Dr. Urano’s September Update

September 24th, 2018

Dear Friends,

Thank you so much for your support. I hope you had a nice summer season with your family. I feel that autumn is coming, and it is time for me to update you about our progress. Today, I’d like to talk about one of the new drugs we are developing as we have made significant progress on this drug in the past few months. I call it “Molecular Prosthetics.”

To provide a cure for Wolfram syndrome, we need to stop the disease progression. A common problem in patients with Wolfram syndrome is a particular type of cell stress, endoplasmic reticulum stress (ER stress), caused by the expression of mutant Wolfram protein (WFS1 protein) produced in patients’ cells. ER stress can ultimately result in dysfunction and death of insulin producing cells, retinal cells, and brain cells.  To resolve this issue, we have been developing molecular prostheses that can optimize the structure and conformation of mutant Wolfram protein. If we can restore the structure of mutant Wolfram protein, it should result in resolution of ER stress and reduction of cell death.

I have been working with Amylyx Pharmaceuticals in Cambridge, MA, and NIH/NCATS to evaluate a novel molecular prosthesis in brain cells derived from induced-pluripotent stem cells (iPSCs) of patients with Wolfram syndrome to determine whether this therapeutic has potential to act as a molecular prosthetic/ER stress reducer to treat the disease. We have been getting encouraging results using cells from patients. My goal is to confirm the results in our humanized mouse and rat models of Wolfram syndrome for conducting a clinical trial. This drug seems to be especially beneficial for brain cells. So it is important for us to know if this drug can improve visual acuity and motor function in our rodent models of Wolfram syndrome.

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. Your encouragement keeps me going. I think about our patients every single day. We will decrease human suffering together.

With passion, hope, and gratitude,

Fumi Urano

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Dr. Urano’s August 2018 Update

Fumihiko “Fumi” Urano, MDAugust 9, 2018

Dear Friends,

I’d like to begin by thanking all of you for your continued support, trust, and faith in me. I always feel your support and energy. It is always my pleasure to update you about our progress. 

To achieve a cure for Wolfram syndrome, we need breakthrough treatments. We currently have three new candidate drugs that can potentially delay or halt the progression of Wolfram syndrome. In parallel, we are developing regenerative gene therapy to protect and regrow remaining eye and brain cells. We usually test the efficacy of candidate drugs and gene therapies in cell models of Wolfram syndrome first. Wolfram cell models are cells derived from our patients or cells lacking normal Wolfram syndrome 1 gene. These cells are sensitive to cell stress and susceptible to cell death. So we are looking for candidate drugs and gene therapies that can reduce cell stress and cell death in Wolfram cell models. The advantage of using cell models is that we can test multiple drug candidates at the same time within a few months. As a next step, we use a mouse model of Wolfram syndrome to test the efficacy of new treatments on visual acuity, brain function, and diabetes. These are genetically engineered mice that do not have Wolfram syndrome 1 gene and develop diabetes, visual impairment, and brain dysfunction. Although these mice are quite useful, it is challenging to test the efficacy of a type of gene therapy called gene editing because they don’t carry abnormal Wolfram syndrome 1 gene variants that our patients carry. In addition, because mice are so small, it is challenging for us to test the efficacy of new treatments in their eyes. Their eyes are so small. To overcome these challenges, I have designed mice and rats carrying Wolfram syndrome 1 gene variants that our patients carry. We call them humanized Wolfram mice and rats. If successful, we can test our new gene therapy and assess the efficacy of new treatments on visual acuity in these humanized Wolfram mice and rats. This will accelerate the pace of our therapeutic development. 

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. I cannot thank you enough.

With passion, hope, and gratitude,

Fumi Urano

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Dr. Urano’s July 2018 Update

Fumihiko “Fumi” Urano, MDJune 28, 2018

Dear Friends and Supporters,

It is nice to see you again. I always appreciate your support, trust, and faith in me. I see patients with Wolfram syndrome every week and receive phone calls and emails from patients and their families every single day. It is definitely urgent to slow the progression of the disease and develop novel treatments for achieving a cure.

