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.

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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.

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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

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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

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I Have The Best Sister In The World – By Lauren Gibilisco

Photo of Lauren and Megan Gibilisco

Lauren and Megan Gibilisco

Last year my sister came up with a great idea for a Christmas present. It’s hard to get something for someone who is blind. She got tickets for us to go to Mannheim Steamroller.

I thought this was a great idea because I could hear the music and they were going to play some Christmas songs which I love. The morning of the event, it started to snow. By evening it was a blizzard and the event got cancelled. My sister was very sad that we had to miss the show.

After Christmas she heard that the Lion King Musical was being performed in Omaha which is where she lives. So she got tickets for us to go to that. Again, I can’t see the stage but I could enjoy the music and I would know what was going on because I had seen it many times when I still had vision. We got all dressed up and went out to dinner and then to the show. We forgot to get my handicap sticker so we had to walk several blocks and it was very cold and windy. We arrived there just before it was to start. My sister handed the tickets in and was informed that it was for the following night and I had other plans. So my sister took a friend with her the next night. She was very disappointed again that she was unable to give me my Christmas present.

This April she was given tickets to see the Cinderella Musical. It is in the theater in Omaha again. She called me up and told me that we were going to go to this since the last two events didn’t take place. This time we got there on the right night and sat down to listen to the music and singing. Cinderella was a favorite of mine. Again I couldn’t see the stage but I could hear the music and would know what was going on from what they were singing. So the lights went down and the singing started. My sister and I looked at each other….they were singing in Italian. We couldn’t understand a word they were saying. We did enjoy the music and spending time with each other. When we left the musical, my sister said “never again are we doing this.” After three times it was apparent that this just wasn’t the great Christmas present she imagined.

The next night we were watching a movie at her apartment. She turned to me and asked “Lauren, is it too dark in here for you?” I guess from the stunned look on my face she realized what she had just said to me. We rolled on the ground laughing at that one.

The moral of the story is that I have the best sister in the world.

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Just Waiting Around – By Adam Zwan

Photo of Adam Zwan at the beach.

Adam Zwan

When looking at the past 12 months I have noticed all the patient waiting I have taken part in.  It seems that the time of waiting is the hardest part of anything.  Whether it is waiting on a medical cure, an employment decision, or an everyday event, waiting to see how things turn out is the greatest challenge.

In my days, I am forced to wait and see what I can accomplish due to available transportation.  Each day involves waiting for a ride or waiting to see if anyone is available to give me a ride to complete tasks and or chores, like work, the gym, grocery store etc.  The waiting for transportation also involves waiting to receive phone call that transportation is not available or has been canceled.

In addition, I have been applying for full time job opportunities everywhere from Charlotte, NC to Portland, OR and the hard truth of waiting is no different.  The process of searching followed by the detailed effort of applying is all finished with a long term of waiting on email messages and phone calls.  After questions are answered and an interview takes place comes the unbearable wait to hear of the final decision.  It is all the nature of the business but telling myself that does not make things easier.

Similarly, waiting for a successful cure for Wolfram Syndrome presents the same restless wait.  It is said that a cure, which stops the progression of Wolfram Syndrome, is the first step.  The next step is taking action to repair damages that have occurred due to the breakdown of my central nervous system.  While waiting to see how the possible cure turns out, I cannot help but dream of living without diabetes and kidney failure.  Also, the possibility of a cure creates optimistic thoughts of obtaining 20/20 vision and being able to drive again.  These thoughts and dreams only make the time of waiting seem like forever.  All in all, the patient waiting continues until conclusions are discovered.

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