Four pillars to provide a cure for Wolfram syndrome and type 1 diabetes

I always carry a card articulating my strategy to provide a cure for Wolfram syndrome. I think there are four pillars to provide a cure for Wolfram syndrome.

1. Stop the progression of the disease.
We are looking for FDA-approved drugs that can delay the progression of Wolfram syndrome. These drugs are currently used for other indications. We are also developing new drugs specifically designed for Wolfram.

2. Raise Awareness
It is important to raise awareness of Wolfram in health care professionals and the general public. We need a list of doctors who have experience in managing patients with Wolfram.

3. Replace damaged tissues
We are creating eye cells, brain cells, and pancreatic beta cells from patients' skin cells (iPS technology). We are also correcting genetic mutations in these cells (genome editing technology).

4. Protect remaining tissues
We are looking for a trophic factor that can protect remaining brain cells and beta cells from dysfunction and death. MANF and MANF-related molecule that we have identified are good candidates.

Patient-based therapeutics part 11- Making eye cells 3

As I mentioned in my previous blogs, we are creating eye cells from iPS cells derived from skin cells of our patients. 
http://wolframsyndrome.blogspot.com/2014/03/patient-based-therapeutics-part-7.html
http://wolframsyndrome.blogspot.com/2014/05/patient-based-therapeutics-part-9.html
We are also correcting genetic mutations in these cells using the genome editing technology. We started seeing a type of eye cells in our dishes. We will keep moving forward.

Thank you to all who keep me going.

Today, I would like to show my gratitude to all the people who keep me going. Who are they? They are patients with Wolfram syndrome and type 1 diabetes. I get around 20-30 emails per day from them. They ask me questions and share their experiences and feelings. I try to respond to every email. They empower me and keep me going. I also thank my colleagues, collaborators, and friends who help me develop therapeutics for Wolfram and raise awareness of the disease. Thank you all.

Our current efforts May 28, 2014

I would like to briefly outline our current efforts.

1. Develop drugs that can delay the progression of Wolfram syndrome.
As of today, we are focusing on one FDA-approved drug. We are testing the efficacy of this drug in iPS cells from patients and two animal models of Wolfram syndrome. We are also testing two new types of drugs.

2. Making eye cells using iPS cells derived from Wolfram syndrome patients.
As of today, we started seeing eye-like cells in our dishes. I am excited by this. We will keep on differentiating these cells and test the efficacy of our candidate drugs to develop treatments for eye manifestations in Wolfram syndrome.

3. Measuring the levels of disease-progression biomarkers
We have identified two potential disease-progression biomarkers. As of today, we are measuring the levels of these markers in blood samples from patients and control subjects.

4. Correcting genetic mutations using CRISPR technology in cells from Wolfram syndrome patients.
In the future, we need to correct genetic mutations in pancreatic beta cells, brain cells, and eye cells derived from patients' skin cells before they are transplanted. We are performing a "molecular surgery" to replace a mutated segment of WFS1 gene with a normal segment of WFS1 gene in cells from patients.

A cure for Wolfram syndrome could lead to a cure for diabetes.

Here is my concept. Wolfram syndrome is the most difficult form of diabetes. Thus, a cure for Wolfram could lead to a cure for diabetes.

Wisdom from Richard Branson

Richard Branson is one of my heroes. His Top Ten Tips for success has been recently published, and I have been encouraged by his words.

1. Follow your dreams and just do it.
2. Make a positive difference and do some good.
3. Believe in your ideas and be the best.
I like this one best. I believe in my ideas.
4. Have fun and look after your team.
5. Don't give up.
I agree. Don't give up.
6. Make lots of lists and keep setting yourself new challenges.
7. Spend time with your family and learn to delegate.
8. Try turning off the TV and get out there and do things.
9. When people say bad things about you, just prove them wrong.
10. Do what you love and have a sofa in the kitchen.
http://www.bbc.com/news/entertainment-arts-26575792 My visit to Japan was fruitful. I am flying back to Saint Louis to make a positive difference!

