.
The study is funded by the Snow Foundation and the Ellie White Foundation. Both are advocacy groups that support Wolfram syndrome research. Urano also has applied for federal funding to support the clinical trial and wants to expand it to other medical centers.
He doubts that dantrolene can reverse the illness. “But hopefully, we can at least delay the progression of the disease,” he said.
For more information, call study coordinator Ashley Simpson at 314-286-1550, or e-mail firstname.lastname@example.org.
Article by Jim Dryden
Trials Taking Place Abroad
Tim Barrett lay person summary
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 are life limiting, and almost all have no cure. Wolfram syndrome is a rare disease (1:700,000; about 100 people in the UK) that causes diabetes and blindness in children and young people. These children may grow up to develop other problems such as deafness, loss of bladder control, loss of balance, and sometimes depression. The disease is life limiting because of damage to brain cells and 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.
The goal of our research team is to develop a treatment that will prevent or delay the disease getting worse. We believe that such a treatment will offer longer, better quality of life for affected people.
Our research team at Birmingham University developed a cell model of Wolfram syndrome, and used it to screen for medicines that can treat the disease. We found one, sodium valproate, that reduces cell death in our cell model of Wolfram. Sodium valproate is a really promising candidate as it has been used for decades to treat epilepsy in children. It is licenced for use in epilepsy. We also know that it improves the diabetes in a mouse model of Wolfram syndrome. However, like all medicines, it does have side effects. It should not be used in people with liver disorders, or people with mitochondrial disorders caused by mutations in the POLG gene. It must not be used in pregnancy. It can sometimes cause mood changes, anaemia, nausea, disturbed periods, weight increase, and tremor. Therefore, we need to test its safety and effectiveness for Wolfram patients, in a clinical trial. We are only allowed to prescribe it to patients, once we have shown that it is safe; and that it works to slow down the disease process.
On 14th December, the UK Medical Research Council awarded £2million ($2.5Million) funding to the Birmingham UK team to lead a clinical trial of sodium valproate in children and adults with Wolfram syndrome. This will be the first randomised controlled trial in Wolfram syndrome. The aim of the clinical trial is to show that sodium valproate is safe, and effective, in people with Wolfram syndrome. We will invite 70 children and adults with Wolfram syndrome to take part. These will be from people attending 5 centres: Birmingham adults (Dr Ben Wright) and children (Dr Renuka Dias); Almeria (Dr Gema Esteban Bueno); Paris (Pr Christophe Orssaud); Montpellier (Pr Christian Hamel); Lodz (Pr Wojciech Mlynarski).
The study period will run for 36 months. We will check that valproate is safe, and effective as a treatment for Wolfram. We will do this by closely monitoring for any side effects; and by careful measurements of vision, brain volume, and other features, as the trial continues. We already know how quickly the disease gets worse with no treatment. This trial will give us a clear answer as to whether sodium valproate slows down the disease process, or not.
If the trial shows us that valproate is safe in Wolfram syndrome and slows down the progress of the disease, then this will give us the evidence to prescribe valproate to Wolfram patients in the clinic. Most importantly, we hope this trial will improve the quality and length of life in patients with Wolfram syndrome.