I attended two important meetings in the past two weeks. From June 11th to June 12th, I attended the International Wolfram Syndrome Workshop in Paris, France, hosted by the French Wolfram Syndrome Association. I attended the first workshop in 2009 together with just 11 other researchers from all over the world. I was the only researcher from the US then. At the first workshop, we agreed to create patient registries and research & service clinics for future clinical trials. As of today, these goals have been achieved, and two drug-repurposing clinical trials are ongoing (https://wolframsyndrome.dom.wustl.edu/clinical-trials/). I met with late Dr. Alan Permutt from Washington University and Mrs. Stephanie Snow Gebel who founded the Snow Foundation at the workshop in 2010, which made me decide to move to Washington University in 2012. At this year’s workshop, almost 50 researchers attended and presented their progress. I presented our progress on our clinical trial and gene therapy strategies. My colleague, Dr. Tammy Hershey, presented MRI findings in patients with Wolfram syndrome. My long-term collaborator, Dr. Tim Barrett in the UK, presented his progress on their clinical trial. I met with multiple collaborators and saw representatives of patient organizations from US, UK, Italy, Spain, Belgium, and France. I was glad to see that the International Wolfram research group had grown. I was glad that all the researchers had been collaborative. I was grateful for everything patient organizations had done for our patients and families, doctors, and researchers.


On Monday, June 25th, I presented my concept of Wolfram spectrum disorder at the American Diabetes Associationmeeting in Orlando, Florida. I believe there are at least three different types of clinical manifestations in Wolfram syndrome and Wolfram-like disorder: mild, intermediate, and severe. I have been developing genetic testing to further understand the spectrum of Wolfram syndrome. Some of our new treatments could be beneficial for patients with all three types in theory. We also need to develop specific treatments for each type.

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. Good things happen to people who do good things.

With passion, unity and gratitude,

Fumi Urano

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Dr. Urano Update June 2018

Fumihiko “Fumi” Urano, MD

“I believe that Wolfram syndrome is an underdiagnosed disease. Wolfram syndrome is characterized by juvenile-onset diabetes, optic nerve atrophy, diabetes insipidus, deafness, neurogenic bladder, and symptoms related to brain cell dysfunction. However, I have discovered that Wolfram syndrome gene (WFS1) mutations result in manifestations that range from mild to severe. I know diabetes patients who carry WFS1 gene mutations and have not developed any other cardinal symptoms of Wolfram syndrome, such as optic nerve atrophy. This is called the spectrum of disease. To provide an accurate diagnosis, I have been developing “genetic testing” for screening Wolfram syndrome and Wolfram-related diseases. Using a single tube of blood, I would like to provide an accurate diagnosis. An accurate diagnosis serves as a basis for targeted therapy. An accurate diagnosis provides a sense of relief”.

As always, please feel free to contact me with any questions or concerns.

– Fumi Urano (urano@wustl.edu)

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May 2018 Update from Dr. Urano

Fumihiko “Fumi” Urano, MDDear Friends,

First of all, I would like to express my gratitude to you for coming to see me today. Thank you so much for following my mission & vision and being the kindest person. I think about patients with Wolfram syndrome and their families and friends every morning. That’s one of the first things I do every day at 4:30 am. I would like to support, help, and save them. I would like to know their challenges and help them overcome these challenges. Three things are always on my mind: 1. Improve Clinical Care, 2. Raise Awareness, and 3. Provide a Cure. We are clearly making progress in #1 and #2. How about #3? Is it possible? If so, how long?

Here is my answer. “We are making progress. We are this close.”

This close = my head size. I have all the strategies and ideas for developing cutting-edge treatments for Wolfram syndrome in my head. My challenge is to realize these ideas. There are technical roadblocks for developing gene therapy. There are regulatory issues to bring new drugs from bench (lab) to bedside (patients). There are financial constraints. These are not so easy to overcome, but these are much smaller challenges than those our patients have been experiencing. I would like to articulate my strategies again. There are three steps. Step 1: Drug Therapy for halting progression. Step 2: Regenerative therapy for protecting and regrow remaining eye and brain cells. Step 3: Gene therapy for replacing pathogenic genes. To achieve these goals and accelerate our progress, I have started creating three new animal models (mice and rats) carrying human Wolfram gene mutations. They are humanized Wolfram mice and rats. I plan to use these animals to test gene therapy and regenerative therapy.

In addition, I have been developing “genetic testing” for screening Wolfram syndrome and Wolfram-related diseases. I believe that Wolfram syndrome is an underdiagnosed disease. Using a single tube of blood, I would like to provide an accurate diagnosis. An accurate diagnosis serves as a basis for targeted therapy. An accurate diagnosis provides a sense of relief. 

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. Our potential is limitless. We have superpower to overcome this challenge.