Thank you again, Jon.

We are revising our human study protocol and removing names of people who are no longer working in my team. Jon Wasson's name has been removed. 

When I took over Dr. Permutt's research program on Wolfram syndrome, two staff members from his group joined my team, Mr. Jonathon Wasson and Mrs. Cris Brown. Jon had worked with Dr. Permutt for more than 20 years and had been a manager for the International Wolfram syndrome registry. With Dr. Permutt, Jon had identified many genes associated with diabetes, including Wolfram syndrome 1 gene. Jon was tall, kind, and relatively quite. He was like an elder brother for all the Wolfram patients and their family members of our study. When I met with him, he told me that he had been battling with metastatic cancer. He tried to teach me about the culture of Washington University, the Wolfram study, Dr. Permutt's research program, and etc. He was dedicated to our Wolfram project. He believed that we would find a cure for Wolfram. Until he had to start his hospice care, he worked for my team diligently. Jon was a really nice human being. Thank you again, Jon. You can still see him here.
https://www.youtube.com/watch?v=BQgQXomUftM

Endoplasmic reticulum disease theory

I feel that we are hitting the tipping point. Our "Endoplasmic reticulum (ER) dysfunction" theory for Wolfram and diabetes is getting attention, which is good news.

Accumulating evidence in my research team indicates that restoring ER calcium homeostasis is beneficial for Wolfram syndrome patients. We are testing this theory using three animal models and cells derived from patients. There are two ways to restore ER calcium homeostasis.

1. Increase calcium influx to the endoplasmic reticulum.
2. Decrease calcium efflux from the endoplasmic reticulum.

At this point, the second strategy seems to be working, but we are trying both. My hope is to test the second strategy in healthy individuals and patients soon.

Denver, Paris, and Saint Louis

I am at the Denver Airport and waiting for the connecting flight. I will give three lectures on Wolfram syndrome in the next few days. The city of Denver always reminds me of one of our patients, Ellie White. I got to know Ellie and her mother Beth White several years ago. We started exchanging email about Wolfram syndrome. I also met with Beth in person several years ago in Denver when I was invited to give a talk on Wolfram at a medical science meeting. Ellie was a courageous young girl and was trying to raise awareness and funds for Wolfram syndrome, which really impressed me. Later on, her dance team, the Silhouettes, were asked to attend an audition for America’s Got Talent Season 6 in 2010. They advanced to the final and finished in second place in the competition. Ellie wanted to talk about Wolfram on TV and finally got a chance to do it at the end.

In Paris, I met with Nolwen, in Denver I met with Beth, and in Saint Louis I met with Stephanie. They are all dedicated mothers. I always feel that it has been my privilege to work for patients with Wolfram syndrome. Stephanie's efforts were featured in our local news paper. I hope you will read it and ask your friends to read it.
http://www.laduenews.com/society/charities-nonprofits/the-jack-and-j-t-snow-scientific-research-foundation/article_2623d048-c42a-558e-8d59-4c9deb04478b.html

A cure for Wolfram syndrome could lead to a cure for diabetes Part 6

I moved to Washington University Medical Center in July, 2012. My focus has been to develop novel treatments for Wolfram syndrome. I believe in the strong power of rare diseases, especially Wolfram syndrome, to understand the pathogenesis and develop novel therapeutic modalities for more prevalent forms of diabetes, type 1 diabetes and type 2 diabetes. 

It has been shown that genetic variations of WFS1, a causative gene for Wolfram, are associated with type 2 diabetes. My hypothesis is that a certain variation of WFS1 gene makes our pancreatic beta cells more susceptible to environmental stress, more specifically endoplasmic reticulum (ER) stress. Drugs that can alleviate ER stress should be beneficial for this group of patients with type 2 diabetes. 

