Washington University Wolfram Research Clinic completes its 8th consecutive year!

Washington-University-School-of-MedicineWashington-University-Wolfram-Study-group

Dear Wolfram Families and Supporters:

The Washington University Wolfram Research Clinic (or ‘natural history) study just finished its 8th consecutive year of assessing patients with Wolfram Syndrome. This work began in 2010, supported in part by the Snow Foundation. For the past 5 years, it has been supported by a National Institutes of Health grant in Dr. Hershey’s lab (Tracking Neurodegeneration in Wolfram Syndrome; Hershey, Principal Investigator). The focus of this grant is on understanding the neurological changes that may occur over time in Wolfram Syndrome, including the function of the brain (e.g. vision, balance) and the structure of the brain (e.g. the volume or integrity of different regions of the brain).

This year, we focused on assessing new patients, and those who had only been seen once or twice before. We hosted 9 families from all over the country and performed 106 exams and 8 MRIs. This clinic was smaller than previous years due to limitations in funding and the ongoing Dantrolene safety study. However, this focus allowed us to increase our understanding of how symptoms change over a 2 year time period, which are critical data for planning and implementing clinical trials. Altogether, over the past 8 years, we have assessed 40 unique individuals with Wolfram Syndrome and their families, some up to 7 times.

Just weeks before the clinic, we got the good news that our request to extend this work for another 5 years was reviewed very favorably! We received a score which should ensure that we get the funding we need, but will only know for sure this fall. In anticipation, we are going to start planning for next summer’s research clinic soon and hope to open it to anyone who has been seen in the past or any new patients that come to our attention. We will work together with Dr. Urano on any ongoing drug safety or efficacy studies to make sure that families do not have to choose between studies and that each study can support the other’s goals. 

As always, we will keep you up to date with our WU Wolfram Research Clinic newsletters, the Snow Foundation newsletters, our website (http://hersheylab.wustl.edu) and emails or calls. Please contact any of us at any time if we can provide more information or assistance!  We would love to hear from you!

Thank you!

Tamara Hershey, Ph. D.

Professor & Principal Investigator,
WU Wolfram Research Clinic

314 362-5593

tammy@wustl.edu

Bess Marshall, MD

Pediatric Endocrinologist & Research Clinic Medical Director

314 454-6051
Marshall@kids.wustl.edu

Samantha Ranck, MSW

Research Clinic Coordinator

314 362-6514
rancks@npg.wustl.edu

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TreatWolfram Clinical Trial update – June

Dear Friends and colleagues,

I would like to give you an update as to progress with our clinical trial of a treatment for Wolfram syndrome.

We had the final confirmation of funding from the UK Medical Research Council on December 16th 2016, so were able to start work on the study protocol early in the New Year. We were fortunate to have Ms Rebecca Storey appointed as Senior Trials Coordinator in January. She has lots of experience in running clinical trials, and is based in the Clinical Trials Unit, University of Birmingham. She hopes to attend the family conference in October, so I hope some of you will meet her.

We then appointed local lead investigators for the UK: this will be Dr Renuka Dias for the children’s hospital clinic, and Dr Ben Wright for the Queen Elizabeth Hospital adult clinic. Also in January, Tracy kindly met with me at my parents’ house near Gatwick Airport, where we discussed what the clinical trial would look like, and what to include in the participant information sheets. The main point was that families would prefer partipants to have an increased chance of receiving the study medicine rather than the placebo. I took this back to our trial statistician Kristian Brock, who has been able to include this request. Participants will now have a 2:1 chance of being given the study medicine rather than the placebo. Kristian Brock is an expert in statistics and trial design, and will also try to attend the family conference.

In February we started discussions with Guy’s and Thomas’s Pharmacy manufacturing unit to prepare the medicine and placebo. We also prepared the ethics application form, and had a telephone conference with our international partners in Spain, France and Poland.

