The Heroes of Wolfram Syndrome

I receive around 200 emails from patients with Wolfram syndrome and Type 1 diabetes every week. They ask me questions, and they share their stories with me. I can keep on going because of them. Please read the stories of patients with Wolfram syndrome, and help us spread the word. It is my privilege to serve for patients with Wolfram syndrome.
http://thesnowfoundation.org/our-story/the-heroes-of-wolfram-syndrome/

Endoplasmic Reticulum Disease Clinic 4: Personalized Medicine again

One of my goals is to practice "Personalized Medicine" in our clinic because each patient is different. The power of genetic medicine should be fully utilized. I believe that whole genome sequencing and exome sequencing are useful for making an accurate diagnosis. The information we get from patient's DNA can be utilized to choose the best specialists for each patient and design a regenerative therapy or gene therapy. I will talk about this more.

I feel that something wonderful is going to happen to you today!

The Last Advice from late Dr. Alan Permutt

I talked about medicine and DNA too much in the past several days. So let's take a break and talk about Dr. Permutt.

As many of you know, I took over Dr. Alan Permutt's research program on Wolfram syndrome two years ago. I believe that it was controversial that a young foreign physician would take over Dr. Permutt's position. As I mentioned in my previous blogs, I was leaving research when Dr. Permutt asked me to come to Washington University. So I talked with him many, many times before I made a decision. He assured me that other Washington University doctors, including Dr. Semenkovich, Dr. Fraser, Dr. Hershey, Dr. Marshall, Dr. White and others, would help me. He also told me that the Snow Foundation would support me. What he told me was all true. All the doctors have been supportive and helping me a lot, which I always appreciate. The support from the Snow foundation is enormous. I always feel that our higher power lets us work together.

The last advice from Dr. Permutt was the following.
"Fumi, All of my colleagues will help you. Just trust them. You will take us to the next level, and all of your new colleagues will help you."

I see a big smile in your face! I hope you will have the best day in your life. I am sending kind thoughts towards you!

Endoplasmic Reticulum Disease Clinic 3: Personalized Medicine

I received many questions about yesterday's blog describing the clinical application of a new DNA sequence technology.
http://wolframsyndrome.blogspot.com/2014/07/endoplasmic-reticulum-disease-clinic-2.html
So I would like to clarify a few things.

1. Cost
There is a lot of discussion about the cost. Will our health insurance cover this? I believe that it will be covered in the near future. To sequence all the genes in each patient is equivalent to taking the perfect past medical history and family history. So there is a tremendous value in doing this.

2. Personalized Medicine
It is critical to sequence all the genes in each patient for designing a treatment strategy. Each patient is different, and we should design a personalized treatment plan for each patient. I am designing a few treatments for Wolfram syndrome patients. One of the treatments that I have designed should work for patients who have WFS1 gene mutations, but not for patients who have WFS2 gene mutations. I have many other examples.

I hope that you will have the best week in your life! Talk to you tomorrow!

Endoplasmic Reticulum Disease Clinic 2: First Step

What is the first step to provide the best care for patients with rare endoplasmic reticulum diseases, including Wolfram syndrome? The answer probably applies to any undiagnosed disease. 

My answer as of today is"exome sequencing." What is exome sequencing? Exome sequencing is a new technology to sequence all the genes in each patient. This is available at our medical center. By looking at all the genes instead of one gene (such as WFS1 gene), we have a better chance to understand what is really going on in each patient. This is also critical for designing "personalized" treatment. As I mentioned before, each patient is different, and should be treated differently. We should look at all the genes, not one.

Stem cell-based therapy using skin cells from patients

I have been thinking a lot about stem cell-based therapy for patients with Wolfram syndrome. We have created many induced pluripotent stem cell lines (iPS cell lines) using skin cells from patients with Wolfram syndrome. In theory, we can create any types of cells using these iPS cells. 

The idea of stem cell-based therapy for diabetes and neurodegenerative diseases is not new anymore, and there are multiple ongoing clinical trials. The key to success for stem cell-based therapy is to establish methods for creating high-quality insulin-producing cells, eye cells, and different types of brain cells. We should keep on working on stem cell-based therapy for Wolfram syndrome.