In type 1 diabetes, ER dysfunction may produce abnormal structure of insulin in pancreatic beta cells, leading to autoimmune-mediated destruction of beta cell and diabetes. We have scientific evidence supporting this model, and are trying to publish the data. For this group of patients with type 1 diabetes, drugs that can restore ER dysfunction should be beneficial.

Its monogenic aetiology makes Wolfram syndrome more amenable to dissecting out the mechanisms underpinning cellular responses to ER dysfunction than other diabetic conditions, type 1 and type 2 diabetes, in which multiple factors typically interact to produce the disease manifestations. Thus, Wolfram syndrome represents an ideal model to identify novel biomarkers and drugs for type 1 and type 2 diabetes. I believe that "A cure for Wolfram syndrome could lead to a cure for diabetes."

A cure for Wolfram syndrome could lead to a cure for diabetes Part 5

http://wolframsyndrome.blogspot.com/2014/05/a-cure-for-wolfram-syndrome-could-lead.html
http://wolframsyndrome.blogspot.com/2014/05/a-cure-for-wolfram-syndrome-could-lead_17.html
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http://wolframsyndrome.blogspot.com/2014/05/httpwolframsyndrome.html

I received a call from Dr. Permutt when I was getting off the airplane. I asked him to give me some time and called him back. He said that he wanted me to join the faculty of Washington University of School of Medicine. He also asked me to look at the Wolfram clinic. So I visited the Washington University's Wolfram clinic in the summer of 2011. Dr. Barrett and Dr. Tanizawa were also there. I met with physicians and researchers involved in the Wolfram clinic, including Dr. Tamara Hershey PhD, Dr. Bess Marshall MD, Dr. Neil White MD, and Mr. Jonathan Wasson MS. The clinic was well organized. I realized that the Washington University Medical Center was a huge complex. I also met with Dr. Clay Semenkovich MD who was heading the endocrinology division there. I was really impressed by the clinic and the medical center.

I came back to the Washington University in the Fall of 2011, gave a lecture on Wolfram syndrome, and met with many faculty members, including the Head of Medicine, Dr. Victoria Fraser MD, and the Director of the Diabetes Research Center, Dr. Jean Schaffer MD. They were enthusiastic and supportive. Dr. Permutt was very sick because of the metastatic cancer and asked me to take over his research program. I also met with Mrs. Stephanie Snow Gebel whose daughter had Wolfram syndrome. She said that she would raise money for our research program just like Nolwen said to us. I was moved by her.

I decided to leave the University of Massachusetts and join the Washington University Medical Center early in 2012. I was determined to find a treatment for Wolfram syndrome. Around that time, the concept of "ER stress in beta cells" hit the tipping point. Many established researchers started publishing articles related to ER stress in beta cells. I moved to Washington University on July 1, 2012.

Wolfram syndrome is a prototype of human endoplasmic reticulum disease

It has been established that endoplasmic reticulum (ER) dysfunction is the root cause of Wolfram syndrome. It would be possible to identify biomarkers reflecting ER health and develop treatments targeting the ER in mechanistically homogeneous Wolfram syndrome patients, which may lead to a breakthrough for treatments of common diseases, such as type 1 and type 2 diabetes and neurodegeneration, in which ER dysfunction is involved.

Cell-based therapy for Wolfram syndrome and Type 1 Diabetes?

We are looking for drugs for Wolfram syndrome to prevent or halt the progression of the disease. In parallel, we are developing "cell-based" therapies.

What is "cell-based" therapy? What I mean by this is the following.

1. Take the cells from patients.

2. Correct the genetic mutations and add additional features to the cells to enhance viability.

3. Bring these cells back to patients.

This strategy has been successful in the cancer field, and has provided a cure for patients with certain forms of cancer. I will elaborate this and keep you updated about our progress in my future blogs.

