Wolfram Research Clinic – Day 0

By Dr. Fumihiko Urano

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.

WS Clinic2014_Raquel Consent

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.

Wolfram syndrome timeline

Photo of J.T. Snow, Dr. Permutt, Jon Wasson, Stephanie Gebel

J.T. Snow, Dr. Permutt, Jon Wasson, Stephanie Gebel

2008 – Studies show that WFS1 is one of top ten causative candidate genes for T2D. (ref 5).

2010 – Wolfram Syndrome International Registry and Research Clinic started.

2011 – Snow Fund contributes to Research Clinic beginning in year two and to Permutt lab research 2011.

2012 – Dr. Permutt dies June 6, 2012.

Photo of Dr. Fumihiko Urano

Dr. Fumihiko Urano

2012 – Dr. Fumihiko Urano arrives at Washington University and assumes Permutt lab work in WS August, 2012.

2013 – Snow Fund and Foundation contributes to work in Urano lab looking for WS biomarkers and possible drugs to treat disease.

 

 

1. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, Mueckler M, Marshall H, Donis-Keller H, Crock P, Rogers D, Mikuni M, Kumashiro H, Higashi K, Sobue G, Oka Y, Permutt MA. Nat Genet. 1998 Oct;20(2):143-8.

2. Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. Osman AA, Saito M, Makepeace C, Permutt MA, Schlesinger P, Mueckler M. J Biol Chem. 2003 Dec 26;278(52):52755-62. Epub 2003 Oct

3. Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. Osman AA, Saito M, Makepeace C, Permutt MA, Schlesinger P, Mueckler M. J Biol Chem. 2003 Dec 26;278(52):52755-62. Epub 2003 Oct 3.

4. Common variants in WFS1 confer risk of type 2 diabetes. Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A, Lango H, Frayling TM, Neumann RJ, Sherva R, Blech I, Pharoah PD, Palmer CN, Kimber C, Tavendale R, Morris AD, McCarthy MI, Walker M, Hitman G, Glaser B, Permutt MA, Hattersley AT, Wareham NJ, Barroso I. Nat Genet. 2007 Aug;39(8):951-3. Epub 2007 Jul 1.

5. Candidate gene studies reveal that the WFS1 gene joins the expanding list of novel type 2 diabetes genes. Wasson J, Permutt MA. Diabetologia. 2008 Mar;51(3):391-3. doi: 10.1007/s00125-007-0920-9. Epub 2008 Jan 15.

 

 

Wolfram Syndrome Links

Picture of Wolfram syndrome linksWolfram syndrome Links Of Interest

Please click on the links listed below to visit other web sites that can help you find more information to obtain knowledge on Wolfram syndrome.

Washington University School of Medicine – Wolfram Syndrome Blog
Wolfram syndrome (OMIM)
Wolfram syndrome
Family support: Worldwide Society of Wolfram syndrome Families
UK Wolfram Syndrome Support Group
Optic nerve atrophy (NIH)
Diabetes mellitus (American Diabetes Association)
Diabetes mellitus (NIH)
Diabetes Insipidus (NIH)
National Diabetes Clearinghouse
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Tax Fraud Alerts from the IRS

Study to analyze brains of kids with rare disorder

October 26, 2012

Researchers at Washington University School of Medicine in St. Louis have received a five-year, $2.7 million grant to detect and analyze differences in the brains of children with a rare illness, Wolfram syndrome.

The disorder, which is caused by mutations in a single gene, includes a severe form of diabetes, hearing and vision loss and kidney problems. Eventually, patients lose muscle control and coordination due to degeneration in the brain. More than half of the patients die before they turn 40, often due to atrophy in the brainstem that contributes to respiratory failure. The illness affects an estimated one in 770,000 children.

As part of the new study, researchers will conduct MRI scans to measure and quantify changes in the brain during the course of the disorder.

“In preliminary studies, we have been able to detect differences in the size and volume of several brain structures in kids who have Wolfram syndrome,” says principal investigator Tamara Hershey, PhD, professor of psychiatry, of neurology and of radiology. “Our goal in the new study is to look for patterns of changes in the brain that might help us identify problems earlier, with the eventual hope of being able to intervene.”

Hershey says work in animal models of Wolfram syndrome is progressing rapidly toward possible interventions and treatments, so it is important to better understand how the disorder develops and progresses. She says using MRI scans and conducting behavioral testing to measure changes in the brain provide an opportunity to do that.

