We have joined the Global Rare Disease Registry Program of NIH/NCATS

I have some good news to share with you. We have just joined the Global Rare Disease Registry Program of the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS). Dr. Austin, Director of NCATS, and Dr. McInnes, Director of the Office of Rare Disease Research, helped me to make this happen. Dr. Yaffa Rubinstein who is leading this program is a wonderful person. I will work with Dr. Rubinstein to make this program successful. If you know anyone who has an abnormal form of type 1 diabetes, please ask him/her to contact me. http://wolframsyndrome.dom.wustl.edu/

I started our Wolfram syndrome International Registry with late Dr. Alan Permutt in 2009 when I was a faculty member at the University of Massachusetts Medical School. I presented my idea at the executive committee meeting of the diabetes center. Dr. David Harlan and other committee members offered help and the registry was established at Washington University. It was 6 years ago, and I did not expect that I would take over the registry then.

The registry led to the creation of the research clinic. I hope we can expand our clinic and create the consultation clinic. I hope we can create the Wolfram clinics all over the world. The Snow Foundation and our medical center have been supportive. I will keep on moving forward. The clinics help patients. To save patients, we need novel treatments. I will keep on moving forward.

I feel so grateful today. To achieve a cure for Wolfram is challenging. We need to recruit the smartest investigators and raise funds to make this happen.

Looking forward with fingers crossed,

Fumi Urano, MD, PhD

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Drug development for Wolfram syndrome with NIH, NCATS

My visit to NIH, NCATS, with Stephanie Snow Gebel, Chairman of the Board of the Snow Foundation, was quite successful. We have had multiple discussions in the past two weeks and agreed to develop novel chemical compounds (i.e., drugs) for Wolfram syndrome. We will target the endoplasmic reticulum. This will be a three-way collaboration with NCATS, Snow Foundation, and my Wolfram research team at Washington University. We are very excited by this because NCATS has a strong drug development team. They said that their mission is to develop novel treatments for rare and neglected diseases. I appreciate this opportunity, and grateful for all the people who made this possible, including Dr. Francis Collins, NIH Director, and Dr. Christopher Austin, NCATS Director. The drug development team at NCAST is so strong. I look forward to working with Dr. Ajit Jadhav, Dr. David Maloney, and Dr. Anton Simeonov. This is wonderful news to the Wolfram syndrome community. Thank you, Thank you, Thank you.

With gratitude,

Fumi Urano

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Tomorrow is already a day late

My major focus is to develop treatments and provide a cure for Wolfram syndrome. Because Wolfram is a prototype of ER stress-related disease, I am running projects related to other ER stress-related diseases, Type 1 diabetes and ALS, on the side because I can learn new things and come up with new ideas. I often watch the website created by Mr. Hiro Fujita who is a patient with ALS. I agree with him. We should to everything we can do to speed up the process for developing treatments for rare diseases including ALS and Wolfram syndrome. Tomorrow is already a day late. Instead of worrying about who is going to take responsibilities or intellectual property rights, we should develop novel treatments and bring these to our patients as soon as possible.

http://end-als.com/#movie

Thank you for your continued support.

Take care,

Fumi Urano

Clock face showing time past midnight on white background

Renovation of an old drug

One of the exciting things that were offered during our visit to NIH, NCATS, was to renovate old drugs and make them more specific for Wolfram syndrome and other endoplasmic reticulum-related diseases. We have identified three FDA-approved drugs that can potentially delay the progression of Wolfram syndrome. These drugs were originally designed and indicated for other disorders. We are certainly interested in using one of these drugs for our interventional study after we determine the dose of the drug using our animal models and cell models of Wolfram syndrome. In parallel, they recommend that we modify the structures of these old drugs and make them more suitable for Wolfram syndrome. Their medicinal chemists have the ability to do this. This is a “renovation” of an old drug. I look forward to this exciting collaboration. Thank you, Thank you, Thank you.

Thank you for your continued support. I am quite hopeful.

Kindest regards,

Fumi Urano

renovation in progress

Our visit to NIH was fruitful

Stephanie Snow Gebel, the founder of the Snow Foundation, and I visited NIH, National Center for Advancing Translational Sciences, yesterday. Our visit to NIH was quite fruitful. I learned a lot about the NIH’s efforts on developing novel treatments for rare diseases. I met with Dr. Christopher Austin’s team and discussed our potential collaboration on Wolfram syndrome and related disorders. We will further discuss our collaboration on April 17th. They have a very strong drug development team. If we can develop a new drug targeting the endoplasmic reticulum specifically designed for Wolfram, this may lead to a novel treatment for diabetes. I am excited by this opportunity. Please stay tuned!

