I always appreciate the efforts of all the medical staff, administrative staff, volunteers, researchers, interpreters, and others who have been involved in the Wolfram syndrome research clinic.
It is my privilege to serve for patients with Wolfram syndrome and work with dedicated people who have been involved in our Wolfram syndrome research. My team has been working very hard to develop a novel drug for Wolfram syndrome.
I believe that our patients who are attending this year’s clinic are a little tired now. Thank you for your patience. Thank you for your faith in us. We have one more day to go!
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-07-18 20:52:442020-09-07 20:10:39Wolfram Research Clinic Day 2: Thank you and Thank you
Wolfram research clinic is ongoing and our patients are going through many tests. At this year’s clinic, we are collecting blood samples from not only patients but also their parents and siblings. Why? The reason is we plan to measure “BIOMARKER” levels in these samples.
What is a biomarker? A biomarker is a molecule found in blood or tissues that is a sign of a disease. We found two candidate biomarkers for Wolfram syndrome. The levels of these biomarkers are higher in patients’ blood samples than in non-patients’ blood samples. These biomarkers can be used to see how patients respond to a treatment.Here is an example. Blue: Patients, Red: Non-Patients.
Here is another one. 1: Non-Patients, 2: Patients, 3: Patients after a treatment
Our annual Wolfram syndrome research clinic will start today, and I met with most of the patients and their families last night. I have been very impressed by them.
9-year old Raquel Gebel signing her own consent form to participate in the 2014 clinic.
In this clinic, we don’t provide any treatment. We just collect information and samples from patients, their parents and siblings. All of them are so patient and wonderful human beings. My team has been working very hard to identify the best FDA approved drugs (currently used for other diseases) that could delay the progression of Wolfram syndrome (off-label). In parallel, we are developing new drugs specifically designed for Wolfram syndrome to stop the progression (requires clinical trials). We have made significant progress in the past 12 months and I plan to present my strategy on this coming Saturday.
Why are we creating eye cells using skin cells from patients? More accurately, we are creating two different types of retinal cells using stem cells derived from skin fibroblasts of patients with Wolfram syndrome. We can immediately use these cells to understand the mechanisms of the disease and test the efficacy of candidate drugs. That’s a practical goal and should be achievable.
My audacious goal is to use these cells to replace damaged eye cells in patients. There are many theoretical and practical hurdles to accomplish this, but we should try. Every accomplishment starts with the decision to try.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-07-11 19:43:502020-09-07 20:10:39Why are we creating eye cells using skin cells from patients?
As I mentioned in my previous blogs, we have identified three FDA-approved drugs, one supplement, and new groups of drugs that can potentially delay the progression of Wolfram syndrome. We have been testing the efficacy of these drugs in cells from patients and two animal models of Wolfram syndrome. Preliminary data look good, and we have been working very hard to bring at least one drug to patients.
We have also identified a potential biomarker that would be useful for monitoring the efficacy of our new treatment. I would like to thank patients who donated blood samples to us. Recently, some families donated blood samples from patients’ siblings, and these samples were really helpful to confirm our findings.
I have been trying to establish firm relationships with biotech companies and nonprofit organizations to bring these drugs to our patients through clinical trials. Our lawyers have been helping us a lot. I will keep on pushing the envelope with my wonderful team and colleagues.
Dr. Fumihiko Urano
Dr. Fumihiko Urano is a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-04-24 20:03:042020-09-07 20:10:39Patient Based Therapeutics – New Drug Candidates
I received many emails regarding our progress on Wolfram syndrome induced pluripotent stem cells (iPS cells) in the past two weeks. I would like to update you on a few things. As I mentioned in my previous blogs, we have created many iPS cells from skin cells of patients with Wolfram syndrome. These iPS cells can differentiate into various types of cells including brain cells and pancreatic beta cells that are damaged in patients with Wolfram syndrome
1. Disease modeling
We could successfully differentiate these iPS cells into neural progenitor cells. These are immature brain cells. We found that neural progenitor cells from patients are not completely damaged, which was surprising, but good news to us. Instead, they have altered calcium homeostasis. My impression right now is that cells from patients with Wolfram syndrome are “sensitive” to environmental stress, especially stimulus that changes cellular calcium levels. So we are looking for drugs that can modulate calcium homeostasis in cells to develop a treatment for Wolfram syndrome.