In March I went to our local Young Persons’ Advisory Group. This is a group of 11-23 year olds, who kindly volunteer to read study information and critically appraise it so that it is readable and easily understood. I took them the participant information sheets I had prepared, and I am sorry to say they looked them over very critically! They pointed out that the layout could be improved; that there was some repetition; and that a glossary of medical terms would help. I am very grateful to them and the information sheets are now shorter and clearer to read.

In April I attended the European Medicines Agency in London with Julie Warner, from Boyd Consultants, who provide regulatory advice. They agreed that we must check if the treatment slows the rate of deterioration of vision; however they would like a second outcome measure that is important for families. We are now working with experts on patient reported outcome measures, and would like to propose some ideas to you – things to measure which are important for a treatment to improve.

I also visited the French Wolfram association in Paris, just before Easter, and attempted to present the clinical trial in French. The audience was very polite and tolerated my schoolboy French! In May I gave a similar presentation to Spanish families in Almeria, hosted by Dr Gema Esteban, our Spanish collaborator. There is a lot of enthusiasm to take part, and there were many questions. Some of these related to randomisation, and I had to explain that the European Medicines Agency insist that some people receive the medicine and some the placebo. This is in order to provide the strongest evidence that our medicine works.

We are now hoping to sign the contract with the pharmacy manufacturers; submit the ethics application package in September; and recruit the first participants in the UK at the end of November. The timescale has been extended as we have to show that the medicine is stable outside the manufacturer’s packaging, when we put it in airtight plastic containers. This stability testing started last week, and takes 3 months.

Later this month, we have a local investigator meeting, where we will sort out the practical aspects of what tests we will be asking participants to have. I would like to write another update at the beginning of July when I can feed back on this meeting.

Please don’t hesitate to get in contact if I can help at all with any questions. Meantime, thankyou all for your kind interest and support!

Sincerely

Prof Tim Barrett

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Dr. Urano’s June Wolfram Research Update

Fumihiko “Fumi” Urano, MDDear Friends,

It’s a spectacular Saturday morning in Saint Louis as I write this to you. I always appreciate your continued support, encouragement, and kind words.

I have received many questions regarding our ongoing clinical trial, as well as questions related to our next step lately.

Although we don’t have a concrete plan yet, we consider the following possibilities.

  1. A longer duration, More participants, Multi-center
  2. Compare the efficacy of dantrolene sodium, valproic acid, and dantrolene sodium plus valproic acid

We are also developing breakthrough treatments for Wolfram syndrome as dantrolene and valporic acid are old drugs originally developed for other medical conditions.

Here are our new plans.

  1. We have been developing a new drug designed for Wolfram syndrome  (ER stress stabilizers) together with NIH/NCATS to delay/halt the progression of the disease. Pre-clinical studies in mouse models of Wolfram have been designed. We are seeking funds to complete these studies.
  2. Regenerative therapies using a novel neurotrophic factor in combination with gene transfer technology for visual impairment have been designed. We are seeking funds for testing these new therapies in mouse models of Wolfram syndrome.

I think we are making progress, and need to speed up as we are racing against time. Thank you again for your support.

Take care,

Fumi Urano, MD

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Dr. Barrett meets with Wolfram Associations across the globe

Dear Friends and colleagues,

I have been fortunate to visit the French Wolfram Association meeting in April in Paris; and the Spanish Wolfram association meeting in May in Almeria.

I was humbled by the friendship and community spirit of these families; and they were very tolerant of my poor French and Spanish language skills.

On the research front, we have just published the online mutation database of genetic variants in the Wolfram gene. This was work undertaken by Dr Dewi Astuti, and is a freely available database to support scientists worldwide. The database is available at: https://lovd.euro-wabb.org

Regarding the Phase II clinical trial, we are negotiating manufacture of the investigational medicinal product and placebo. We hope to complete this in the next 4 weeks and are still aiming to begin recruitment in the UK in November.

Thank you for all your interest and support, and I will try to provide regular updates on our progress

Sincerely,

Prof Tim Barrett

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Clinical Trial Update by Fumihiko Urano, M.D.