A cure for Wolfram syndrome could lead to a cure for diabetes Part 4

http://wolframsyndrome.blogspot.com/2014/05/a-cure-for-wolfram-syndrome-could-lead.html
http://wolframsyndrome.blogspot.com/2014/05/a-cure-for-wolfram-syndrome-could-lead_17.html
http://wolframsyndrome.blogspot.com/2014/05/a-cure-for-wolfram-syndrome-could-lead_18.html

Between 2009 -2011, many things happened around me, and I decided to stay in academic medicine and find a cure for Wolfram syndrome at the end of 2011. I felt that this was my last research project. I changed my plan. One of the incidents that changed my trajectory was my meeting with Nolwen.

I flew to Paris in the Spring of 2009, and met with Nolwen who had a son with Wolfram syndrome. What I learned there was that she also asked Dr. Timothy Barrett MD, PhD in England, Dr. Yukio Tanizawa MD, PhD in Japan, and Dr. M. Alan Permutt MD in the US to come to Paris. They were the best Wolfram syndrome researchers in the world at the time. Dr. Permutt was not there because of his illness, but I met with Dr. Barett, Dr. Tanizawa, and other Wolfram researchers in Europe. I was much younger than others, but was recognized as a leader in the field, which surprised me. Nolwen was very clear. She asked us to find a cure for Wolfram and promised that she would raise money for the research.

We discussed the strategies for two days and agreed to establish the Wolfram syndrome patient registry to understand the disease as a first step. I came back to the US and called Dr. Permutt. He sounded weak but agreed to establish the patient registry together. With the funding supports from Washington University and University of Massachusetts, the International Registry of Wolfram Syndrome was established in the Fall of 2009 and Dr. Permutt became the founding director of the registry. He also established a research clinic in 2010.

Between 2009 -2011, I felt that many researchers started accepting my ER stress theory although it was still controversial. Dr. Decio Eizirik MD, PhD, a prominent diabetes research in Europe, published multiple articles that supported our theory, which really helped me. I felt encouraged.

In the Spring of 2011, I was trying to decide whether or not I should stay in academic medicine. I gave a lecture on Wolfram in California and was on my way back to Massachusetts. That's when I got a surprising call from Dr. Permutt when my plane landed at Newark airport.

A cure for Wolfram syndrome could lead to a cure for diabetes Part 3

http://wolframsyndrome.blogspot.com/2014/05/a-cure-for-wolfram-syndrome-could-lead.html
http://wolframsyndrome.blogspot.com/2014/05/a-cure-for-wolfram-syndrome-could-lead_17.html

I felt that I was at dead end because of a few reasons. I had to keep on defending my "ER stress" theory of Wolfram syndrome and diabetes by myself. I also realized my limitations as an "immigrant" doctor. Although I took exactly the same three-step medical license exams and clinical skills assessment as American doctors, I was not from top notch medical schools in the US, such as Harvard, Yale, Hopkins, Columbia, Stanford, UCSF, and Washington U. When I attended the ceremony for the new members of the American Society for Clinical Investigation, I realized that most of them were from these top notch American med schools. They were well-connected and knew important people in the medical research community. I was not well-connected at all. In addition, my mentor, Dr. Aldo Rossini MD, retired and left the Diabetes Research Center at the University of Massachusetts. He went back to the Diabetes Center at Harvard as a visiting professor. Dr. Rossini was my biggest supporter, believed in my ER stress theory, and always gave me kind advice. I felt that Dr. Rossini was like my father especially because I lost my father at a young age. He was a wonderful physician, scientist, and human being. I was seriously thinking about leaving academic medicine and research, and becoming a doctor in a small town. I planned to close my research lab after my trainees, fellows, and students graduated. I started spending time in hospitals and attending more clinical conferences.

I still believed in my theory that ER dysfunction in beta cells is a key to understand Wolfram syndrome, type 1 and type 2 diabetes. My team was getting results supporting my theory. Around the same time, unexpected things started happening. The first thing was email from a woman in France. Her email struck me. Her name was Nolwen, and she asked me to come to Paris to help her son who had Wolfram syndrome. I exchanged email with her several times and realized that she was really serious. I decided to fly to Paris, and the meeting with her changed my trajectory.

