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.

​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

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

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.

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

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

 

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.

We have joined the Global Rare Disease Registry Program of NIH/NCATS

I have some good news to share with you. We have just joined the Global Rare Disease Registry Program of the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS). Dr. Austin, Director of NCATS, and Dr. McInnes, Director of the Office of Rare Disease Research, helped me to make this happen. Dr. Yaffa Rubinstein who is leading this program is a wonderful person. I will work with Dr. Rubinstein to make this program successful. If you know anyone who has an abnormal form of type 1 diabetes, please ask him/her to contact me. http://wolframsyndrome.dom.wustl.edu/

I started our Wolfram syndrome International Registry with late Dr. Alan Permutt in 2009 when I was a faculty member at the University of Massachusetts Medical School. I presented my idea at the executive committee meeting of the diabetes center. Dr. David Harlan and other committee members offered help and the registry was established at Washington University. It was 6 years ago, and I did not expect that I would take over the registry then.

The registry led to the creation of the research clinic. I hope we can expand our clinic and create the consultation clinic. I hope we can create the Wolfram clinics all over the world. The Snow Foundation and our medical center have been supportive. I will keep on moving forward. The clinics help patients. To save patients, we need novel treatments. I will keep on moving forward.

I feel so grateful today. To achieve a cure for Wolfram is challenging. We need to recruit the smartest investigators and raise funds to make this happen.

Looking forward with fingers crossed,

Fumi Urano, MD, PhD

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Drug development for Wolfram syndrome with NIH, NCATS

My visit to NIH, NCATS, with Stephanie Snow Gebel, Chairman of the Board of the Snow Foundation, was quite successful. We have had multiple discussions in the past two weeks and agreed to develop novel chemical compounds (i.e., drugs) for Wolfram syndrome. We will target the endoplasmic reticulum. This will be a three-way collaboration with NCATS, Snow Foundation, and my Wolfram research team at Washington University. We are very excited by this because NCATS has a strong drug development team. They said that their mission is to develop novel treatments for rare and neglected diseases. I appreciate this opportunity, and grateful for all the people who made this possible, including Dr. Francis Collins, NIH Director, and Dr. Christopher Austin, NCATS Director. The drug development team at NCAST is so strong. I look forward to working with Dr. Ajit Jadhav, Dr. David Maloney, and Dr. Anton Simeonov. This is wonderful news to the Wolfram syndrome community. Thank you, Thank you, Thank you.

With gratitude,

Fumi Urano

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