Endoplasmic Reticulum Disease Clinic 1

Thank you for your feedback for my blog.
http://wolframsyndrome.blogspot.com/2014/07/a-platform-for-providing-immediate-care_24.html
We need to consider multiple factors and logistics for establishing "Endoplasmic Reticulum Disease Clinic." We need space, motivated physicians and nurses, and knowledgeable administrators. To accept out-of-state patients, we need to provide information and discount of hotels nearby. I feel that we can accomplish this.

A platform for providing an immediate care for patients 2

Thank you for your valuable feedback for my yesterday's blog.
http://wolframsyndrome.blogspot.com/2014/07/a-platform-for-providing-immediate-care.html

I feel that we need to create an interdisciplinary clinic where the integration of physicians across disciplines can lead to an improvement in the management of patients with Wolfram and Wolfram-related disorders (diseases related to ER stress). The key is that all the physicians are on the same floor and a patient can see them on the same day. I am working on a blueprint. Let's call it "Endoplasmic Reticulum Disease Clinic".

A platform for providing an immediate care for patients 1

I often think about this topic. What is the best platform for providing an immediate care for a patient with Wolfram and other rare diseases? My idea is to establish a multidisciplinary clinic for Wolfram and related diseases. When an undiagnosed patient comes to a hospital, he/she will see a medical geneticist/internist to get a correct diagnosis, and then a patient is referred to multiple specialists on the same floor. The key is that all the doctors are on the same floor so that a patient does not need to walk around a big medical center. I will keep on thinking about this. I welcome any feedback from you.

Please contact us if you receive a medicine for an "off-label" use

If you are a patient with Wolfram syndrome and have been prescribed a medicine for an "off-label" use, I would appreciate if you contact us (Phone: 314-362-8683, urano@dom.wustl.edu). 
http://wolframsyndrome.dom.wustl.edu/

As I mentioned in my previous blogs, the law let physicians prescribe a FDA-approved drug to treat a condition for which it is not approved. This is called an "off-label" use. Many physicians are compassionate, and try to help their Wolfram patients by prescribing a drug for an "off-label" use. I often get questions from physicians and patients related to an "off-label" use. Although I don't recommend any specific FDA-approved drugs at the moment, I would gladly answer your questions. If you are receiving a drug for an off-label use, we can monitor biomarker levels for you and your physician. I respect your and your physician's decision. So please contact us. I just want to help.

Consultation Clinic 2

As I mentioned in my previous blog, it would be important to establish a consultation clinic for Wolfram at Saint Louis Children's Hospital for pediatric patients and at Barnes-Jewish Hospital for adult patients. We can do this using regular clinic space or set up new space. For the latter, we probably need to include other rare diseases into our platform. There are several advantages for this. My big idea is to set up a platform for regular care for patients with rare diseases.
http://wolframsyndrome.blogspot.com/2014/07/consultation-clinic.html

Three Step Formula to Provide a Cure for Wolfram Syndrome July 20, 2014

I presented my strategy for providing a cure for Wolfram syndrome yesterday. I think there are three steps to achieve this.
1. Stop the progression
2. Protect and Regrow remaining tissues
3. Replace damaged tissues

Our current focus is to "Stop the progression" of the disease. We are testing if FDA-approved drugs currently used for other diseases may be beneficial for Wolfram syndrome patients, and we have four candidates. We are also developing new drugs specifically designed for Wolfram syndrome. 

We plan to use MANF for protecting remaining tissues, especially eye cells. Our final step is to replace damaged tissues using regenerative medicine. I will keep on talking about these.

Wolfram Research Clinic Day 3 and Today

Our annual Wolfram research clinic was done yesterday. It was a big success! We will have a workshop today, and I will present our strategy for providing a cure for Wolfram syndrome. 

Wolfram Research Clinic Day 2: Thank you and Thank you

I always appreciate the efforts of all the medical staff, administrative staff, volunteers, researchers, interpreters, and others who have been involved in the Wolfram syndrome research clinic. It is my privilege to serve for patients with Wolfram syndrome and work with dedicated people who have been involved in our Wolfram syndrome research. My team has been working very hard to develop a novel drug for Wolfram syndrome.

I believe that our patients who are attending this year's clinic are a little tired now. Thank you for your patience. Thank you for your faith in us. We have one more day to go!

Wolfram Research Clinic Day 1: Biomarker???

Wolfram research clinic is ongoing and our patients are going through many tests. At this year's clinic, we are collecting blood samples from not only patients but also their parents and siblings. Why? The reason is we plan to measure "BIOMARKER" levels in these samples.