A cure for Wolfram syndrome could lead to a cure for diabetes Part 2

My first meeting with Dr. Permutt was in 2003. I gave a lecture on Wolfram at Washington University, but he could not come because of the Jewish holiday. So he came to my hotel next day. We had breakfast together and exchanged our ideas. Dr. Permutt was a renowned diabetes researcher and I was nervous. I still remember that I was sweating a lot and he asked me why, but I explained him my concept that Wolfram syndrome is endoplasmic reticulum (ER) disease. I also told him the possibility that ER dysfunction could play a role in beta cell dysfunction in major forms of diabetes, type 1 and type 2 diabetes. Interestingly, he accepted my "crazy" idea and offered help. I also met with his fellows, Dr. Andrew Riggs MD and Dr. Mitsu Ohsugi, MD. They were analyzing their mouse model of Wolfram syndrome.

Dr. Permutt and I started working together in 2003 and we started receiving samples from patients with Wolfram syndrome. From 2005 to 2006, my team could publish multiple papers showing that Wolfram is ER disease. We also started publishing that ER dysfunction plays a role in beta cell death in major forms of diabetes. The concept was controversial, but some researchers and doctors started showing interest in our idea. We kept on working on the role of ER dysfunction in beta cell death to prove our theory.

In 2010, Dr. Permutt and I could publish another paper showing that Wolfram is ER disease. Around this time, many researchers and doctors became interested in my theory. In 2011, I gave more than 30 lectures around the world on this topic, received a tenure from the University of Massachusetts Medical School, and was elected to the American Society For Clinical Investigation because of my contribution to the Wolfram syndrome and diabetes research, one of the highest honors as a young physician. However, I was feeling that I was at dead end and seriously thinking about leaving research and academic medicine because of several reasons. However, two incidents brought me back to research.

Electrolytes and sodium levels in Wolfram syndrome

What are electrolytes and sodium? Electrolytes are "salts" in our blood and cellular fluids. The difference between the concentrations of these salts inside and outside the cells regulates the contraction of muscle cells and the signal transduction in brain cells (neurons). Sodium is the major salt outside the cells. The reference range for serum sodium is 135-145 mmol/L.

It seems like some patients with Wolfram syndrome experience "low sodium." Our body regulates sodium levels by balancing water in the body with use of antidiuretic hormone. DDAVP is often prescribed for patients with Wolfram syndrome because they tend to produce less antidiuretic hormone and produce excess amount of urine. DDAVP is a synthetic antidiuretic hormone, regulates the body's retention of water, and decreases the volume of urine. The challenge for Wolfram patients is that they tend to have bladder problems and may need to go to bathroom often. This is not because of the excess production of urine, but they may increase the dose of DDAVP, which increases the body's retention of water and may lead to low sodium levels. As our colleague Dr. Marshall recommends, Wolfram patients should consult with their endocrinologists if they feel their serum sodium levels are low.

In addition, serum sodium levels may not be reliable when patients have poor renal functions or have severe hyperglycemia.

A cure for Wolfram syndrome could lead to a cure for diabetes Part 1

Why did you start studying Wolfram syndrome? Do you believe that a cure for Wolfram syndrome could lead to a cure for diabetes?

I believe that a cure for Wolfram syndrome could lead to a cure for diabetes. That's the reason I started working on Wolfram syndrome 12 years ago although many people thought I was crazy. I was finishing my fellowship under the supervision of a prominent physician and scientist, Dr. David Ron, MD. He was from a Jewish family, trained at Harvard, and incredibly smart and practical. He was also a very good teacher. I learned a lot from him and I was getting multiple fabulous offers as a promising academic doctor. However, I came up with an idea that Wolfram syndrome is an accelerated form of diabetes and really wanted to prove it as a scientist. I learned more about Wolfram syndrome and wanted to help Wolfram patients as a doctor. So I looked for an institution which allowed me to study an orphan disease, Wolfram syndrome. This was not so easy because most of them were interested in common diseases such as cancer and type 1 diabetes.

