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Dr. Urano’s August update

Fumihiko “Fumi” Urano, MD

Dr. Fumihiko “Fumi” Urano, MD

Dear Friends,

I hope you had a wonderful summer season. I would like to update you about our progress.

Our clinical trial of dantrolene sodium in patients with Wolfram syndrome is ongoing. We have been monitoring the safety, tolerability, and efficacy of the drug. Some patients have been taking dantrolene sodium for more than 6 months, and we have started getting the safety, tolerability, and efficacy data. We plan to publish the data once we collect the information from 20 patients. I have started preparing for the next phase of this trial. As I mentioned in my previous blog, we are considering the following possibilities.

  1. A longer duration, More participants, Multi-center
  2. Include the placebo arm. I understand that nobody wants to take the dummy drug for a long period of time. So I have been getting advice from medical officers conducting clinical trials for rare diseases.

In addition to dantrolene sodium, my team has been looking into two new drugs for Wolfram. Unlike dantrolene sodium, these drugs are new. So we need to carefully collect more data from mouse models of Wolfram and healthy human subjects.

  1. The first drug is an endoplasmic reticulum (ER) calcium stabilizers which we discovered together with NIH/NCATS. This drug is for delaying/halting the progression of the disease. Pre-clinical studies in mouse models of Wolfram are ongoing.
  2. The second drug is a chemical chaperone which reduces ER stress. We have started collaboration with a biotech company on this new drug.

I am aware that we need to find a way to improve visual acuity. I am trying to secure funds for testing our new regenerative gene therapies for optic nerve degeneration using a novel neurotrophic factor in combination with gene transfer technology. I have applied for multiple grants and am quite hopeful about the outcome.

Thank you for your continued support. I cannot thank you enough.

Take care,

Fumi Urano, MD

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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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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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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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3 Things on my Mind When I Work on Wolfram syndrome

While working on Wolfram syndrome there are three things that are always on my mind: improving clinical care, raising awareness, and providing a cure. These three things motivate myself and my team to work hard every day.

 

Improving Clinical Care

Our effort to understand the progression and neurological symptoms of Wolfram syndrome will help improve the clinical care we give our patients. Clinical trials throughout the world have specific qualifications before they begin and thanks to our researchers from around the globe in the last few years there has been significant progress and we now know the appropriate measurements to use in our clinical trials. There are also new hypotheses on how Wolfram syndrome affects the brain that will soon be tested in research models, which will lead to more targeted treatments for the neurological systems and improve the clinical care for the patients. This is all thanks to multiple foundations around the world like The Snow Foundation who are helping us raise awareness and helping us raise funds to make these trials possible.

 

Raising Awareness

Awareness for Wolfram syndrome has grown significantly with help from advocate groups such as The Snow Foundation and the Ellie White Foundation. We could not have accomplished the research we have conducted so far without these organizations and other advocate groups  and we want to thank and recognize all the groups for being a part of our research efforts. However we still depend heavily on NIH (National Institutes of Health) grants to help us with a significant amount of funds for our research to find a cure. NIH grants have increasingly difficult to get and we are working on getting more funding in the next year. The awareness and research funds play the largest part in helping us find a cure for Wolfram syndrome.

 

Providing a Cure

To provide a cure, we need to first delay the progression of the disease so that we have more time to develop regenerative therapies and gene therapies. To accomplish this milestone, I have been focusing on “repurposing” one of the FDA-approved drugs (i.e. existing drugs) for the treatment of patients with Wolfram syndrome.  We have been making steady progress on this.

As I reported before, we discovered that dantrolene sodium currently approved for the treatment of spasticity (muscle stiffness) could delay the progression of Wolfram syndrome in animal and cell models. We obtained the orphan drug designation of dantrolene sodium for the treatment of Wolfram syndrome from the US FDA early in 2016.

