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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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Living With Wolfram Syndrome – Lauren Gibilisco

Lauren GibiliscoHello Everyone,

The last few weeks have been fun and entertaining.  It started out on St. Patrick’s Day.

I am 75% Irish and our family has always celebrated it.  When I went to work on St. Patrick’s Day I was dressed as a leprechaun.  My clothing was green and I wore a green hat. I had shamrock on my face and of course I had the height of a leprechaun because I am a wee bit short.  I have a pretty good Irish accent and I went around saying “top of the morning to ya.”

After that I went back with my mom to the grocery store.  I became the leprechaun greeter.  The customers all loved me sharing my heritage with them.

Then last week I went to the endocrinologist.  The resident asked me questions and took my information down.  She said she would discuss my health with the doctor.  The door opened seconds later and I expected to see the doctor.  But it was the nurse who came in.  She asked me if I had my machine and if I would test my blood sugar.  I said I had just checked it before coming in here and I was fine.  She said to check it anyway.  Then my mom asked “why do they think she is low?”  The nurse said that the resident thought I was talking too much and too fast and might have a low blood sugar.  I checked my blood sugar and it was fine.  The nurse said “as soon as I saw you I knew that wasn’t the case.”  She said “that’s just typical Lauren.” LOL

I went out to dinner with a couple of friends.  One of them had just gotten engaged.  She said it was going to be a small wedding and she had to limit the invitations, but she said I made the cut.  A couple of days later I received a phone call from two of my friends who are in college.  I hadn’t heard from them in over a year so it was a pleasant surprise.  They came over to my house and we just talked and got caught up on our lives and watched a movie.

This last weekend I went up to Omaha to see my cousin who was in a musical at college.  The musical was the Phantom of the Opera.  I had seen the Broadway show in New York City about nine years ago.  At that time I could still see.  So even though I was not able to see the characters on stage I knew from the music what was going on.  All my aunts came down to see the musical so I was able to spend time with them and my grandparents.  It is always nice sharing memories and laughs.

The last few weeks have been busy and fun.  It was great seeing old friends, new friends and relatives.  Every time we get together we create a lasting memory.

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Living With Wolfram Syndrome – Adam Zwan

Photo of Adam ZwanPatience

All great things are worth waiting for.  Being patient has proven to be one of my greatest attributes and has served me well throughout life.  No matter the task, managing time wisely and being patient has given me the ability to start things, do them well, and finish with satisfaction.

While in grade school, I would start assignments, projects, and other school work as soon as the task was given.  Early in life, I discovered that procrastination always led to an overwhelming and rushed ending.  My to-do list would get cluttered with assignments and I would have to rush to get things done on time.  By 3rd grade I changed my tactics and began breaking things down and completing them little by little so that by the deadline I would only have to make the final touches.  Working piece by piece I could patiently complete any task on time and in a manner that met all demands.

The next chapter in life involved college and driving.  College went very well because I tackled the studying, work, and assignments the same way I did in grade school, with patience and good time management.  Patience also helped me regarding college graduation.  Instead of rushing to graduate and be done with school, I patiently completed course after course and made sure that each school semester ended with grades that I could be proud of.  Fortunately, I was able to graduate with a grade point average that took my resume to new heights.  In the same era, driving was a privilege that I valued and understood that by beginning a journey ahead of schedule I could patiently make my way to a destination and avoid rushed road rage.  I always felt that if I was early, I was on time, and if I was on time, I was late.

Currently, I am patiently awaiting a successful cure for Wolfram Syndrome.  The last I heard, drugs and stem cell research were showing successful results using mice and pigs; in approximately two years medical trials will begin on human patients.  Patience will serve me well in this instance because if researchers are patient in discovering a cure, testing the cure, and proving that it works then the path of patiently waiting will end with a great outcome.  By holding on and letting things take place as they should, I will be able to sustain the health I still have and look forward to successful repairs of damaged nerves.

All in all, patience has served me well in life and taught me that impatience can lead to unsatisfactory finish lines.  Life’s lesson: all great things are worth waiting for!

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A Word From the Wolfram Study Group

Photo of Bess Marshall

Dr. Bess Marshall
(Photo courtesy of Robert J. Boston)

By Dr. Bess Marshall

All of the people working on the Wolfram studies at Washington University are grateful every day for the support of the Snow Foundation and all of the other groups that support our work.  The Washington University Wolfram Study group is continuing to work on analyzing the data that we have and to plan for collecting data that we still are lacking to come up with a reliable way to track progression of Wolfram Syndrome so that we will be prepared to be able to determine whether any intervention is helping.  Although we don’t yet have an intervention, we are hopeful that that day is not far off when we begin an intervention trial.  We are also accumulating as much information as we can to help provide recommendations for clinical care until that day arrives.  I am happy to provide letters to anyone with Wolfram who needs help with insurance, work, school, or disability issues, just contact me at marshall@kids.wustl.edu.