Dear Friends,

I would like to update you about the status of our clinical trial of dantrolene sodium in patients with Wolfram syndrome. Dantrolene is a US Food and Drug Administration (FDA)-approved drug currently used for different medical conditions. Based on our data, we received orphan drug designation of dantrolene sodium for the treatment of Wolfram syndrome from US FDA and European Medicines Agency (EMA) in 2016. We also ​received the​ green light from ​the ​FDA and Washington University Medical Center to proceed to a pilot clinical trial (phase 1b) to assess the safety and efficacy of dantrolene on patient’s vision, brain functions, and diabetes.

Thanks to the generous support from the Snow Foundation in collaboration with Ellie White Foundation and other private donors, I was able to commence the clinical trial and slowly started recruiting patients. I would like to recruit at least 24 patients and hope to secure more funds to accommodate all the patients who are eligible for this trial. Stephanie Gebel​ has told me that she will do her best to make this happen. ​I was just informed ​​this week that we will receive grant funding from the National Institutes of Health (NIH) to support this trial.

I ​have not forgotten​ about our patients in other countries. Dr. Tim Barrett in the UK and I are closely working ​to conduct international clinical trials for Wolfram syndrome. In parallel, we keep on developing novel drugs and regenerative therapies for Wolfram syndrome. Dantrolene could be a band-aid for Wolfram, but cannot provide a cure. Thus, we need pipelines for developing breakthrough treatments.

Thank you for your continued support.

Sincerely,

Fumi Urano, MD

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End Of The Year Update

Dear Friends,

My highest priority right now is to work out the logistics for the upcoming clinical trial. As our medical center announced in November this year, we plan to start a phase 1b safety clinical trial of dantrolene sodium in patients with Wolfram syndrome. Dantrolene sodium is an FDA-approved drug utilized for the treatment of muscle stiffness. We found that dantrolene could prevent 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 in 2014 after the 12 years of research. This drug can target the molecular pathways altered in Wolfram syndrome in cell and animal models of Wolfram syndrome. Nobody has ever tested dantrolene in patients with Wolfram syndrome, so our first and most important objective is to make sure it’s safe. We will also closely monitor patients’ vision and brain function, as well as the function of their remaining insulin-secreting beta cells based on the data collected through our research clinic study.

The major question that I get from every patient I see is, “Is there any treatment?” As you are aware, there is currently no treatment that can slow, halt, or reverse the clinical manifestations of Wolfram syndrome including vision impairment and diabetes. I sincerely hope that this study can help change that. I have been working diligently to commence the trial early next year, hopefully in January 2017, and secure additional funding from the National Institutes of Health to recruit more patients. Please contact my nurse coordinator, Ms. Ashley Simpson (+1-314-286-1550, ashley.simpson@wustl.edu) or check our medical center’s website (http://wolframsyndrome.dom.wustl.edu/clinical-trials/) for more information. I appreciate the support from the Snow Foundation and Ellie White Foundation for the upcoming trial.

I have been working with Dr. Tim Barrett in the UK to conduct international clinical trials for Wolfram syndrome. In parallel, we keep on developing novel drugs and regenerative therapies for Wolfram syndrome.

As we near the end of this year, I would like to take this opportunity to thank you all for your continued support. You have provided patients with hope and emotional support. Together with you, we can make a difference in the future of our patients. Thank you again for your generous support and continued encouragement. You gave me the power and courage to continue. I cannot thank you enough. I hope you have a wonderful holiday season.

Sincerely,

Fumi Urano, MD

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Researchers launch first clinical trial for Wolfram syndrome

The drug dantrolene is a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity. Recent research also suggests it can prevent the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome. Researchers at Washington University School of Medicine in St. Louis are beginning a clinical trial to assess the drug as a treatment for patients with Wolfram syndrome.

The drug dantrolene is a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity. Recent research also suggests it can prevent the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome. Researchers at Washington University School of Medicine in St. Louis are beginning a clinical trial to assess the drug as a treatment for patients with Wolfram syndrome.