“The neurological features of the disease may be the most feasible thing to target and monitor in clinical trials,” she explains. “That’s because by the time a child gets a diagnosis of Wolfram syndrome, the insulin-producing cells in the pancreas already are damaged or destroyed, and the child has developed insulin-dependent diabetes. By identifying time points at which it’s possible to intervene, we may be able to prevent some of the severe problems that occur later in the course of Wolfram syndrome.”

Hershey

Hershey’s group already has identified some key differences in the brainstem and the cerebellum. They have learned that in children with Wolfram syndrome, those structures tend to be smaller than those of other children their age, and there are differences in the thickness of the brain’s cortex, especially in an area related to vision.

By tracking patients with Wolfram syndrome over time with regular MRI scans and other neurological tools, Hershey says it may be possible to distinguish between changes that occur as the brain develops during childhood and those that occur due to degeneration related to the disorder.

Wolfram syndrome is caused by mutations in the WSF-1 gene, which was first identified in 1998 by the late M. Alan Permutt, MD, a former professor of medicine and of cell biology and physiology at the School of Medicine. He later developed an animal model of the disorder and set up an international patient registry.

In 2010, Washington University organized the world’s first, multidisciplinary clinic for patients with Wolfram syndrome, funded in part by the Snow Foundation, a family organization dedicated to raising funds for Wolfram syndrome research. Children worldwide came to St. Louis for testing and evaluation. Those clinics now are an annual event at St. Louis Children’s Hospital.


The Internet address for the Wolfram Syndrome International Registry’s website is  http://wolframsyndrome.dom.wustl.edu/medical-research/Wolfram-Syndrome-Home.aspxWashington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

2012 Wolfram Syndrome Research Update

WashU-BannerCompiled By: Tamara Hershey, Ph.D., Bess Marshall, M.D., Fumi Urano, M.D., Ph.D.
and the WU Wolfram Study Group members

Overview
This past year has been an exciting but also difficult one for our group and for the Wolfram community. While we have made great gains in our research efforts, we also lost our friend, colleague and leader in this field, Dr. M. Alan Permutt, M.D. on June 10th 2012. Although we mourn his death, we are comforted by the fact that his vision for Wolfram Syndrome research at Washington University is continuing, aided by Dr. Fumi Urano, M.D., Ph.D, who has newly arrived here. His exciting work in the cellular and molecular aspects of Wolfram Syndrome complements the human interdisciplinary studies that are ongoing here. Together, we hope to make great strides in the coming years towards identifying potential interventions for the degenerative processes in Wolfram Syndrome.

Human studies
For the past 3 years, our research group has conducted an annual interdisciplinary research clinic for children and young adults with Wolfram Syndrome. The goal of this research clinic is to understand the natural history of the disease process, particularly in its earliest stages. This information will help us select appropriate markers of disease progression, which will be essential for establishing the efficacy of any future interventions through clinical trials. We received funding from the American Diabetes Association and Washington University to set up our operation. More recently, the National Institutes of Health awarded us a 5 year, several million dollar grant to continue this work. To our knowledge, this is the first NIH award for the study of Wolfram Syndrome in people with the disorder. Our work is now beginning to be published; see below for a summary.

Animal studies
We have developed five different animal models of Wolfram syndrome. These are WFS1-deficient (whole body, beta cells or neurons), mutant WFS1 H313Y expressing, and WFS2 deficient mice. We have been carefully analyzing phenotypes of these animals. These animals will be used to test the efficacy of candidate drugs in the future.
Mechanisms of cell death in Wolfram syndrome
We discovered two enzymes that play important roles in cell death during the progression of Wolfram syndrome. These enzymes are promising targets for developing drugs for Wolfram syndrome.

Therapeutic Development
We have developed four screening methods for identifying drugs that have the ability to prevent cell death in Wolfram syndrome. The efficacy of candidate drug will be tested using animal models and cells from patients with Wolfram syndrome.
Recently Published Research Findings:

1) T. Hershey, H.M. Lugar, J. Shimony, J. Rutlin, J.M. Koller, D.C. Perantie, A.R. Paciorkowski, S.A. Eisenstein, M.A. Permutt and the Washington University Wolfram Study Group. Early brain vulnerability in Wolfram syndrome; PLoS One; 2012; 7(7). http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0040604
This paper uses the magnetic resonance images (MRIs) that were collected from participants. We compared these scans to scans of children/young adults with and without type 1 diabetes, using software that allows us to measure the volumes of different structures across the brain. We found that brainstem and cerebellum volumes are smaller in Wolfram Syndrome compared to other groups and that these differences can be shown at relatively early stages of the disease, something that had not been known before. We now need to compare scans across time, to understand how these volumes change over time and correlate with disease severity.

