Tag Archive for: WFS1 gene mutations

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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. 

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Patient-Based Therapeutics Part 5 – Wolfram Syndrome iPSCs

Wolfram Syndrome iPSCs

Today I would like to discuss how we use induced pluripotent stem cells (iPS cells) derived from patients with Wolfram syndrome for developing treatment. Our group as well as a group in Columbia University have created iPS cells from patients with Wolfram syndrome.What are induced pluripotent stem cells (iPS cells)?
iPS cells are a type of stem cells that can be generated directly from adult cells, including skin cells. We can make pancreatic beta cells and neurons from these iPS cells.How can we use Wolfram syndrome iPS cells for treatment?
We can expect that Wolfram syndrome patients iPS cell lines and Wolfram iPS cell-derived beta cells to be a cornerstone for developing novel therapeutic modalities for Wolfram syndrome and other diseases involving endoplasmic reticulum (ER) dysfunction. We can utilize these cells to screen and identify drugs for treating patients with Wolfram syndrome and other ER-associated diseases.Regenerate Damaged Tissues
In the future, we can utilize these cells to regenerate damaged tissues including pancreatic beta cells, retinal ganglion cells (eye cells), and neurons in patients with Wolfram syndrome. Rapid progress in genetic editing technologies and regenerative medicine will make it possible to correct WFS1 mutations in patient-specific iPSC lines and regenerate patients’ damaged cells. Our current progress:
1. Using these Wolfram iPS cells, we have identified a drug target for developing treatment (our manuscript is in review.)
2. As I reported before, we are currently testing the efficacy of five different drugs using iPS cell-derived neurons.
3. We are correcting a WFS1 gene mutation by genetic editing and making eye cells using these iPS cells.We should make the best use of these cells to develop treatments for Wolfram syndrome, efforts that may lead to breakthroughs in diabetes treatment. I have articulated my strategy in the article just published in Diabetes.
http://diabetes.diabetesjournals.org/content/63/3/844.full

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.

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Research Reports From Washington University

Introducing… the Washington University Wolfram Syndrome Study Group!

By Dr. Tamara Hershey

Photo of Dr. Tamara Hershey

Dr. Tamara Hershey

I would like to tell you about the big picture of research and clinical activities at Washington University focused on Wolfram Syndrome. There are three parts to this effort 1) Diagnostic markers and treatment  development for Wolfram syndrome using animal models and human cells, led by Dr. Fumi Urano (see his previous blog postings here); 2) Patient-oriented natural history studies, led by me — Dr. Tamara Hershey) to determine the trajectory of Wolfram Syndrome-related neurological changes, providing the necessary background information for future clinical trials and 3) Expert clinical screening and care for Wolfram Syndrome, led by Dr. Bess Marshall. Dr. Marshall and other WU physicians now have the most in-depth clinical experience with Wolfram Syndrome in the nation and perhaps the world, providing the basis for a true clinical center of excellence.

Photo of Wash U Team of Drs.

(Left to Right): Dr. Fumihiko Urano, Dr. Tamara Hershey, and Dr. Bess Marshall

Fumi, Bess and I work as a team on all three of these aspects of Wolfram Syndrome research and care. We are in almost daily contact with each other to push our work further and problem solve together. It has been a privilege to work with both of them on something we are all so passionate about. In addition, we work with a large team of dedicated clinical and research faculty and staff, who we collectively refer to as the WU Wolfram Syndrome Study Group. Their names are below. I want you to know that there are a lot of talented and dedicated people here at WU working hard on the behalf of all Wolfram Syndrome families!

Photo of Dr. Timothy Barrett

Dr. Timothy Barrett

We are also in contact with collaborators across the world, including Dr. Tim Barrett in the UK and others, to pool our experimental and clinical data and share measurement tools and ideas. We hope that in the future, these collaborations will provide the basis for a multi-center international clinical trial network. We are committed to being ready to implement an efficient, high quality clinical trial, as soon as a safe drug is identified with strong experimental evidence suggesting that it might help.

WU Wolfram Syndrome Study Group Leaders:  F. Urano (Medicine), T. Hershey (Psychiatry, Radiology, Neurology) and B. Marshall (Pediatrics)  P. Austin, M.D. (Surgery) G. Earhart, Ph.D. (Physical Therapy) S. Eisenstein, Ph.D. (Psychiatry) J. Garbow (Radiology) J. Hoekel, O.D. (Ophthalmology) T. Hullar, M.D. (Otolaryngology) R. Karzon, Ph.D. (Audiology & Communication Sciences) H. M. Lugar, M.A. (Psychiatry) L. Manwaring, M.S. (Pediatrics) A. R. Paciorkowski, M.D. (Neurology, U Rochester) K. Pickett, Ph.D. (Physical Therapy) S. Ranck, MSW (Psychiatry) J. Rutlin, B.S. (Psychiatry) J. Shimony, M.D., Ph.D. (Radiology) A. Viehoever, M.D. (Neurology) N. H. White M.D., CDE (Pediatrics) In memoriam: A. Permutt, M.D. (Medicine) J. Wasson B.S. (Medicine)

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Hypersensitivity to Heat – Lauren Gibilisco

“Some Like It Hot and Some Sweat When The Heat Is On”- Hypersensitivity to Heat

Hello Everyone,

I told you last week the main symptoms of Wolfram Syndrome.  Today I am going to talk about a lesser symptom that greatly impacts my life. This symptom is hypersensitivity to heat. My body has a problem regulating temperatures.  “Some Like It Hot” only begins to describe my house.