With passion, hope, and gratitude,

Fumi Urano

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Dr. Urano’s April Update

Dear Friends,Fumihiko “Fumi” Urano, MD

Thank you so much for “coming to see me” today. It is always my pleasure and privilege to see you and talk to you. I feel your support and encouragement, and I am grateful for everything you have done for me, the Snow Foundation, patients, and their families and friends. Just reading this blog is helping me because I can feel your support, which makes me feel stronger and committed.

I would like to share my ideas on how to provide a cure for Wolfram with you today as our first clinical trial is ongoing and we are making steady progress in the development of new drugs, regenerative therapy, and gene therapy. I have been thinking and presenting my strategy for therapeutic development of Wolfram syndrome, CURE4WOLFRAM, since 2002. My current version, 4.0, is the following.

1. Stop Progression

ER Calcium Stabilizers
One of the common molecular pathways altered in patients with Wolfram syndrome and diabetes patients is imbalanced cellular calcium homeostasis. More specifically, endoplasmic reticulum (ER) calcium levels are lower in patients with Wolfram syndrome, leading to cell dysfunction and death. To overcome this challenge, we are currently testing if an ER calcium stabilizer, dantrolene sodium, can delay the progression of Wolfram syndrome. Dantrolene sodium is a FDA-approved drug for the treatment of muscle spasticity and high fever induced by anesthesia. We previously reported that dantrolene sodium stabilizes ER calcium levels and prevents cell death in cell and mouse models of Wolfram syndrome. We are currently conducting a clinical trial of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. In collaboration with NIH/NCATS, we are also developing novel ER calcium stabilizers (i.e., second generation dantrolene) for the treatment of Wolfram syndrome.

Molecular Prosthetics
Another common issue in patients with Wolfram syndrome is ER stress caused by the expression of mutant Wolfram protein produced in patients’ cells. To resolve this issue, we have been developing molecular prosthetics that can optimize the structure of mutant Wolfram protein together with NIH/NCATS and Amylyx, a biotech company in Cambridge, MA.

2. Protect and Regrow Remaining Tissue

Our second step towards a cure for Wolfram syndrome is to protect and regrow remaining tissue using regenerative therapy. We have discovered a naturally produced molecule in our body that can activate the proliferation of damaged beta cells and brain cells. Expression levels of this molecule, MANF, are usually low in our body. We are developing a method to enhance the activity of MANF using a pill that can mimic the functions of MANF and gene therapy (i.e., produce safe virus expressing MANF).

3. Replace Pathogenic Genes

Towards a cure for Wolfram syndrome, a genetic condition, we need to target the root cause of the disease, which is the loss of function of Wolfram syndrome gene, WFS1. Using CRISPR/CAS9 technology, we are attempting to replace a pathogenic Wolfram gene (WFS1 gene) with a healthy Wolfram gene. We are also trying to introduce safe virus expressing normal WFS1 gene into patients’ cells.

Thank you so much for being with me today. Good things happen to people who do good things. I am always hopeful.

With grace and gratitude,
Fumi Urano

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Dr. Urano’s January 2018 Update

Fumihiko “Fumi” Urano, MDHello Everyone,

As this is the first time to see you in 2018, I would like to begin by thanking all of you for your continued support and encouragement. I appreciate it immensely. I am so grateful to have such supportive friends. I would like to update you about our latest developments as usual.

Our drug-repurposing clinical trial of dantrolene sodium is ongoing. The trial began in January 2017. Twenty-two patients with Wolfram syndrome enrolled. Two patients decided to leave the study due to personal reasons and one patient could not start the study because of medical reasons. So nineteen patients started taking dantrolene sodium. As of today, fifteen of them have been taking dantrolene for more than 6 months. At this stage, my team has found few side effects and has identified safe dosage levels in adult and pediatric patients. I saw some beneficial effects on remaining beta cell functions, visual acuity, and neurological functions in some patients, but did not see any beneficial effects in other patients. Because all the participants are taking dantrolene, we cannot conclude that any effects are due to dantrolene. Nevertheless, I have sent the data of fifteen patients to statisticians who have not been involved in our Wolfram studies (myself and my colleagues are biased as you can imagine). We will find out more about the outcome of this study in the next several months.

