Regenerative Therapy and Modern Medical Genetics

I think a lot about a new platform for endoplasmic reticulum disease and other rare diseases.

The new clinic requires new expertise in addition to conventional neurology, ophthalmology, and endocrinology. I feel that regenerative therapy and modern medical genetics based on high-throughput sequencing are the key players.

I found an interesting video describing regenerative medicine.

I hope you will have the best week in your life.

Developing novel therapeutics to stop the progression of eye diseases

Some people say that it is not realistic to develop a novel therapy to stop the progression of eye manifestations in Wolfram syndrome. I don’t agree.

It is possible. If we can modulate ER stress in retinal cells, we can slow or stop the progression of optic nerve atrophy in Wolfram syndrome. I have found a biotech company in Seattle that is developing novel therapeutics for “sight-threatening” eye diseases. If they can do it, we can do it.

A tablet for eye diseases?

The biotech I mentioned above is taking a very interesting strategy. They are trying to use a tablet (i.e., a pill) for delaying the progression of eye diseases.

I was envisioning that I would use ophthalmic suspensions (eye drops) or intravitreal injections (injection into eyes) for stopping eye manifestations in Wolfram syndrome, but we should also think about using pills.


Endoplasmic Reticulum Disease Clinic 2: First Step

By Dr. Fumihiko Urano

What is the first step to provide the best care for patients with rare endoplasmic reticulum diseases, including Wolfram syndrome? The answer probably applies to any undiagnosed disease.

My answer as of today is “exome sequencing.” What is exome sequencing? Exome sequencing is a new technology to sequence all the genes in each patient. This is available at our medical center. By looking at all the genes instead of one gene (such as WFS1 gene), we have a better chance to understand what is really going on in each patient. This is also critical for designing “personalized” treatment. As I mentioned before, each patient is different, and should be treated differently. We should look at all the genes, not one.

Wolfram Research Clinic Day 1: Biomarker???

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


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’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 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

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).
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.