What is a biomarker? A biomarker is a molecule found in blood or tissues that is a sign of a disease. We found two candidate biomarkers for Wolfram syndrome. The levels of these biomarkers are higher in patients' blood samples than in non-patients' blood samples. These biomarkers can be used to see how patients respond to a treatment.

Here is an example. Blue: Patients, Red: Non-Patients.

Here is another one. 1: Non-Patients, 2: Patients, 3: Patients after a treatment

Wolfram syndrome Research Clinic Day 0

Our annual Wolfram syndrome research clinic will start today, and I met with most of the patients and their families last night. I have been very impressed by them. In this clinic, we don't provide any treatment. We just collect information and samples from patients, their parents and siblings. All of them are so patient and wonderful human beings.

My team has been working very hard to identify the best FDA approved drugs (currently used for other diseases) that could delay the progression of Wolfram syndrome (off-label). In parallel, we are developing new drugs specifically designed for Wolfram syndrome to stop the progression (requires clinical trials). We have made significant progress in the past 12 months and I plan to present my strategy on this coming Saturday.

A small biotech may be ideal for developing a new drug for Wolfram?

I feel that a small biotech may be ideal for developing a new drug for a rare disease like Wolfram syndrome. A small biotech has a narrow focus, which may be suitable for creating a drug targeting a specific pathway and a specific disease. Mr. John Crowley and Dr. William Canfied (trained in Internal Medicine at Washington University) took this strategy and created a novel drug for Pompe Disease. They started a company in 2000, and Mr. Crowley's children with Pompe disease received their drug in 2003. Their small biotech was eventually acquired by Genzyme. 

Medicine is ART. What are our options?

Yesterday, I told you that each patient was different and should be treated differently. Medicine is ART.

http://wolframsyndrome.blogspot.com/2014/07/each-patient-is-different-for-sure.html

What are our options right now? Our current option is: 
Use FDA-approved drugs currently indicated for other diseases to delay the progression of Wolfram syndrome. 

We have identified two diabetes drugs, one neuronal disease drug, and one immunosuppresive drug as candidate drugs for Wolfram. After we complete the preclinical studies for all of these drugs, we need to choose the best one for each patient.

Each patient is different for sure. Medicine is ART.

The more I know of Wolfram syndrome, the more I am convinced that each Wolfram patient is different. My team recently found a molecular pathway altered in Wolfram patients. The altered pathway is the same, and the manifestations are different. How should we treat them? I feel that each patient should be treated differently. We need a patient-based therapy. My mentor, Dr. Aldo Rossini, once said to me, "Medicine is ART." Interestingly, my medical license in Missouri was issued by the Board of HEALING ARTS. Here is the ART created by one of our patients. I feel the same. Take care everyone. I hope you will have the best Sunday in your life.

Patient-based therapeutics 13: Molecular Surgery 2

We have been trying to replace the disease-causing Wolfram gene segment with a "healthy" Wolfram gene segment in iPS cells from patients with Wolfram syndrome.

http://wolframsyndrome.blogspot.com/2014/05/patient-based-therapeutics-part-10.html

Why do we need to do it? Even if we can successfully make high-quality eye cells and brain cells from iPS cells of Wolfram syndrome patients, these cells may degenerate again because of the disease-causing WFS1 segment (called mutations). 

Using an engineered enzyme and artificial DNA, we are replacing the disease-causing segment with the healthy one. We designed artificial DNA, confirmed its efficacy in vitro, and introduced it into patients' iPS cells. It took a few months to do these because this is a new technology. Currently we are checking if the disease-causing segment has been successfully replaced using DNA sequencing. I will keep you updated about our progress.

Have the best weekend of your life!

Patient-based therapeutics 12: Making eye cells 4

We are creating different types of eye cells using iPS cells derived from skin cells of patients with Wolfram syndrome. We plan to use these cells to understand the mechanisms of eye manifestations in Wolfram and test potential drugs. In the future, these cells could be used to replace damaged tissues after the abnormal gene segment is replaced with the normal one.

http://wolframsyndrome.blogspot.com/2014/05/patient-based-therapeutics-part-9.html

Yesterday, we got the first type of eye cells! I got so excited. It took more than two months to do it, and one of my scientists came to the lab every day including holidays and Sundays in the past few months. I really appreciate his efforts and support from others, including the funding support from the Snow Foundation and the Internal Medicine of Washington University Medical Center. Now we can start testing MANF and other drugs. We will make the best use of these cells!