All the best to our good friends in the Wolfram community!

Dr. Marshall’s research interests have included intermediary carbohydrate metabolism, glucose transporter structure and function, and metabolic engineering to alter insulin resistance. She is currently funded by a National Institutes of Health Clinician-Investigator Development award, the Diabetes Research and Training Center, and is a scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University. Dr. Marshall’s clinical interests include all aspects of endocrinology and metabolism.

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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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Living With Wolfram Syndrome – Adam Zwan

Self-confidence

Photo of Adam ZwanHaving confidence in one’s self is as important in life as breathing.  Without an adequate amount of confidence a person suffers throughout life dealing with mental health.  Having a lack of confidence may make it difficult to finish tasks, create new goals, initiate relationships, and can make a person feel severely depressed.  One must be satisfied with one’s self before he or she can enjoy life.

As a Wolfram patient, I have struggled to increase and maintain self-confidence most of my life.  Psychology claims that a child’s confidence is first developed in middle school (5th-8th grade).  When I was a middle school student I was overweight, payed too much attention to what other students would say or do to me, and did not have an outgoing personality that initiated relationships.  The next stepping stone took place in high school.  I started eating right, becoming more physically active, and worked on my personality, which all helped me to boost my confidence.  While helping out the baseball team and socializing more with peer students, I was feeling better about myself and my surroundings.

My level of confidence was decent while in high school and college but after graduating with a bachelor’s degree a few things changed.  Transferring through three different colleges before graduating made it tough to develop a network of friends and contacts.  Wolfram Syndrome began taking a toll and sending me to the emergency room for various reasons.  With worsening vision, I lost the luxury of driving and independent travel.  After numerous twists and turns, my confidence was again shattered.

Fortunately, I am too strong to just break down and quit.  I continue to exercise everyday to clear my head of any negativity and jumpstart each day relaxed and refreshed.  If I begin a task I make sure that I finish it and finish it well to emphasize the feelings of accomplishment.  The next step in becoming satisfied with myself is to live in an area with a system of public transportation so that I may live and travel independently.  Like most things in life, having a high level of confidence and perseverance will lead to great outcomes.

 

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Patient Based Therapeutics – Part 4

Photo of Dr. Fumihiko Urano

Dr. Fumihiko Urano

Patient-Based Therapeutics Part 4 – Drug Screening Progress

Based on the data obtained from our patients, animal models, and cell models of Wolfram syndrome, we found that calcium depletion of the endoplasmic reticulum (ER) plays a role in the pathogenesis of Wolfram syndrome. So we have been looking for drugs that can prevent ER calcium-depletion-mediated cell death.  As of today, we have found 4 FDA-approved drugs (currently used for other diseases), one supplement, and a new category of drugs (not approved by the FDA). One of the FDA-approved drugs can prevent ER calcium-depletion and cell death in the tissue culture dish. It seems like that this drug can relieve ER stress in one animal model of Wolfram syndrome. We are working very hard to complete these preclinical studies. The ER calcium-depletion releases a molecule called MANF from the ER to the circulation. So we are carefully monitoring levels of MANF in human blood samples.
So how long will it take to bring one of these drugs to our patients? I would like to share a few thoughts.
1. There is no guarantee that these drugs will work in our patients.
2. It is a little challenging for me to predict exactly how long it will take to bring these drugs to our patients.
3. However, I have a clear plan, and am doing my best to make it happen.
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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It’s The Little Things

Hi Everyone,

I have had a couple of busy weeks.  It started out with a trip to Cabela’s.  My father is an avid fisherman and he and I snuck out of the house to go there. When we go there I had to use the restroom.  I was not familiar with this restroom.  As I was leaving I was reaching for the door and flipped off the light switch accidentally.  There was another lady in the bathroom at the time.  She laughed and I apologized and then she told me where to find the door knob.

Since we are on the subject of bathrooms I am going rant a little.  Why can’t bathrooms all be made the same way.  Next time you go in a restroom, close your eyes and try to find where the toilet paper is, how to and where to flush the toilet, find the sink, paper towels and soap.  I can tell you, it is not a place where you want to be feeling around.  They have laws requiring bathrooms to be modified for people in wheel chairs, so why can’t they design a universal way to have bathrooms all be the same for blind people?