2. Testing drugs
As I mentioned above, we are focusing on drugs that can modulate calcium homeostasis in cells, especially endoplasmic reticulum calcium levels, to develop a treatment. Three drugs out of five candidate drugs that we have identified so far can control endoplasmic reticulum calcium levels. We are testing these three drugs using iPS cells.
3. Correcting a mutation
Using a special enzyme and artificial DNA, we are replacing an abnormal segment of Wolfram gene with a normal segment of Wolfram gene in patient-derived iPS cells. In theory, we should be able to correct altered calcium homeostasis through this process.
4. Making eye cells
A group in Columbia University Medical Center in New York could successfully make pancreatic beta cells from Wolfram syndrome iPS cells. We are collaborating with this group. So we are focusing our own efforts on making eye cells from Wolfram syndrome iPS cells. This is a collaboration project with a group in a major medical center in Japan. They have a special “recipe” for making eye cells. Because a clinical trial using this technology for an eye disease will start in a few weeks in Japan, I feel that this collaboration is so important for us. A physician and scientist who is working on this collaboration project will come to the US and work with us in a few months. The arrangement has been made, and the Japanese agency will partially support this effort.
Dr. Fumihiko Urano is a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.
Today I would like to discuss how we use induced pluripotent stem cells (iPS cells) derived from patients with Wolfram syndrome for developing treatment. Our group as well as a group in Columbia University have created iPS cells from patients with Wolfram syndrome.What are induced pluripotent stem cells (iPS cells)?
iPS cells are a type of stem cells that can be generated directly from adult cells, including skin cells. We can make pancreatic beta cells and neurons from these iPS cells.How can we use Wolfram syndrome iPS cells for treatment?
We can expect that Wolfram syndrome patients iPS cell lines and Wolfram iPS cell-derived beta cells to be a cornerstone for developing novel therapeutic modalities for Wolfram syndrome and other diseases involving endoplasmic reticulum (ER) dysfunction. We can utilize these cells to screen and identify drugs for treating patients with Wolfram syndrome and other ER-associated diseases.Regenerate Damaged Tissues
In the future, we can utilize these cells to regenerate damaged tissues including pancreatic beta cells, retinal ganglion cells (eye cells), and neurons in patients with Wolfram syndrome. Rapid progress in genetic editing technologies and regenerative medicine will make it possible to correct WFS1 mutations in patient-specific iPSC lines and regenerate patients’ damaged cells. Our current progress:
1. Using these Wolfram iPS cells, we have identified a drug target for developing treatment (our manuscript is in review.)
2. As I reported before, we are currently testing the efficacy of five different drugs using iPS cell-derived neurons.
3. We are correcting a WFS1 gene mutation by genetic editing and making eye cells using these iPS cells.We should make the best use of these cells to develop treatments for Wolfram syndrome, efforts that may lead to breakthroughs in diabetes treatment. I have articulated my strategy in the article just published in Diabetes. http://diabetes.diabetesjournals.org/content/63/3/844.full
Dr. Fumihiko Urano
Dr. Fumihiko Urano is a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.
Patient-Based Therapeutics Part 4 – Drug Screening Progress
Based on the data obtained from our patients, animal models, and cell models of Wolfram syndrome, we found that calcium depletion of the endoplasmic reticulum (ER) plays a role in the pathogenesis of Wolfram syndrome. So we have been looking for drugs that can prevent ER calcium-depletion-mediated cell death. As of today, we have found 4 FDA-approved drugs (currently used for other diseases), one supplement, and a new category of drugs (not approved by the FDA). One of the FDA-approved drugs can prevent ER calcium-depletion and cell death in the tissue culture dish. It seems like that this drug can relieve ER stress in one animal model of Wolfram syndrome. We are working very hard to complete these preclinical studies. The ER calcium-depletion releases a molecule called MANF from the ER to the circulation. So we are carefully monitoring levels of MANF in human blood samples.
