Patient-based therapeutics part 5 - 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

Support from the Juvenile Diabetes Research Foundation

I was fortunate to receive the grant from the Juvenile Diabetes Research Foundation with Dr. Emil Unanue, a world-famous type 1 diabetes researcher.

My group discovered that Wolfram syndrome is caused by the interaction between a particular type of cell stress, ER (endoplasmic reticulum) stress, and genetic factors. I believe that the same type of cell stress is involved in type 1 diabetes and autoimmunity. Through our collaboration, we will elucidate a common biological process altered in Wolfram syndrome and type 1 diabetes. Our study can lead to a breakthrough in treatments for Wolfram syndrome and type 1 diabetes. I always appreciate the support from the Juvenile Diabetes Research Foundation.

Here is our press release:
http://endo.wustl.edu/2014/dr-urano-receives-jdrf-funding/

Three step formula for developing therapeutics - revised

I will give three lectures on Wolfram in the next several weeks. So I am working on my presentations. I feel that I need to revise my three step formula for developing therapeutics for Wolfram syndrome. Here is the updated one. I welcome any feedback.

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.
http://www.youtube.com/watch?v=36m1o-tM05g
http://directorsblog.nih.gov/2014/01/12/in-memory-of-sam-berns/

Pushing the envelope in juvenile diabetes research.

In 1873, the top British surgeon predicted, "The abdomen, the chest, and the brain will forever be shut from the intrusion of the wise and humane surgeon." This has turned out to be wrong. I always feel that we need to keep on pushing the envelope and keep faith with our novel theories. Just a thought on a Sunday morning.

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.

Wolfram syndrome information

I receive emails and phone calls every day from patients with Wolfram syndrome and type 1 diabetes, their family members, and physicians. Although there are many wonderful websites providing information on type 1 diabetes, we don't have many websites related to Wolfram syndrome. I always feel that we need a website providing accurate information on Wolfram syndrome. So I have decided to make one. My previous lab website was too scientific, and only doctors and scientists could understand the contents. So I am trying to make my new website simple. I plan to expand the Q&A section and other sections. I welcome any feedback from you!
http://www.erstress.com/

Diabetes and Optic Atrophy

I often get the following question, “Is there any relationship between diabetes and optic nerve atrophy?” This question implies a few different things. So here is my answer.

1. Type 1 Diabetes
I believe that there is no direct relationship between type 1 diabetes and optic atrophy. Type 1 diabetes is an autoimmune disease. Our immune cells attack antigens highly expressed in pancreatic β cells in type 1 diabetes. These autoimmune cells usually do not attack optic nerve although patients with type 1 diabetes are susceptible to other autoimmune diseases. As I mentioned in my previous blog, patients with type 1 diabetes may develop retinopathy if there blood sugar levels are not properly controlled.

2. Wolfram syndrome
In Wolfram syndrome, there is probably a direct relationship between diabetes and optic nerve atrophy. Both pancreatic β cells and optic nerve are susceptible to endoplasmic reticulum dysfunction. So β cell death and death of retinal ganglion cells  have the same etiology, i.e. ER dysfunction.

3. Do all patients with Wolfram syndrome have diabetes and optic nerve atrophy?
The answer is, “No.” In most cases, diabetes is the first manifestation of Wolfram syndrome, followed by optic atrophy. However, there are some patients who develop optic atrophy first and don’t develop diabetes for a long period of time. I know one patient with Wolfram whose diabetes was diagnosed at 40 years old. I don’t know why, but it seems like these patients tend to have milder symptoms. I am very interested in carefully studying these patients because I may be able to find a way to delay the progression of Wolfram through these patients. This effort is underway (i.e., modifying my human study protocol).