2015 Wolfram Research Clinic Update

Three Drug Targets. What is the difference?

We have identified three drug targets for Wolfram syndrome in the past two years. These are MANF, Calpain 2, and IRE1. What is the difference between these three molecules. Here is a short summary.

MANF: Enhances survival and proliferation of remaining cells.
Caplain 2: Activates cells death signal in Wolfram and Diabetes. So we need an inhibitor.
IRE1: Prevents the activation of cell death signals.
IRE1 and Calpain 2 are enzymes. So we need drugs that can control their activation levels.

MAFN is a secreted molecule. We can potentially use an artificial MANF (i.e., recombinant MANF) for treatment. Another pathway is to identify a receptor for MANF and develop a drug that can activate the MANF receptor.

Thank you for reading my blog. I always appreciate your encouragement. I think about our patients every day.

Take care,

Fumi Urano

Business man under the question mark

Business man under the question mark

The “Mini-Clinic”: News from the Wolfram Research Clinic at Washington University

imgresLast summer, we had a successful research clinic, with 24 patients and their families attending from all over the world and the US. We welcomed three new patients to our group this year and in a whirlwind 4 days, we performed 22 MRI scans and over 350 individual appointments!

Since then, we have identified additional patients that are good candidates for this study or who are interested in a clinical consultation (or both). Rather than waiting until next summer to collect the research data, we have started to bring these families in to WU one at a time. We call this a ‘mini-clinic’. Each patient undergoes the same tests with our usual wolfram research clinic doctors and investigators, staying overnight in St. Louis. So far, we have done this with 2 families, and 2 more are being scheduled. The mini-clinic has been working quite well and is a nice option for families that can’t or don’t want to travel to St. Louis in July. It also helps us get more data at a quicker pace, which is in the best interests of everyone.

We have also seen four new patients for clinical consultations and for diagnosis of Wolfram.   We are always happy to consult with patients or their physicians about whether they might have Wolfram and how to obtain testing. We can also arrange for them to have care by any of our team who has experience with Wolfram.

Thank you to all of the families for participating in all of our research, and to all of our colleagues and staff who help make the big research clinic and our new mini-clinics happen so smoothly.

Tamara Hershey, Ph.D.
Professor
Psychiatry, Neurology and Radiology
Washington University School of Medicine
Scientific Director of Clinic and PI, NIH R01 “Tracking Neurodegeneration in Early Wolfram Syndrome”

Bess Marshall, M.D.
Professor
Pediatrics
Washington University School of Medicine
Medical Director of Clinic

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.

2014 Wolfram Research Clinic Update

Participants of the 2014 Wolfram Clinic

Participants of the 2014 Wolfram Clinic

Updates from the 2014 Wolfram Research Clinic at Washington University

We had an exceptionally successful research clinic this year, with 24 patients and their families attending from all over the world and the US. We welcomed three new patients to our group this year and in a whirlwind 4 days, we performed 22 MRI scans and over 350 individual appointments!

We now have patients who have been seen up to 5 years in a row, providing an incredibly important view of the pattern of changes in symptoms that patients experience.

These data are now being analyzed so that we can determine the natural history of neurological changes in Wolfram Syndrome. We believe that neurological symptoms need to be targets of intervention and that we must have reliable markers of change that relate to meaningful outcome.  These are critical steps before any clinical trial can be initiated.

So far, our data indicate that there are very common, early neurologic features in Wolfram Syndrome, including reduced retinal thickness, color vision, smell identification, gait and balance and size and integrity of specific brain structures. Furthermore, we have early indications that some of these measures do not change reliably over a year’s time, whereas others may be more likely to change in a specific manner. This information could thus guide us in selecting the measures to monitor in any future clinical trial.

We hope to continue to collect data on our existing group of families, and add new families as we are able to get to these important answers more quickly and reliably.

Thank you to all of the families for participating, and to all of our colleagues and staff who helped make this unique and complicated clinic happen so smoothly.

Tamara Hershey, Ph.D.
Professor
Psychiatry, Neurology and Radiology
Washington University School of Medicine
Scientific Director of Clinic and
Principle Investigator, NIH R01 “Tracking Neurodegeneration in Early Wolfram Syndrome”

Bess Marshall, M.D.
Associate Professor
Pediatrics
Washington University School of Medicine
Medical Director of Clinic

Dr. Fumihiko Urano gave a presentation at the clinic on “A Cure for Wolfram Syndrome – 3 Steps”.  Click the link below to view the presentation.

2014 Wolfram Clinic Update

 

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iPS cells and Personalized Medicine

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.

The article I read over and over

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. 

Regenerative Therapy and Modern Medical Genetics

I think a lot about a new platform for endoplasmic reticulum disease and other rare diseases.

The new clinic requires new expertise in addition to conventional neurology, ophthalmology, and endocrinology. I feel that regenerative therapy and modern medical genetics based on high-throughput sequencing are the key players.

I found an interesting video describing regenerative medicine.
https://www.youtube.com/watch?v=v-Q2kghHwq4

I hope you will have the best week in your life.

Developing novel therapeutics to stop the progression of eye diseases

Some people say that it is not realistic to develop a novel therapy to stop the progression of eye manifestations in Wolfram syndrome. I don’t agree.

It is possible. If we can modulate ER stress in retinal cells, we can slow or stop the progression of optic nerve atrophy in Wolfram syndrome. I have found a biotech company in Seattle that is developing novel therapeutics for “sight-threatening” eye diseases. If they can do it, we can do it.  http://acucela.com/About-Us

A tablet for eye diseases?

The biotech I mentioned above is taking a very interesting strategy. They are trying to use a tablet (i.e., a pill) for delaying the progression of eye diseases.
https://clinicaltrials.gov/ct2/show/NCT02130531?term=acucela&rank=1

I was envisioning that I would use ophthalmic suspensions (eye drops) or intravitreal injections (injection into eyes) for stopping eye manifestations in Wolfram syndrome, but we should also think about using pills.

 

Endoplasmic Reticulum Disease Clinic 2: First Step

By Dr. Fumihiko Urano

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.