In 2012, I got an offer from a new research institute at the University of Massachusetts Medical School, which I did not know very well, but I decided to accept it. In retrospect, I made a right decision. I met with wonderful colleagues there, Kathryn Lipson, Karen Sargent, Sonya Fonseca, Jenny Allen, and Dr. Mariko Fukuma, PhD. I also met my mentor, Dr. Aldo Rossini, MD. In 2013, my team made an important discovery indicating that Wolfram syndrome is an accelerated form of diabetes, and is caused by endoplasmic reticulum dysfunction. Around the same time, I met with Dr. Alan Permutt, MD, who was Professor at Washington University and a pioneer of Wolfram syndrome research. My meeting with Dr. Permutt in Saint Louis in 2013 really changed my career and led to the discovery of the mechanisms of Wolfram syndrome. I will talk about this more tomorrow.

Is there a Wolfram doctor in my town?

One of the questions I often get is, "Is there a doctor who sees a patient with Wolfram syndrome in my town?" Based on my experience, there is usually one or two doctors who have experience in Wolfram syndrome in major hospitals in the US. I know a few medical centers that have more than 10 patients with Wolfram syndrome. I feel that it would be important to make a list of doctors and put it on our website. As usual, I welcome any feedback from you. I get more than 100 emails from patients with Wolfram and type 1 diabetes every week. I always learn something from each email.

Patient-based therapeutics part 10: Molecular Surgery 1

We have three major strategies for developing novel treatments and providing a cure for Wolfram syndrome. These are:

1. Develop drugs that can stop or delay the progression of declining brain and eye functions, and diabetes.
2. Develop drugs that can restore the function of damaged brain cells and pancreatic beta cells.
3. Replace damaged tissues using induced pluripotent stem cells (iPS cells) derived from skin cells of Wolfram syndrome patients.

We will focus on the third strategy today. This strategy has one major challenge. Even if we can successfully make high-quality eye cells and brain cells from iPS cells of Wolfram syndrome patients, these cells may be still susceptible to cell death because of the mutations in the WFS1 gene. To overcome this challenge, we are conducting "molecular surgeries" in these cells.

Using an engineered enzyme and artificial DNA, we are replacing a "disease-causing DNA sequence" with a "healthy DNA sequence." We have designed a sequence of procedures and are moving forward step by step. We designed four artificial DNA sequences so far and could confirm that all of these properly worked in a test tube last week! So we will move on to the next step. I will keep you updated about our progress. I was excited by our progress last week, and appreciated my team's efforts.

Happy Mother's Day to All Mothers!

Patient-based therapeutics part 9 - Making eye cells 2

As I mentioned in my previous blog, one of our new important projects is to make eyes cells from iPS cells of our patients with Wolfram syndrome. These iPS cells are originally generated from skin cells of our patients.

http://wolframsyndrome.blogspot.com/2014/03/patient-based-therapeutics-part-7.html

We have prepared necessary reagents and cells, and the differentiation process is ongoing (i.e., we are converting iPS cells from patients to eye cells). In several weeks, we will get the first results. These cells will be used for understanding the mechanisms of optic nerve dysfunction in Wolfram and testing the efficacy of candidate eye drugs. In the future, these cells could be used for replacing damaged eye cells.

I plan to keep you updated about our progress regularly.

Raise Awareness of Wolfram syndrome

It has been already 12 years since I started working on Wolfram syndrome. When I started working on this disorder, even physicians and diabetes investigators did not know about this disease. This has dramatically changed in the past few years, and I get more than 100 emails every week from Wolfram syndrome patients, their families, type 1 diabetes patients, and physicians. I have to thank patient organizations, including the Jack and JT Snow Scientific Research Foundation, the Ellie White Foundation, and the Team Alejandro, for their efforts on raising awareness.

I will keep on working hard to develop a novel treatment and a cure for Wolfram, and raise awareness of the disease.