Photo of Lauren Gibilisco and her parents

My Dad, me and my Mom

My dad decided we needed a little treat and he wanted to go to Dairy Queen.  The problem is that my dad gets lost a lot.  So he asked me, a blind person, to lead him there and I did! Speaking of treats, I have made the supreme sacrifice of giving up sweets for Lent.  I have a love of ice-cream.  It is the one food that is cold and slides down my throat so I don’t have trouble with choking issues, which is a major problem I have.  So I am sorry if my blogs aren’t as sweetly written as before.

A friend of mine picked me up for lunch one day last week. She took me to a buffet.  She had to walk with me through the buffet naming all the items.  She didn’t think of that when deciding where to eat.  That’s something sighted people don’t have to think about.  It’s the little things.

Later we went to a potluck for our church.  My mom had to help serve so she was busy and my dad had to help me.  My dad is not used to helping me.  My mom is usually always around to help.  He went to my mom and said “what do I do?” She replied “you go pick up a plate and fill it with things you know Lauren would like to eat.”  Then she turned to the other ladies in the kitchen and said “Lord help if I die first.  Lauren would probably starve to death or never leave the house.”  Going out with my dad and having my mom not there is always an adventure.  He often just walks away and expects that I will follow, so he turns around to talk to me and I’m not there.  He then panics and runs back to find where he left me.  My dad is a little helpless but I love him for trying.

Hope everyone has a good week.

Lauren

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Living With Wolfram Syndrome – Adam Zwan

Are You Trigger Happy?

Photo of Adam ZwanPortion distortion is one of the many reasons for the rapid increase in obesity among individuals in the United States.  One category of food that people tend to splurge on is called trigger food.  Trigger foods are those that individuals go to when they are multi-tasking.  For example, while watching a movie, reading a book, working on a computer, or studying for an exam a person may have a snack item at their side and by the time he or she pays attention the entire bag has been eaten.  Depending on a person and their taste buds, trigger food may include chips, candy, popcorn, trail mix, cheese cubes, and list goes on.

There are no bad food groups or bad foods just improper serving sizes.  The good news is that trigger foods do not have to be eliminated from one’s diet; they should just be eaten in the right amount.  Luckily, many methods can be practiced to eat more mindfully.  For one, take your chosen trigger food and measure out a single serving and then placed the remaining food back in the pantry or fridge.  In turn, a smaller amount will be eaten and a limited amount will cause a slower eating pace, which will also help with healthy metabolism.

A popular method in defeating trigger foods is when grocery shopping, shop the perimeter of the store. Fat, salt, and sugar are the three taste good ingredients, which is why manufactured products all contain one or a combination of the three giving snack foods an addictive quality.  By staying on the perimeter of a store a person is less likely to buy trigger foods and have them in the household increasing temptation to overeat.  Also, shopping the perimeter increases the ability to substitute trigger foods with fresh fruits and vegetable.  Instead of having an entire bag of chips while multi-tasking have an apple; now, a bag of chips is defeated with healthier item.

As a Wolfram patient, controlling diabetic glucose levels is extremely important when slowing nerve damage.  Trigger foods can easily boost glucose levels, so eating more mindfully can promote controlled diabetes.  Limiting and substituting trigger foods has proven to be a valuable lesson in living healthier and increasing the quality of life.

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In Memory of K by Dr. Fumihiko Urano

A Few weeks ago, a young woman who had been battling Wolfram syndrome for many years passed away.  Everyone knew, loved and supported her.  Below is a touching blog post from Washington University School of Medicine’s Dr. Fumihiko Urano about our friend, Ms. K.

In Memory of K

Yesterday I was heartbroken because I learned of the death of Ms. K, a young woman with Wolfram syndrome. I was not helpful. I could not even find a way to delay the progression of the disease. I felt devastated. I really felt devastated. I was very sad and could not respond to any emails for several hours.
As a person, I sometimes feel scared. Although I am always doing my best and determined to figure out a way to help patients with Wolfram syndrome, I know that I am not a god. The treatment I am planning to test may not be effective. I often wake up at midnight and feel scared. However, as a physician, I swear to figure out a way to stop the progression of Wolfram syndrome, find a way to regenerate damaged tissues, and give patients hope. I think I should keep on running to figure out a way to help patients with Wolfram syndrome.
I saw Ms. K reading a poem entitled a single second in time, which reminded me of Sam Berns, a wonderful young man with progeria, a rare disease characterized by accelerated aging. Sam passed away earlier this year. Although he was much younger than myself, I learned a lot from him and his interviews. You may want to watch the following video and read Dr. Francis Collin’s blog on him. His philosophy for a happy life is a wonderful piece to watch. Take care everyone, and have a nice weekend. I will appreciate a single second in time just like Ms. K.
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