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.

/by

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.

/by

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

/by

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

/by

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.

/by

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.
Read more

/by

The therapeutic potential of chemical chaperones in protein folding diseases

Publication: www.ncbi.nlm.nih.gov | Publication Date: May 12, 2014

Authors: Leonardo Cortez and Valerie Sim

Abstract

Several neurodegenerative diseases are caused by defects in protein folding, including Alzheimer, Parkinson, Huntington, and prion diseases. Once a disease-specific protein misfolds, it can then form toxic aggregates which accumulate in the brain, leading to neuronal dysfunction, cell death, and clinical symptoms. Although significant advances have been made toward understanding the mechanisms of protein aggregation, there are no curative treatments for any of these diseases. Since protein misfolding and the accumulation of aggregates are the most upstream events in the pathological cascade, rescuing or stabilizing the native conformations of proteins is an obvious therapeutic strategy. In recent years, small molecules known as chaperones have been shown to be effective in reducing levels of misfolded proteins, thus minimizing the accumulation of aggregates and their downstream pathological consequences. Chaperones are classified as molecular, pharmacological, or chemical. In this mini-review we summarize the modes of action of different chemical chaperones and discuss evidence for their efficacy in the treatment of protein folding diseases in vitro and in vivo.

Read the entire publication article here.

/by

Trust Your Gut – Lauren Gibilisco

Photo of Lauren GibiliscoI love to exercise and it gives me something to do during the day. So much so that last Wednesday I did 4000 leg lifts throughout the day. By Thursday my legs were hurting very badly and my mom said it was probably from doing too much exercise. She told me no exercise for the next several days because I probably strained my muscles. I rested all day Thursday but on Friday morning they felt a little worse. My mom rubbed some Ben-Gay on my legs, gave me some Ibuprofen and again said to rest. I had plans on Saturday morning to go out to breakfast with a friend and do some shopping. I made it through breakfast but by the time she got to the store my legs were really hurting. I just sat in the car while she picked up a few things she needed. By the time I got home I could hardly walk. My mom had an appointment and told me to go soak in the tub. She was gone two hours and during that time I felt very paranoid and called her four times. I asked her if it could be low sodium. I had very low sodium two years ago. For those that know sodium levels, mine was 109. She said no but after she hung up the phone she called my aunt who is a nurse. My aunt said I would be confused not paranoid. She said it wouldn’t hurt to have me eat some salty foods like ham and see if I felt better. So my mom stopped and bought meat lovers pizza that had bacon, pepperoni, ham and sausage on it. She brought it home and I ate it and said my legs were feeling better. My mom waited for my dad to come home and then she called the emergency room to talk to the doctor. She asked if we could come up and get my sodium checked. She described how my legs hurt, my exercises and being paranoid. He also said I would be confused and it sounded like muscle strain. She told him that last time I was very paranoid also. He said to wait till Monday and see my regular doctor. My mom had to do some work at the store so she told my dad to watch me carefully and call her if anything happened. About 45 minutes later I had my dad call her. I was feeling very weak and felt like passing out. My jaw was hurting badly and my mouth was quivering. My mom said she would be right home. She got home and took me immediately to the emergency room.

By that time I was feeling very bad and was very quiet. For those that know me, you know that would be a huge sign that something was wrong. LOL. The hospital just installed a new computer system and so we had to input all my information into the system. It took forever. My mom told them to test my sodium while we were waiting. It was an hour later before we had the results. The doctor came in and told us that I had a sodium level of 121 and would have to be admitted. Lord only knows how low I would have been if my mom hadn’t had me eat that pizza. They immediately began an IV sodium drip. All this time my mom was answering their questions. First she had to tell them all my medications, which are 11 different ones and the dosage. She always carries a list so she can just hand it to them. They didn’t know what most of these drugs were, and of course had no idea what Wolfram Syndrome was. As my mother was explaining everything a nurse asked my mom if she was a nurse or doctor. She laughed and said, no, she was just an informed mom of a child with a rare disease that no one knows anything about. She said she had a team of people that have taught each other so very much about Wolfram Syndrome. That team was all the mothers and dads. She was very impressed with my mom’s knowledge. About this time I started talking again. Yep, ….I was feeling much better and my jaw didn’t hurt anymore so I was able to start talking nonstop again. I was on my way to recovery.