So how long will it take to bring one of these drugs to our patients? I would like to share a few thoughts.
1. There is no guarantee that these drugs will work in our patients.
2. It is a little challenging for me to predict exactly how long it will take to bring these drugs to our patients.
3. However, I have a clear plan, and am doing my best to make it happen.
Dr. Fumihiko Urano a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.
A Few weeks ago, a young woman who had been battling Wolfram syndrome for many years passed away. Everyone knew, loved and supported her. Below is a touching blog post from Washington University School of Medicine’s Dr. Fumihiko Urano about our friend, Ms. K.
In Memory of K
Yesterday I was heartbroken because I learned of the death of Ms. K, a young woman with Wolfram syndrome. I was not helpful. I could not even find a way to delay the progression of the disease. I felt devastated. I really felt devastated. I was very sad and could not respond to any emails for several hours.
As a person, I sometimes feel scared. Although I am always doing my best and determined to figure out a way to help patients with Wolfram syndrome, I know that I am not a god. The treatment I am planning to test may not be effective. I often wake up at midnight and feel scared. However, as a physician, I swear to figure out a way to stop the progression of Wolfram syndrome, find a way to regenerate damaged tissues, and give patients hope. I think I should keep on running to figure out a way to help patients with Wolfram syndrome.
I saw Ms. K reading a poem entitled a single second in time, which reminded me of Sam Berns, a wonderful young man with progeria, a rare disease characterized by accelerated aging. Sam passed away earlier this year. Although he was much younger than myself, I learned a lot from him and his interviews. You may want to watch the following video and read Dr. Francis Collin’s blog on him. His philosophy for a happy life is a wonderful piece to watch. Take care everyone, and have a nice weekend. I will appreciate a single second in time just like Ms. K.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-02-28 23:52:472020-09-07 20:10:40In Memory of K by Dr. Fumihiko Urano
Why do I study such a rare disease as Wolfram Syndrome?
I am often asked, “Why do you study such a rare disease, Wolfram?” My answer is, “It is the weapon to combat common diseases.” My secret answer is, “I want to help Wolfram patients and their families.”
Why it is so important to study Wolfram syndrome, a rare condition characterized by juvenile-onset diabetes, optic atrophy, and neurodegeneration? It is a frightening condition. Wolfram syndrome is always on my mind just like pediatric cancer was always on my mind when I was a young doctor (some people still think that I am a young doctor…thank you). I just want to help them. That’s all I want. This is my last research project.From a scientific standpoint, I always believe that there is a tremendous benefit for us to study Wolfram syndrome. Increasing evidence now indicates that endoplasmic reticulum (ER) dysfunction is involved in more common diseases, especially type 1 diabetes. I propose that Wolfram syndrome is the “weapon to combat type 1 diabetes.“Despite its rarity, Wolfram syndrome probably represents the best model currently available for identifying treatments for diseases associated with ER dysfunction. Wolfram syndrome arises from mutation of a single gene (WFS1), a gene shown to be also involved in β cell dysfunction and death in other forms of diabetes mellitus. Its monogenic etiology makes Wolfram syndrome more amenable to dissecting out the mechanisms underpinning cellular responses to ER dysfunction than other diabetic conditions, such as type 1 diabetes mellitus, in which multiple factors typically interact to produce the disease manifestations.
Dr. Fumihiko Urano
Dr. Fumihiko Urano a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-02-01 21:19:332020-09-07 20:10:40The Power of Wolfram: The Weapon to Combat Type 1 Diabetes
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