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.
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Publication: American Diabetes Association | Publication Date: March 2014
Authors: Fumihiko Urano
Wolfram syndrome is a rare autosomal recessive genetic disorder with clinical signs apparent in early childhood. This condition is characterized by childhood-onset diabetes, optic nerve atrophy, deafness, diabetes insipidus, and neurodegeneration, and it results in death in middle adulthood (1–3). Genetic and experimental evidence strongly suggest that endoplasmic reticulum (ER) dysfunction is a critical pathogenic component of Wolfram syndrome (4,5). However, there is a lack of complete understanding of the pathways and biomarkers involved in the disease process due to the limitations of animal models that do not accurately reflect human patients. As a result, despite the underlying importance of ER dysfunction in Wolfram syndrome, there are currently no therapies that target the ER, a deficiency that points to the urgent need to develop a human cell model of this condition. In this issue, Shang et al. (6) report that this has been successfully accomplished.
Dr. Bess Marshall
(Photo courtesy of Robert J. Boston)
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.
The Ups and Downs of Vision Loss
Lauren and Megan Gibilisco
My week turned out to be quite eventful. I am going to give you the ups and downs of vision loss.
It all started out when I knocked some sense into myself. Inside the house I do not use my cane. I went to go turn off the television and thought I was walking towards the light. Unfortunately I didn’t see the wall in front of me and ran smack into it. It knocked me right on my butt. I went downstairs to show my mom my mouth. I didn’t know but I had blood running down my face. I had split my lip all the way back to the gum. My lower lip had teeth impressions where I bit down. My upper lip was already starting to get a fat lip. I am very fortunate that I did not knock out any teeth or break my nose. So I had my mom take a picture and send it to my phone. Three days later when I went to work I showed everyone my pictures. They asked how did I do that. My reply was I was standing outside and a large bird ran into me beak first. I couldn’t believe that several people actually believed that. My mom told everyone that I was fine because I am still able to talk.
My sister came home from Omaha for the weekend. She brought her new puppy home for us to see. She is a shorkie. Her mom was a shih ti and her dad a yorkie. Her name is Emmy. This puppy is little. She only weighs two pounds and will only grow to be five pounds. I do not like animals much but I have grown fond of this puppy. She loves to play and I love that I can play with her even though I can’t see her. The only problem I have is that I worry about stepping on her. She loves to run beside me when I leave a room. So if she is going to be around me she will just have to learn not to walk in front of me.
My sister wanted to show off the puppy to her best friend. We drove to her house. Luckily her brother came over to visit also. Zach and I have been best friends since we were little. He is getting married in July. He wanted me to be a part of the wedding and asked me if I would like to be in charge of the guest book. I asked him if I had to sign people’s names and he said no. Zach said I would be like a greeter. I think the job is perfect. I just get to sit there looking lovely and greet people as they come in. Perfect job for someone who likes to talk.
So for a week that I thought would be boring turned out to be quite exciting. That just teaches you that losing your vision doesn’t mean your life will stop. So you never know what is going to jump in front of you….even if it’s a wall.
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:
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
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
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.
Having 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.
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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.
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.
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?
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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