iPS cells and Personalized Medicine

We have created many induced pluripotent stem cells (iPS cells) from skin cells of Wolfram syndrome patients.

Because these cells can be differentiated into any types of cells, including brain cells, eye cells, and insulin-producing pancreatic cells, we can use these cells to replace damaged tissues in our patients in the future.

In addition to this, there is another advantage in making iPS cells. We can use these cells now. We can test the efficacy of different candidate drugs using brain cells and eye cells differentiated from iPS cells. It seems like that patients’ cells respond to different treatments based on their genetic make-up. So these cells are useful for designing personalized medicine for the treatments of Wolfram syndrome. This would apply to any other diseases. Thank you again for donating your cells. I would like to expand this program and make iPS cells from all the patients with Wolfram syndrome in the world.

The article I read over and over

I have read many articles related to Wolfram syndrome.

The most-read article is entitled “Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome” describing the natural history of Wolfram syndrome. This article was written by Timothy Barrett, MB, BS (MD), PhD in 1995.
http://www.ncbi.nlm.nih.gov/pubmed/7490992

I read this paper over and over when I started working on Wolfram syndrome in 2002. I recommend that all the researchers in diabetes, neurodegeneration, and genetic diseases, read this article. 

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.
https://www.youtube.com/watch?v=v-Q2kghHwq4

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.  http://acucela.com/About-Us

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.
https://clinicaltrials.gov/ct2/show/NCT02130531?term=acucela&rank=1

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

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.