Photo of Lauren GibiliscoFor those that don’t know me, I am from Nebraska.  The weather here can be very windy and unpredictable.  This last week has been extremely cold (for normal people).  The temperature was in single digits with wind chills below zero.  We also had three days where the regular temperature was -10 to -15 with wind chills -20 to -30. In simple terms, I hate the heat and love the cold.

Here is where I have a constant argument with my mom.  She wants me to wear a coat in the winter.  She lectures me on how the cold can affect my skin.  I hate wearing a coat.  It always makes me hot no matter what the temperature.  Here is how I respond to people.  “I never wear a coat unless I can see my breath.”  Ha-ha, I can never see my breath so I always win that argument. I like to exercise at home, especially during the winter, so when I get hot I can just go outside to “chill out”.

In the summer, it can get very hot and humid here.  This makes me a prisoner in my home.  I sweat profusely and I am unable to be outside for any length of time. I can no longer take walks, go to amusement parks or baseball games. The only activity that works for me is swimming.  The cold water keeps my body cool.  My parents had to install a separate central air conditioner upstairs just to keep me cool.  I don’t like it to be any warmer than 65 degrees.  So picture this, it is 100 degrees outside and my mom is wearing a sweater and socks trying to stay warm inside the house.  So what a family we are.  I hate to wear a coat in the winter and my mom has to wear a sweater in the summer.  Oh well I’ve always loved being unique.

Have a great week everyone and enjoy the weather. ☺

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Diabetes, Wolframs and Botox, Oh My! – Lauren Gibilisco

Photo of Lauren Gibilisco

Lauren Gibilisco

Hello everyone.  My Botox surgery was a success.  I am happy to report that I am getting up only two or three times a night instead of every hour. I don’t feel as tired anymore through out the day.  This has made me feel so much better. I am able to drink a lot more and hold a lot more than every before.  This gives me a lot more energy so I can talk a lot more which is just what my mom needs. LOL.

I was also able to go back to my volunteer job this week where I shred paper.  Who better to shred confidential papers than someone who can’t see anything on them. ha-ha.  I’ve had this job since high school which I really enjoy.  The people there treat me like anyone else.  They don’t pity me.  In fact quite the opposite.  They love to give me a hard time and tease me.  It’s hard to know who is getting more harassed, them or me. My mouth is the only part of me that is not affected by WS.

I should back up and tell you a little about me.  I am affected by all aspects of DIDMOAD.  DI (DIABETES INSIPIDUS), DM (DIABETES MELLITUS), OA (OPTIC ATROPHY, D (DEAFNESS).  I am legally blind and use a cane to get around. I wear hearing aids for high frequency hearing loss. I was diagnosed with Diabetes Mellitus when I was two years old and take insulin shots.  The Diabetes Insipidus is controlled by medication. I take 20 prescription pills every day to control my WS. I was diagnosed with WS when I was 12. I have other symptoms but I will talk about them another day.

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Research Update – Patient Based Therapeutics Part 1

Patient Based Therapeutics – Part 1

Photo of Dr. Fumihiko Urano

Dr. Fumihiko Urano

We are taking an unconventional approach to develop therapeutics for Wolfram syndrome. I would call it “patient-based therapeutics.” Our extensive molecular characterization of patient cells, especially iPSC-derived cells, has been providing us remarkable insights into the root cause of Wolfram syndrome. Based on these insights, I have been carefully choosing molecular targets and processes for developing therapeutics. These are the endoplasmic reticulum (ER) membrane integrity, ER calcium leakage, calpain-2, and WFS1 gene mutations.How we target WFS1 gene mutations? We have started testing genome editing to accomplish this. Genome editing is a process that involves cutting out pathogenic genetic material (i.e., mutations in the WFS1 gene) and replacing it with healthy genetic material. This is a molecular surgery. So I am becoming a molecular surgeon. In short, we are trying to repair a genetic defect in Wolfram syndrome.

Currently, we are repairing a genetic defect in iPS cells from patients with Wolfram syndrome to see if the molecular surgery can restore the normal function of neural progenitor cells derived from Wolfram iPS cells. This is an important step. When the transplantation of iPSC-derived retinal ganglion cells and beta cells are available in the clinic in the future, we need to repair the genetic defect before the transplantation.

Dr. Fumihiko Urano 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.

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