Thank you for your continued support and encouragement.

Take care,

Fumi Urano

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Brain Functions and Medication

Patients with Wolfram syndrome face multiple challenges in addition to diabetes. That’s why I always feel that Wolfram is the most difficult form of diabetes.

Photo of Dr. Fumihiko Urano

Dr. Fumihiko Urano

Mood swings, anxiety, and depression are commonly seen. Although the molecular mechanisms underlying these symptoms are not clear, we assume that these are related to the dysregulation of neurotransmitter secretion. Endoplasmic reticulum is involved in the maturation and secretion of secreted factors in the brain cells, and Wolfram protein is localized to the endoplasmic reticulum and secretory granules.

Because Wolfram is diabetes with brain cell dysfunction, our candidate drugs should pass the blood-brain barrier. Many drugs cannot reach the brain because blood vessels in the brain have a special structure called the blood-brain barrier. I always make sure that our candidate drugs pass the blood-brain barrier and reach brain cells.
Thank you for reading this. I would like to send kind thoughts toward you. I would like you to stay optimistic. Thank you again.
Take care,
Fumi Urano

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Stem cell-based therapy Q & A – Medical Use

Here are two other questions I often get.

Q: How can we use stem cells for the treatment of Wolfram syndrome and Type 1 diabetes.

Image of iPS cellsA: Stem cells can differentiate into specific cell types including insulin-producing cells, retinal cells, and brain cells.  The most important function of stem cells, especially induced pluripotent stem cells (iPS cells), is their potential use as “cell-based therapies.” iPS cells are a type of stem cells derived from patients’ own skin cells and could be used to repair damaged tissues. For patients with Type 1 diabetes, iPS cells could be prompted to differentiate into insulin-producing cells and transplanted into the body. The body wouldn’t reject these new cells as they would with donated cells or tissues from other individuals (called immune rejection). For patients with Wolfram syndrome, iPS cells could be stimulated to differentiate into insulin-producing cells, eye cells, and brain cells and transplanted into the body. Insulin-producing cells could be transplanted under the skin. We need to find the best way to transplant eye cells and brain cells, and the research is ongoing to figure this out.

Q: iPS cell-derived insulin-producing cells may be attacked again by autoimmune cells in Type 1 diabetes. iPS cell-derived insulin-producing cells and eye cells may degenerate again in Wolfram syndrome. What is the solution?

A: This is a very important question. Before we transplant iPS cell-derived cells, we need to modify disease-causing gene structure in Type 1 diabetes and Wolfram syndrome. In Type 1 diabetes, we probably need to modify insulin gene structure. In Wolfram syndrome, we need to modify Wolfram gene structure. This can be accomplished by genome editing. The genome editing technology is a new type of gene therapy. Using an enzyme and artificially designed guide RNA, we can modify gene structure. We are actively working on this.

Thank you for reading this blog.

Wolfram Syndrome Q&A

I receive many questions related to Wolfram syndrome and other medical conditions. Here are some of them. Please feel free to contact me if you have any questions.

Photo of Dr. Fumihiko Urano

Dr. Fumihiko Urano

Q: What is diabetes insipidus?

A: Diabetes insipidus is one of the common symptoms in patients with Wolfram syndrome. It is defined as the passage of large volumes of dilute urine. It has the 2 major forms, and patients with Wolfram have the central diabetes insipidus.

1. Central (neurogenic, pituitary, or neurohypophyseal): characterized by decreased secretion of antidiuretic hormone called vasopressin.

2. Nephrogenic: characterized by decreased ability to concentrate urine because of resistance to vasopressin action in the kidney.

Q: What is optic atrophy? Is it different from retinopathy? Is there any treatment?

A: The mechanisms of vision impairment in Wolfram syndrome and type 1 diabetes are different. In short, the vision impairment in type 1 diabetes is a problem in small blood vessels supplying nutrition to the eyes. It is caused by high blood sugar levels and called retinopathy.

The vision impairment in Wolfram syndrome is a problem in neuronal cells in the eyes transferring the electrical signal produced in the eye to the brain. It is caused by neuronal cell death and called optic atrophy.

There is currently no treatment for optic atrophy. One of the major neuronal cells in the eyes declining in Wolfram syndrome are “retinal ganglion cells” which transmit electrical signals to the brain. If we can make these cells and transplant them to Wolfram patients, we can possibly treat blindness or improve eyesight. To accomplish this, we need a source for new retinal ganglion cells. I believe that induced pluripotent stem cells (iPSCs) is the source for the new retinal ganglion cells.