I thought a lot about our therapeutic development for Wolfram syndrome during the holiday season. I feel that drug-repurposing may not be good enough. I firmly believe that we need a breakthrough therapy for Wolfram syndrome. This year, I would like to spend more time for developing regenerative gene therapy, especially for visual impairment. In parallel, I would like to develop a second-generation dantrolene which is more potent and safe. These are my two goals in 2018.

I feel that something new and wonderful will happen to us this year. I feel that we will go into a new stage. Thank you again for your continued support. I am hopeful and grateful.

Looking forward,

Fumi

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Dr. Urano’s November Update

November 4, 2017Fumihiko “Fumi” Urano, MD

Dear Friends,

It has been a while since we last talked. I hope you are enjoying this Fall season with your family and friends. I think about the value of family and friends a lot lately. Support from family and friends keeps me going. So I appreciate your continued support, encouragement, and kind words. Let me update your about our progress on therapeutic development for Wolfram syndrome.

Our drug-repurposing clinical trial of dantrolene sodium is ongoing. The trial began in January, and nineteen patients with Wolfram syndrome from the US and Canada are now involved. Participation requires periodic testing and monitoring at the adult and pediatric clinics at Washington University Medical Center in St. Louis.  The trial is focused on the safety, tolerability, and efficacy of the drug (visual acuity, neurological functions and remaining beta cell functions). At this stage my team has found few side effects and has identified safe dosage levels. More tests and data are necessary before any conclusions can be reached.

I am aware that we need a breakthrough therapy for Wolfram syndrome. In theory, drugs that target endoplasmic reticulum (a cellular compartment damaged in Wolfram patients), such as dantrolene sodium, can delay the progression and may improve functions of remaining beta cells and brain cells, but these drugs cannot reverse symptoms. We need something that can reverse symptoms, such as visual impairment, and we need to tap into new technologies. We are developing a regenerative gene therapy, especially for visual impairment. Our strategy is to introduce a regeneration factor into a type of retinal cells using a gene transfer technology. This is clearly not simple and requires a lot of time and efforts, but we are making progress.

Thank you for taking your time to read my blog. I hope to talk to you again soon.

Warmest regards,
Fumi Urano, MD

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Dr. Urano’s September update

September 22, 2017Fumihiko “Fumi” Urano, MD

Dear Friends,

It is nice to “meet” you again. Thank you for your generous and continued support for our therapeutic development for Wolfram syndrome. With the support from the Snow Foundation, multiple patient organizations and supporters around the world, and federal grants, I could maintain the Wolfram syndrome program to study the disease, which led to fundamental laboratory studies that uncovered the molecular genetic defect, and ultimately to the identification of a therapeutic target that is now being tested in patients. Our first clinical trial of a re-purposed drug, dantrolene sodium, in patients with Wolfram syndrome is ongoing. We have been monitoring the safety, tolerability, and efficacy of dantrolene sodium in 21 patients who have qualified for the study. You can find the information about the inclusion and exclusion criteria on the following website. We have both male and female participants in pediatric and adult populations. https://clinicaltrials.gov/ct2/show/NCT028292680

The planned duration of oral dantrolene sodium administration in this study is 6 months with an optional extension phase up to 24 month. All the participants are required to come to our clinic 9 times in the first 6 months to determine the appropriate dose and ensure the safety. After the first 6 months, participants come to our clinic every 6 months up to 24 months. As of today (September 22, 2017), 20 participants are taking dantrolene sodium and one participant has left the study due to personal reasons. 9 out of 20 patients have been taking dantrolene sodium for more than 6 months. In addition to safety and tolerability, we have been assessing our participants’ visual acuity, remaining beta cell functions (i.e., their ability to produce insulin from their own pancreases), and neurological functions every 6 months. We plan to publish the data once we collect the information from these 20 participants after the 6-month administration of dantrolene sodium.

On a different note, Senator Roy Blunt and the Director of National Center for Advancing Translational Sciences (NCATS), Dr. Christopher Austin (https://ncats.nih.gov/), visited our medical center last month. I had a chance to present our medical center’s efforts on rare disease therapies. I am glad to tell you that our presentations were perceived really well. Stephanie and I met with Dr. Austin a few years ago at the NCATS headquarter in Bethesda, close to Washington DC, and that was the beginning of my collaboration with the drug development team at NCATS. We will keep on working together for developing rare disease therapies.

Thank you for being with me. I plan to update you about our two new drugs and regenerative gene therapy for retinal degeneration in my next blog. I hope you will have a wonderful fall season. See you soon.

Warmest regards,
Fumi Urano, MD

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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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