I have been working on the logistics to commence a clinical trial of dantrolene sodium for the treatment of Wolfram syndrome at our medical center. I hope to start the trial in December of this year and the plan is to enroll 25 patients or more. The trial may last 2 years. I plan to monitor safety, vision, neurological functions, and diabetes in our patients since those are the primary indicators of Wolfram syndrome. As I reported before, type 2 diabetes is associated with Wolfram syndrome 1 gene variations.

We are trying to get more funds from the National Institutes of Health to recruit more patients, and we want to thank The Snow Foundation and Ellie White Foundation for planning to support this trial financially.

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High sugar levels in the brain and neurodegeneration

My top priorities are to: 1) repurpose a FDA-approved drug and 2) develop novel drugs for Wolfram syndrome. I am also looking into environmental factors, diets, and life-styles that can potentially delay the progression of Wolfram syndrome. One of the possibilities I am looking into is to keep our blood sugar steady (i.e., maintain normoglycemia).

I have an impression that patients who maintain normoglycemia may have milder symptoms and delayed progression. I was reading an article introduced in the Wall Street Journal very carefully. This study was led by David Holzman, MD, a renowned Alzheimer’s disease scientist. His team’s study strongly suggests that high sugar levels in the brain accelerate amyloid deposition in the brain, which increases the risk for Alzheimer’s disease. Based on their study, neuronal functions and activities are altered by high sugar levels. We should look into this in our animal models of Wolfram syndrome.

Dr. Holzman’s study might explain the link between Type 2 diabetes and Alzheimer’s disease. Please note that Wolfram syndrome 1 gene variations are associated with the risk of Type 2 diabetes, the most prevalent form of diabetes.

Thank you for reading this blog. I am thinking of one of our patients and sincerely hope that her condition gets better. We really need a treatment for this devastating disorder.

Take care,

Fumi Urano

Various kinds of sugar in wooden bowls

Various kinds of sugar in wooden bowls

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Raise Awareness of Wolfram Syndrome in Asia together with Dr. Barrett

Dr. Barrett and I gave lectures on Wolfram syndrome at the Japan-Korea Diabetes Symposium in Japan this week. Our lectures were successful. I had a chance to speak with Japanese physicians who see patients with Wolfram syndrome. The president of Japanese Diabetes Association, Dr. Tanizawa, and the President of the American Diabetes Association, Dr. Dagogo-Jack, were there.

I felt fortunate that I had a chance to present my progress at the symposium. Our goal is to conduct international clinical trials.

Thank you for your support. Thank you, Thank you, Thank you.

Take care,

Fumi Urano

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Create a new drug based on an old drug

My current priority is to bring an existing drug that can control endoplasmic reticulum (ER) functions to our patients with Wolfram syndrome. However, this is not good enough to halt the progression and/or reverse symptoms. We need to design a new drug that is specifically designed for Wolfram syndrome. How can we achieve this?

We are taking a few different approaches. One of the approaches that I am taking is to extensively test the existing FDA-approved drug and monitor the effects of this drug on ER functions. We are also testing this drug in mouse models of Wolfram syndrome and cells from patients. Based on the data we have, we will test other new drugs that bind to the same molecule as this FDA-approved drug binds. The efficacy of these drugs will be carefully monitored in mouse models of Wolfram and cells from patients. Together with the Snow Foundation, we are raising funds to achieve this goal as quickly as possible.
Thank you for your continued support.

Kindest regards,

Fumi Urano

Medicine

 

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A message from a mother

I receive many emails, letters, and phone calls every day from patients with Wolfram syndrome and unusual forms of diabetes and their families and doctors. Many of these are related to their medical conditions and potential treatments. Some of these are personal.

I received a message from a mother who had lost her daughter due to Wolfram syndrome last week. I was very sorry for her loss. I also appreciated that she shared her thoughts with me. I was encouraged by her message. I face multiple challenges, but a message like this one keeps me going.

I read every single email from you. I try to respond to all of these messages. Thank you again for your continued support. Tomorrow is a Mother’s day, my friends.

Take care,
Fumi Urano

Message in the bottle washed ashore on rocky beach.

Message in the bottle washed ashore on rocky beach.

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