Q: “Is there any relationship between diabetes and optic nerve atrophy?”

A: This question implies a few different things. Here are my answers.

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).

Q: What can you do to improve “neurogenic bladder”?

A: Many patients with Wolfram syndrome experience neurogenic bladder. I always recommend that a patient consult with a urologist if he/she has a problem in urination. Here are my thoughts.

1. What is neurogenic bladder?

Our urination is regulated by two types of muscles in the bladder. These are the detrusor muscle and sphincter muscle. When we urinate, the detrusor muscle pushes out the urine and the sphincter muscle relaxes to open up the way out. These muscles are controlled by a part of the brain and neuronal cells connected to the bladder. Neurogenic bladder is a term applied to dysfunction of the bladder due to dysfunction of a part of brain and neuronal cells. In short, this is a problem in neuronal cells.

2. What can you do?

I always recommend that a patient see a urologist to determine the status of neurogenic bladder and get advice.

3. Our progress

As I mentioned in my previous blog, our recent progress strongly suggests that neuronal cell dysfunction in Wolfram syndrome is caused by dysregulation of cellular calcium homeostasis. We are developing a treatment to manipulate the calcium homeostasis in patients’ cells using a drug, and making significant progress. I hope that my strategy will work out.

Q: What are electrolytes and sodium?

A: 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.

END WOLFRAM, END DIABETES, END ALS

I was watching the video that our friend and patient, Alejandro, was doing an ice bucket challenge.

Photo of Dr. Fumihiko Urano

Dr. Fumihiko Urano

This project originally started for ALS. So I was checking the ALS-related websites and found the following youtube video. As most of you know, ALS (amyotrophic lateral sclerosis) is a neurodegenerative disease, leading to the progressive degeneration of the motor neurons. As a result, patients with ALS may become totally paralyzed.

In these video series, many friends of Mr. Hiro Fujita, who has lost his voice due to ALS, read his messages. The project is called “END ALS.” He was in the advertising business. So many celebrities read his messages. One of his messages was toward his mother. I would probably say the same word. There is an English caption in each video. He said, “Mom, Thank you.”

He has a website, END ALS. He often uses the word, “HOPE.” What do we need to help our patients suffering from life-threatening diseases? How can we create HOPE? Let’s think about the basics.

1. Make correct diagnosis and refer them to the best specialists.

2. Develop therapeutics to stop the progression.

3. Replace damaged tissues.

These three should happen simultaneously. We need all of these. I want to END WOLFRAM, END DIABETES, END ALS, and…

I hope you will have a wonderful day. Thank you for reading this blog. Thank you for your supports. Thank you, thank you, thank you.

Thank you again, and Regenerate to Beat Degeneration.

Posted: 01 Sep 2014 05:53 AM PDT

I was surprised and glad to see that our patient and friend, Alejandro, was doing an ice bucket challenge for Wolfram syndrome. Thank you again, Ale and the team Alejandro!

I often get questions about “regenerative medicine.” I really like the following video created by the Mayo Clinic. “Regenerate” is the opposite of “degenerate.” Because Wolfram syndrome is a degenerative disease, the best way to counteract is to “regenerate” damaged tissues.

http://www.mayo.edu/research/faculty/nelson-timothy-j-m-d-ph-d/bio-00027362

I hope you will have a wonderful Labor day today.

Dr. Freireich said, “You swear to give people hope.”

Today I would like to begin by thanking everyone who has been reading my blogs.

I checked the statistics function of my blogs yesterday and found something unexpected. Several thousand people read my blogs every week! Why? I don’t know, but I was so moved and surprised. I am so glad that many people are interested in Wolfram syndrome and Type 1 Diabetes. Thank you so much. I feel grateful.

I was reading Malcolm Gladwell’s book, David and Goliath. This book describes “Underdogs, Misfits, and the Art of Battling Giants.” I am an underdog and battling giants, Wolfram syndrome and Type 1 Diabetes. So I really enjoyed reading this book. I was struck by a story of Dr. Emil “Jay” Freireich. He was an immigrant doctor and absolutely an underdog. He said, “As a doctor, you have to figure out a way to help them, because people must have hope to live. You swear to give people hope. That’s your job.” Dr. Freireich discovered a novel treatment for acute leukemia and saved many people’s lives. He received Albert Lasker Medical Research Award in 1972.