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

Saturday, March 29, 2014

Meeting with Spanish Patients with Wolfram syndrome, a physician and a researcher

This morning, I had a chance to meet with patients with Wolfram syndrome and their doctors in Spain through the Skype. I had a chance to explain our progress towards the treatment and cure for Wolfram syndrome. We all know that it is not a simple endeavor, but we all have the same goal. It is always my pleasure and privilege to meet with and serve for patients with Wolfram syndrome and their families. Thank you for your patience and encouragement. Take care and have a nice weekend.

Sunday, March 23, 2014

Important Development and Collaborations

I believe we should have three components for the treatment of Wolfram syndrome.

1. Delay the progression of the disease with existing FDA-approved drugs.
This is our current major focus, and we have a rising candidate. We are looking for a simple way to assess the efficacy of this drug in patients and are trying to collect blood samples from patients and their siblings. In parallel, we are also looking for a new group of drugs that can delay the progression of the disease with a company. All of these drugs seem to be related to cellular calcium homeostasis.

2. Enhance the viability of eye cells, brain cells, and pancreatic beta cells.
In Wolfram syndrome, brain cells, eye cells, and beta cells in the pancreas are sensitive to cell stress and susceptible to cell death due to the mutations in the WFS1 gene. We are developing a method to make brain cells, eye cells, and pancreatic beta cells, more resistant to cell stress. We have identified an interesting hormone-like molecule produced in our body called MANF.  MANF can make our cells more resistant to cell stress-mediated cell death. We are trying to establish a collaboration with a pharmaceutical company to develop a drug based on our findings.

3. Replace damaged tissues using patients' skin cells.
As I mentioned in my previous blogs, we have created induced pluripotent stem cells (iPS cells) using skin cells from patients. We are creating brain cells and eye cells using these iPS cells. These cells have been useful to dissect out the mechanisms of the disease and test the efficacy of candidate drugs. We are also replacing a pathogenic WFS1 gene part with a healthy WFS1 gene part in these cells. In the future, we will use these cells for replacing damaged tissues.

Sunday, March 16, 2014

Wolfram: Oxidative Stress and Endoplasmic Reticulum

Is antioxidant good for Wolfram syndrome? Although we don't have clear scientific evidence at this point, it is possible that antioxidants could be beneficial for Wolfram syndrome patients.

Accumulating evidence in my research group strongly suggests that endoplasmic reticulum (ER) dysfunction can lead to oxidative stress. Oxidative stress means that reactive oxygen species (ROS) exceeds the ability of our body to counteract their harmful effects. Our body has the ability to deal with certain amount of ROS, but if there is too much ROS, it leads to oxidative stress.  In theory, antioxidants should be able to mitigate ER stress-mediated oxidative stress and its harmful effects. We are particularly interested in this concept in the context of optic nerve atrophy and neurodegeneration in Wolfram.

We still don't have clear evidence that antioxidants are beneficial for Wolfram syndrome patients. So I recommend that you consult with your physician if you are interested in taking antioxidants.

Sunday, March 9, 2014

Patient-based therapeutics part 7- Making eye cells

I am on my way to Japan to establish a collaboration with a major Japanese medical center on our Wolfram syndrome project. Why Japan? The reason is very simple. They have a technology to make eye cells from patient-derived induced pluripotent stem cells (iPS cells). If my research group can constantly make eye cells from Wolfram syndrome iPS cells, we can understand the mechanisms of optic atrophy in Wolfram syndrome and test the efficacy of our candidate drugs using these eye cells. This is also another opportunity to raise awareness of Wolfram syndrome.

As I repeatedly mentioned in my previous blogs, Wolfram is a weapon to combat diabetes and blindness. I believe that Wolfram is an accelerated form of diabetes and blindness. Many of us will experience beta cell death and death of eye cells later in our lives. A drug that can delay the progression of Wolfram may be helpful for us when we get old.