 

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 ashley.simpson@wustl.edu.

 

Article by Jim Dryden

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7th Annual Washington University Wolfram Syndrome Research Clinic Meeting

The 7th Annual Washington University Wolfram Syndrome Research Clinic Meeting was held in July, bringing together the key opinion leaders and researchers who are leading the fight to bring a cure to Wolfram Syndrome. Here are some exciting highlights of recent findings from the meeting.

Collaboration and Funding is Critical

The effort to understand disease progression of neurological symptoms of Wolfram Syndrome continues, and significant progress has been made in the last year. Researchers now know the appropriate measurements to use in a clinical trial. Several endpoints have been identified, however, visual acuity and the volume of the ventral pons (a structure in the brain) have been shown to change reliably over time and will be used in upcoming trials to determine the efficacy of treatments for Wolfram syndrome. Adding to the challenge of conducting a clinical trial, researchers have also discovered that there is great variability in Wolfram syndrome symptoms and progression. There are also new hypotheses on how Wolfram affects the brain that will be soon tested in models, which may lead to more targeted treatments for the neurological systems.

Progress on these efforts, however, is heavily dependent on funding, with the current NIH grants ending in 2017. Our goal coming out of the 6th International Workshop was to bring researchers together to collaborate, move science forward to treatments and cures. At the 6th International Workshop we had 37 participants, 11 countries, four family associations, and presented 20 talks.  Since then, we’ve accomplished the goals of finding a potentially useful animal model, devising new diagnostic guidelines, and planning two clinical trials.

Defining Wolfram has been challenging. A proposed definition of Wolfram syndrome was presented at the conference, and are:

  1.     Disease-causing mutations in the WFS1 gene.
  2.     Two major criteria (Diabetes mellitus and optic atrophy) or having one major criterion and 2 of: Diabetes insipidus, hearing loss or neurologic deficits.

Most clinical trials have very specific qualifications before they begin, like certain ages, certain sex, at same stage in illness etc.  Since Wolfram syndrome is a rare disease and we cannot have specific qualifications like the list above, the trial could face challenges due to the small patient population, variability in the disease progression, and variability in the severity of the symptoms.

Diet Can Be a Factor

Some recent research suggests that nutritional components of a patient’s diet may be significant to Wolfram patients. Although there has been no study for treating Wolfram syndrome in people, there have been studies and recommendations for some other conditions like heart disease. Dr. Urano presented evidence in cells that DHA and Omega-3 fatty acids may help ER stress, which is the problem in Wolfram. DHA and Omega-3 fatty acids are in food and generally believed to be healthy in moderation.

Wolfram patients can get Omega-3 fatty acids, especially DHA from fish: anchovies, bluefish, herring, mackerel, salmon, sardines, sturgeon, lake trout, and tuna. (Fish like mackerel, wild swordfish, tilefish, shark or farm-raised fish have higher levels of mercury, PCB’s or other toxins, and should be limited). Some vegetarian-friendly sources for Omega-3 include: walnuts, pecans, pistachios, eggs, seaweed, parsley, spinach, kale, and beans. We don’t know the ideal dose for Wolfram patients, but a good range would be 500-1000 mg a day of diet plus supplemental omega-3’s.

Another paper has shown that CoQ10 has a possible improvement in vision in one person with Wolfram. The ideal dose is not known, but the recommended range from manufacturers is 20-400 mg. CoQ10 may have some side effects but is probably safe in higher doses for a limited time.

A low salt diet may be also detrimental in cases of diabetes insipidus. A reasonable amount of salt is a teaspoon or 2000 mg a day. Some foods have a lot of salt so it will count towards your 2000 mg daily-recommended limit.

You can check out the full research clinic presentation below.

Below is the Powerpoint presentation:

wolfram-clinic-2016_research-update_for-posting-1

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2015 Wolfram Research Clinic Update

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