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.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2015-04-10 01:21:472020-09-07 20:10:34Renovation of an old drug
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.
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.
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.
Q: How can we use stem cells for the treatment of Wolfram syndrome and Type 1 diabetes.
A: 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.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-10-27 13:50:452020-09-07 20:10:36Stem cell-based therapy Q & A – Medical Use
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.
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.
I was watching the video that our friend and patient, Alejandro, was doing an ice bucket challenge.
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://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-09-01 22:18:212020-09-07 20:10:36END WOLFRAM, END DIABETES, END ALS
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.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-08-08 19:00:132020-09-07 20:10:38Dr. Freireich said, “You swear to give people hope.”
We have created many induced pluripotent stem cells (iPS cells) from skin cells of Wolfram syndrome patients.
Because these cells can be differentiated into any types of cells, including brain cells, eye cells, and insulin-producing pancreatic cells, we can use these cells to replace damaged tissues in our patients in the future.
In addition to this, there is another advantage in making iPS cells. We can use these cells now. We can test the efficacy of different candidate drugs using brain cells and eye cells differentiated from iPS cells. It seems like that patients’ cells respond to different treatments based on their genetic make-up. So these cells are useful for designing personalized medicine for the treatments of Wolfram syndrome. This would apply to any other diseases. Thank you again for donating your cells. I would like to expand this program and make iPS cells from all the patients with Wolfram syndrome in the world.
I think about this topic every day. I firmly believe that our future clinic for Wolfram syndrome and other ER stress disorders should provide “Personalized Medicine.” This 2 min-video explains about the personalized medicine very well.
Why? As I mentioned before, each patient is different, and should be treated differently. The key is to obtain complete family history and genetic information from each patient. Exome sequencing and genome sequencing should be integrated into our clinic to design the best treatment for each patient.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Dr. Fumihiko Uranohttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgDr. Fumihiko Urano2014-08-06 19:12:232020-09-07 20:10:38A platform for providing the best treatment for patients with ER Disease: Personalized Medicine
I have read many articles related to Wolfram syndrome.
The most-read article is entitled “Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome” describing the natural history of Wolfram syndrome. This article was written by Timothy Barrett, MB, BS (MD), PhD in 1995. http://www.ncbi.nlm.nih.gov/pubmed/7490992 I read this paper over and over when I started working on Wolfram syndrome in 2002. I recommend that all the researchers in diabetes, neurodegeneration, and genetic diseases, read this article.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2014-08-05 19:59:172020-09-07 20:10:38The article I read over and over
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