My mom is going to write the next few lines.

For those reading this, I know you understand what I was going through. Bottom line is trust your gut. If it feels wrong than it probably is. Her symptoms were not the usual ones, but what with Wolfram Syndrome are. Don’t be afraid to respectfully disagree with your doctor and insist that they run tests. There is no one who knows their child better than the parents. Doctors are not always right. This statement does not include Dr. Fumi, Dr. Marshall. Dr. Hershey, Dr. White, Dr. Hoekel etc….. We could be wrong sometimes but very often we are right. Trust yourself and advocate for your child.

/by

Strange Truth – Adam Zwan

Photo of Adam Zwan

Adam Zwan

Do you live a risky life or do you fly straight and narrow? After being diagnosed with Wolfram Syndrome I began paying close attention to my surroundings and the lives of others. Strangely, it became clear that individuals who live life without taking chances or making risky decisions end up with the dull side of the blade. Unfortunately for people who avoid trouble and mischief, consequences are paid with permanent life changes. On the other hand, those who live on the edge seem to have a little more fun in their lifetime; these individuals may be faced with consequences but the price is paid and the risky lifestyle is continued.
Read more

/by

Chores Anyone? – Lauren Gibilisco

Photo of Lauren GibiliscoAs you know, living with Wolfram syndrome poses many challenges for me, including doing my chores.  With my vision impaired, I’ve had to come up with different ways of doing things and I thought I’d share them with you.

I start with making my bed.  My bedspread has two raised rope designs going vertical.  This lets me know how far to pull it on each side so it is even.

Almost every day I empty the dishwasher.  I know how the dishes feel so I know where to put them.  How large the bowl is lets me also know where it belongs.  Every dish has a certain spot in our cabinets so I know exactly where they go.  I run my hands over the spokes in the dishwasher to make sure I have gotten everything out.  Since I know where the dishes are I know how to set the table.  The only thing I have trouble with is the salt and pepper shakers but we put a braille strip on each item so I know what it is.

They do not let me clear the table.  I have broken too many dishes slamming them on top of each other.  Or I run into them when they are coming through.   I am also able to get things out of the refrigerator because again everything has a certain place to go.  Although sometimes my dad doesn’t put it back where it should go. One day when we were having hotdogs for lunch my dad said “why is there chocolate syrup on the table?”  I thought it was mustard.  Good thing he saw it before I put it on my hotdog.  That would not have been good.  My mom doesn’t like me cooking on the stove while she isn’t there.  She said she doesn’t want to come home from a long day at work and find the fire dept there.

I also dust and vacuum both the upstairs and the downstairs.  I’m not sure I get everthing wiped off or picked up but I just try to keep going in a straight line hoping I am going in the right direction.  I also sweep the kitchen and bathroom floors.  I sweep hopefully into a pile and bend down and pick it up with the dustpan. I listen to see how much is coming out of the dustpan so I know how much is still being picked up.  I can’t see what I am doing so I just do it several times until I think everything is gone.  I also use my bare feet to walk around and feel if I missed anything.

I am in charge of doing the family wash.  I know what my dad’s shirts feel like with all the buttons.  I also know the weight and feel of his white tee-shirts so I am able to separate the whites from the darks.  Of course I am able to tell the difference between a top and pants so I know which to hang and which to fold.  My mom also buys the pod detergents so I don’t have to worry about measuring everything or knowing where to pour.  I am also able to put the washer and dryer on the right settings because we use stick on raised dots.  These go on the start buttons and the temperature settings so I know how to adjust for the different types of clothes.

The buttons are also used on the stove and microwave.  It is digital so I have the dots put on the one, the three and the five buttons so I know the correct temperatures or time settings.  Now getting food out of the oven is a little bit harder.  You don’t want to go feeling around too much in a hot oven looking for the pan.  My mom bought the silicon gloves that go up to my elbows.  You cannot get burned with these on.  So I feel confident reaching in the oven.  They also wipe off cleanly or can be put in the dishwasher if anything spills on them.

I spend a lot of time at home alone.  My parents also work very hard and long hours.  Doing all these chores makes me feel good that I am able to contribute to my family.  It also gives me something to do every day instead of just watching tv or listening to the radio.

So there you have it!  That’s how I do my chores while living with Wolfram syndrome.  Now I have to get back to work!

Lauren

/by