Do we need a new drug?

My answer is yes. Our current focus is to choose the best FDA-approved drugs that can delay the progression of Wolfram so that we can immediately start treating our patients (off-label use). Based on our current results, our candidate FDA-approved drugs are not perfect. Because they are designed for other diseases, these drugs should be improved to suppress the abnormal enzymatic activity in Wolfram patients' cells. So we need to develop new drugs specifically designed for Wolfram. As I mentioned in my previous blogs, new drugs for Wolfram could be effective for other ER stress-related diseases such as type 1 diabetes and potentially ER stress-related eye diseases.

Consultation clinic?

We host a Wolfram syndrome research clinic once a year at the Saint Louis Children's Hospital. I get many questions about this clinic. This is a research clinic and invitation only, and we don't provide any treatment. We perform multiple tests to get information from patients. We have learned a lot from these research clinics, and I always appreciate the efforts of patients and all the medical and administrative staff.

I feel that now we need to start a consultation and follow-up clinic at our Children's Hospital and Barnes-Jewish Hospital so that both pediatric and adult patients can come anytime and we can check their medical records and provide the necessary information to patients. This is probably an important stepping stone to enable us to start treating our patients with a FDA-approved drug.

We also need a platform for our patients to get to know each other and exchange information. As usual, I welcome any feedback from you.

Why are we creating eye cells using skin cells from patients?

Why are we creating eye cells using skin cells from patients? More accurately, we are creating two different types of retinal cells using stem cells derived from skin fibroblasts of patients with Wolfram syndrome. We can immediately use these cells to understand the mechanisms of the disease and test the efficacy of candidate drugs. That's a practical goal and should be achievable.

My audacious goal is to use these cells to replace damaged eye cells in patients. There are many theoretical and practical hurdles to accomplish this, but we should try. Every accomplishment starts with the decision to try.

Just sent out my grant application on Wolfram syndrome

I could successfully send out my grant application on therapeutic development for Wolfram syndrome this weekend. I would like to thank my colleagues, collaborators, and administrators for this. It was a lot of work. I sincerely hope that this will be funded to accelerate our research and start an interventional study as soon as possible. Wish me luck!

Stop the progression of the disease

The first step for providing a cure for Wolfram syndrome or any disease is to stop the progression of the disease. We are taking two strategies that are correlated. Here is my concept, and we are making progress in both areas. How do we test candidate drugs? We are using iPS cells derived from skin cells of our patients.

Passionate eye doctors

We are developing a treatment for optic nerve dysfunction and death in Wolfram syndrome, and creating different types of eye cells from iPS cells derived from patients' skin cells. I feel fortunate that I could find eye doctors who are willing to work closely with my team.

I hope you had a wonderful July 4th!

Inhaled insulin

Inhaled insulin has been approved by the FDA, and I received many questions about "inhaled insulin" this week. I recommend that you consult with your physician about the use of inhaled insulin because each patient is different.

Because it is inhaled, it is quickly absorbed from the cells in the lungs. So its levels increase quickly in the blood. Thus, we probably need less insulin to get the same effects, which may be beneficial for patients. Importantly, we don't need needles.

Time will tell if this is a game changer or not. I always feel that we should keep on trying to make a better drug for patients.

Need to know about genetic testing

Although I believe in the power of genetic testing to make a correct diagnosis and create a treatment plan, I acknowledge that there are limitations to it. Genetic testing gives us important information to understand what's going on in each patient, whereas it does not perfectly predict what will happen to the patient at hand. I feel that genetic testing is a tool to choose an appropriate treatment.
http://wolframsyndrome.dom.wustl.edu/

A Three-Step Formula 2.0 for Providing a Cure for Wolfram Syndrome

Here is my new strategy. We are working on all of these steps in parallel.

Each patient is different

As we have learned more about patients with Wolfram syndrome, we have discovered that each patient is different. Dr. Timothy "Tim" Barrett, a world-famous expert of Wolfram syndrome in England, told me the same thing. So what should we do? I think that we should treat each patient differently. We should have multiple options for Wolfram syndrome. I am moving into this direction, and making progress.