Saturday, March 8, 2014

What can you do to improve "neurogenic bladder" ?

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 is 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.

Sunday, March 2, 2014

Mr. John Crowley who saved his children's lives

Mr. John Crowley is a remarkable man. He is a father of two children with Pompe's disease, a rare and terminal neuromuscular disorder, and a biotechnology executive and entrepreneur. There was no treatment for Pompe's disease when his children were diagnosed with Pompe's disease. Instead of being depressed and crying, Mr. Crowley looked for a scientist who could potentially develop a drug for Pompe'e disease, established a biotech with him, created a drug, and saved his children's lives. Because his children were treated at the later stage of the disease, they are still suffering from complications of the disease, but they are alive. Now he is looking for a better treatment to save his children and other patients with Pompe's disease.

His partner, Dr. William Canfield, MD, PhD, was trained at Washington University Medical Center together with my colleague in the Department of Medicine. The story of Mr. Crowley and Dr. Canfield got the attention of Harrison Ford, and he created a film, Extraordinary Measures. Harrison Ford played a role of Dr. Canfield and Brendan Fraser played a role of Mr. Crowley. We can read their story in a book, The Cure. This book was written by a Pulitzer Prize-winning journalist Geeta Anand. I was inspired and encouraged by their story a few years ago, and still read this book from time to time.

Mr. John Crowley said, "I just didn’t want to get years or decades down the road and regret not having done something. I wanted to know, for our peace of mind and the peace of mind of everybody who loved the kids, that – even if things turned out badly – we had done everything we could, everything humanly possible. I just did what I thought I had to do." He is an extraordinary man, and I met many people like Mr. Crowley in the past ten years through my quest to find a treatment for Wolfram syndrome.


Saturday, March 1, 2014

Patient-based therapeutics part 6 - Wolfram syndrome iPSCs progress

I received many emails regarding our progress on Wolfram syndrome induced pluripotent stem cells (iPS cells) in the past two weeks. I would like to update you on a few things. As I mentioned in my previous blogs, we have created many iPS cells from skin cells of patients with Wolfram syndrome. These iPS cells can differentiate into various types of cells including brain cells and pancreatic beta cells that are damaged in patients with Wolfram syndrome

1. Disease modeling 
We could successfully differentiate these iPS cells into neural progenitor cells. These are immature brain cells. We found that neural progenitor cells from patients are not completely damaged, which was surprising, but good news to us. Instead, they have altered calcium homeostasis. My impression right now is that cells from patients with Wolfram syndrome are "sensitive" to environmental stress, especially stimulus that changes cellular calcium levels. So we are looking for drugs that can modulate calcium homeostasis in cells to develop a treatment for Wolfram syndrome.

2. Testing drugs
As I mentioned above, we are focusing on drugs that can modulate calcium homeostasis in cells, especially endoplasmic reticulum calcium levels, to develop a treatment. Three drugs out of five candidate drugs that we have identified so far can control endoplasmic reticulum calcium levels. We are testing these three drugs using iPS cells.

3. Correcting a mutation
Using a special enzyme and artificial DNA, we are replacing an abnormal segment of Wolfram gene with a normal segment of Wolfram gene in patient-derived iPS cells. In theory, we should be able to correct altered calcium homeostasis through this process.

4. Making eye cells
A group in Columbia University Medical Center in New York could successfully make pancreatic beta cells from Wolfram syndrome iPS cells. We are collaborating with this group. So we are focusing our own efforts on making eye cells from Wolfram syndrome iPS cells. This is a collaboration project with a group in a major medical center in Japan. They have a special "recipe" for making eye cells. Because a clinical trial using this technology for an eye disease will start in a few weeks in Japan, I feel that this collaboration is so important for us. A physician and scientist who is working on this collaboration project will come to the US and work with us in a few months. The arrangement has been made, and the Japanese agency will partially support this effort.
You may be interested in a clinical study using iPS cells for an eye disease. Here is some info.