2) K.A. Pickett, R.P. Duncan, A.R. Paciorkowski, M.A. Permutt, B. Marshall, T. Hershey, G.M. Earhart and the Washington University Wolfram Study Group. Balance impairment in Wolfram syndrome. Gait and Posture; 2012
This paper analyzed data from the balance and motor tests given at the clinic. We used a standard rating scale for balance and motor skills with participants and compared results to children/young adults without any disorder. We found that balance was affected in Wolfram Syndrome, even at the relatively early stages of the disease, similar to our MRI findings. We now need to understand how these findings relate to each other, and how balance and other motor skills change over time.

3) C.M. Oslowski, T. Hara, B. O’Sullivan-Murphy, K. Kanekura, S. Lu, M. Hara, S. Ishigaki, E. Hayashi, S.T. Hui, D. Greiner, R.J. Kaufman, R. Bortell, and F. Urano. TXNIP mediates ER stress-induced beta cell death through the initiation of the inflammasome. Cell Metabolism, In press.
We have discovered a crucial cell death pathway under ER stress which is relevant to human diseases caused by ER stress including Wolfram syndrome.

Acknowledgements: We are deeply grateful to the families who have participated in studies for their dedication, time and effort, to the Snow Fund and others for their fundraising efforts, to Washington University for supporting this interdisciplinary research program, and to our funding agencies: ADA, JDRF, NIH and the Snow Fund. In addition, we are grateful to Nolwen Jaffre and the Association du syndrome de Wolfram for hosting us at the International Scientific Workshop in Paris. This annual workshop is the best way for Wolfram Syndrome researchers to find out what advances have been made, discuss what research is needed and to forge new collaborations.

Treatment target for diabetes, Wolfram syndrome

August 7, 2012

Inflammation and cell stress play important roles in the death of insulin-secreting cells and are major factors in diabetes. Cell stress also plays a role in Wolfram syndrome, a rare, genetic disorder that afflicts children with many symptoms, including juvenile-onset diabetes.

The bright green spots are TXNIP molecules, potential treatment targets for diabetes and Wolfram syndrome.

Now a molecule has been identified that’s key to the cell stress-modulated inflammation that causes insulin cells to die, report scientists at Washington University School of Medicine in St. Louis, the University of Massachusetts Medical School in Worcester and elsewhere.

“There are two types of inflammation,” says senior investigator Fumihiko Urano, MD, PhD. “There is local inflammation within cells that can be caused by a specific type of cell stress named ER stress. There’s also systemic inflammation that involves the activation of immune system cells. The molecule we’ve identified is involved in the initiation of local inflammation that can lead to systemic inflammation.”

That molecule, called thioredoxin-interacting protein (TXNIP), provides scientists with a target to direct therapies for diabetes and Wolfram syndrome. The latter disorder causes kidney problems as well as hearing and vision loss. As patients get older, they develop ataxia, a brain dysfunction that causes a loss of muscle control and coordination, and many patients die before their 40th birthday.

The new study is published Aug. 8 in the journal Cell Metabolism.

Urano, an associate professor of medicine in Washington University’s Division of Endocrinology, Metabolism and Lipid Research, studies a type of cell stress known as endoplasmic reticulum (ER) stress. The endoplasmic reticulum is part of a cell that’s responsible for producing proteins and synthesizing cholesterol. Every cell in the body has an endoplasmic reticulum, which also is involved in transporting proteins to the parts of the cell where they are needed.

In ER stress, misfolded proteins accumulate, activating a response in the cell designed to correct the problem by making fewer proteins and eliminating the misfolded ones. But if the stress cannot be resolved, the cells self destruct.

“The endoplasmic reticulum does many important things,” Urano says. “When it doesn’t function properly, it can contribute to several different diseases. In the case of Wolfram syndrome and diabetes, we believe that dysfunction within insulin-secreting cells causes ER stress, which, in turn, contributes to local inflammation and cell death.”

Urano’s team analyzed genes that were activated in insulin-producing cells under ER stress and found that TXNIP was manufactured in large amounts in the stressed cells. Past research demonstrated that the protein was involved in inflammation, and as experiments progressed, the researchers were able to link TXNIP both to ER stress within the cell and to inflammation outside of specific populations of cells that can have an effect throughout the body.

Dr. Fumikho Urano

“We found that ER stress can lead to inflammation activation through the TXNIP protein,” he says. “So if we could somehow block TXNIP, we may be able to mitigate the inflammation and block the progression of diabetes and Wolfram syndrome.”

Urano has found that in animal models of Wolfram syndrome, TXNIP levels are significantly increased in insulin-secreting cells. Meanwhile, other recent research has discovered that a common blood pressure medication called verapamil can interfere with TXNIP production, so Urano’s team plans to test that drug in animals with Wolfram syndrome to learn whether it might delay the progression of the disease. Those experiments, Urano says, are under way.

The TXNIP protein provides the best available target for therapies because the only other known molecule involved in cell death under ER stress conditions is housed in the cell nucleus, he says. TXNIP, on the other hand, exists outside the nucleus and therefore may more easily interact with potential therapeutic agents.

Although this study involves the extremely rare disorder Wolfram syndrome, which affects about one in 500,000 people, Urano says the findings may be important to many other diseases because inflammation contributes to so many disorders, from heart disease to cancer.

“Local inflammation such as ER stress can’t be detected by looking for inflammatory molecules in blood plasma, but it is very important in the pathogenesis of many chronic human diseases,” he says. “By studying TXNIP in Wolfram syndrome, we may be able to uncover clues for treating other chronic diseases, including neurodegenerative diseases, such as Alzheimer’s disease and similar illnesses that cause cognitive problems.”

 


 

Oslowski CM, Hara T, O’Sullivan-Murphy B, Kanekura K, Lu S, Hara M, Ishigaki S, Zhu LJ, Hayashi E, Hui ST, Greiner DL, Kaufman RJ, Bortell R, Urano F. Thioredoxin-interacting protein mediates ER stress-induced beta cell death through the initiation of the inflammasome. Cell Metabolism, vol. 16 (2), Aug. 8, 2012.

Funding for this research comes from the JDRF and from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). NIH grant numbers DK067493, DK016746, DK042394, DK088227, DK93074, DK080339, P60 DK020579, RR024992, UL1 TR000448, HL057346 and HL052172.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Wolfram Syndrome Researcher Makes Headlines

Photo of Tamara Hershey

Tamara Hershey, PhD (left), and Bridget Waller, a student in psychiatry, look at diagrams of the human brain.

Tamara Hershey was recently featured on the Washington University School of Medicine website for her studies in how fluctuations in glucose levels can influence the brain .  As well as her work as a neuroscientist, she devotes much of her time studying Wolfram syndrome.

Photo of a brain of a patient with wolfram syndrome

This brain image shows that the volume of white matter is decreased in the brain stem and the cerebellum (yellow and orange area) of young patients with Wolfram syndrome, compared with brains of young people without diabetes.

“Endocrinologists usually are interested in Wolfram syndrome because it’s a genetic form of diabetes,” she said. “But the diabetes aspect of the disorder isn’t what limits the lifespan of a patient. It’s the features outside of diabetes that are so devastating: optic nerve atrophy and neurodegeneration in the brain stem. Before we began our studies, Wolfram syndrome had not been examined extensively from a brain perspective.”

To read the full article, click the link below.
http://news.wustl.edu/news/Pages/26170.aspx

Snow White Fellowship

Photo of Wolfram syndrome researchers Drs. Bess Marshall, Fumi Urano, and Tamara Hershey working on Snow White Fellowship.

Wolfram syndrome researchers Drs. Bess Marshall, Fumi Urano, and Tamara Hershey.

Wolfram Moms Join Forces to Create “Snow White Fellowship”

In the fall of 2013, Stephanie Snow Gebel and Beth White decided to join forces and create “The Snow White Fellowship” at Washington University School of Medicine. The Jack & J.T. Snow Scientific Research Foundation and The Ellie White Foundation for Rare Genetic Disorders decided to join forces in fighting Wolfram syndrome, TOGETHER!

The fellowship will allow Dr. Fumihiko Urano, lead Wolfram syndrome researcher to hire additional support and expedite a cure for juvenile-onset diabetes, including type 2 and Wolfram syndrome.

“We are very fortunate to have the support of the Snow White Fellowship.  Having additional manpower working on our research and the development of potential drug therapies will allow us to achieve our goals much sooner.” – Dr. Fumihiko Urano

Patient Based Therapeutics – New Drug Candidates

New Drug Candidates

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.

Photo of Dr. Fumihiko Urano

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 6

Wolfram Syndrome iPS Cells Progress

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.

You may be interested in a clinical study using iPS cells for an eye disease. Here is some info.
http://blogs.nature.com/news/2013/07/japan-to-start-stem-cell-study-on-humans.html
http://www.riken.jp/en/pr/press/2013/20130730_1/

Photo of Dr. Fumihiko Urano

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.