The Snow Foundation

Patient Based Therapeutics – Part 4

Dr. Fumihiko Urano

Patient-Based Therapeutics Part 4 – Drug Screening Progress

Based on the data obtained from our patients, animal models, and cell models of Wolfram syndrome, we found that calcium depletion of the endoplasmic reticulum (ER) plays a role in the pathogenesis of Wolfram syndrome. So we have been looking for drugs that can prevent ER calcium-depletion-mediated cell death. As of today, we have found 4 FDA-approved drugs (currently used for other diseases), one supplement, and a new category of drugs (not approved by the FDA). One of the FDA-approved drugs can prevent ER calcium-depletion and cell death in the tissue culture dish. It seems like that this drug can relieve ER stress in one animal model of Wolfram syndrome. We are working very hard to complete these preclinical studies. The ER calcium-depletion releases a molecule called MANF from the ER to the circulation. So we are carefully monitoring levels of MANF in human blood samples.

So how long will it take to bring one of these drugs to our patients? I would like to share a few thoughts.

1. There is no guarantee that these drugs will work in our patients.
2. It is a little challenging for me to predict exactly how long it will take to bring these drugs to our patients.
3. However, I have a clear plan, and am doing my best to make it happen.

Dr. Fumihiko Urano a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.

March 14, 2014/by Dr. Fumihiko Urano

Research

Wolfram Clinic

In September of 2009 we established the Internet-based International Wolfram Syndrome Registry. As the prevalence is estimated at 1 in 200,000-700,000, the Registry was established to provide a cohort of patients for future studies.

We have extended the clinical arm of this project to acquire longitudinal data on the pattern of disease progression and identify potential biomarkers. The first Wolfram Syndrome Research Clinic was held August 6-7, 2010, supported by contributions from the Department of Medicine, Mallinckrodt Institute of Radiology and St. Louis Children’s Hospital. The Clinic was held primarily in the Pediatric Clinical Research Unit located on the 11th floor at St. Louis Children’s Hospital and has six components. This clinic represents a joint research and clinical activity in collaboration with the Divisions of Adult and Pediatric Endocrinology, Ophthalmology, Pediatric Neurology, Radiology, Psychiatry, and Pediatric Otorhinolaryngology. Monitoring disease progression will serve as the basis for clinical intervention when therapeutic agents become available. The second clinic was held in 2011 and largely supported by the Snow Foundation.

Since 2010, we have hosted a research clinic annually for five consecutive years. Our next research clinic will be held in July 2015. These multidisciplinary clinics have also provided the opportunities to assemble a team of physician scientists with first-hand knowledge of this rare disease who can provide a valuable resource for patients and their families now and in the future. Together with the Snow Foundation, we are currently planning interventional studies as well as patient centered Wolfram syndrome subspecialty clinic.

February 24, 2014/by The Snow Foundation

Research, Social Media Posts

Research Reports From Washington University

Introducing… the Washington University Wolfram Syndrome Study Group!

By Dr. Tamara Hershey

Dr. Tamara Hershey

I would like to tell you about the big picture of research and clinical activities at Washington University focused on Wolfram Syndrome. There are three parts to this effort 1) Diagnostic markers and treatment development for Wolfram syndrome using animal models and human cells, led by Dr. Fumi Urano (see his previous blog postings here); 2) Patient-oriented natural history studies, led by me — Dr. Tamara Hershey) to determine the trajectory of Wolfram Syndrome-related neurological changes, providing the necessary background information for future clinical trials and 3) Expert clinical screening and care for Wolfram Syndrome, led by Dr. Bess Marshall. Dr. Marshall and other WU physicians now have the most in-depth clinical experience with Wolfram Syndrome in the nation and perhaps the world, providing the basis for a true clinical center of excellence.

(Left to Right): Dr. Fumihiko Urano, Dr. Tamara Hershey, and Dr. Bess Marshall

Fumi, Bess and I work as a team on all three of these aspects of Wolfram Syndrome research and care. We are in almost daily contact with each other to push our work further and problem solve together. It has been a privilege to work with both of them on something we are all so passionate about. In addition, we work with a large team of dedicated clinical and research faculty and staff, who we collectively refer to as the WU Wolfram Syndrome Study Group. Their names are below. I want you to know that there are a lot of talented and dedicated people here at WU working hard on the behalf of all Wolfram Syndrome families!

Dr. Timothy Barrett

We are also in contact with collaborators across the world, including Dr. Tim Barrett in the UK and others, to pool our experimental and clinical data and share measurement tools and ideas. We hope that in the future, these collaborations will provide the basis for a multi-center international clinical trial network. We are committed to being ready to implement an efficient, high quality clinical trial, as soon as a safe drug is identified with strong experimental evidence suggesting that it might help.

WU Wolfram Syndrome Study Group Leaders: F. Urano (Medicine), T. Hershey (Psychiatry, Radiology, Neurology) and B. Marshall (Pediatrics) P. Austin, M.D. (Surgery) G. Earhart, Ph.D. (Physical Therapy) S. Eisenstein, Ph.D. (Psychiatry) J. Garbow (Radiology) J. Hoekel, O.D. (Ophthalmology) T. Hullar, M.D. (Otolaryngology) R. Karzon, Ph.D. (Audiology & Communication Sciences) H. M. Lugar, M.A. (Psychiatry) L. Manwaring, M.S. (Pediatrics) A. R. Paciorkowski, M.D. (Neurology, U Rochester) K. Pickett, Ph.D. (Physical Therapy) S. Ranck, MSW (Psychiatry) J. Rutlin, B.S. (Psychiatry) J. Shimony, M.D., Ph.D. (Radiology) A. Viehoever, M.D. (Neurology) N. H. White M.D., CDE (Pediatrics) In memoriam: A. Permutt, M.D. (Medicine) J. Wasson B.S. (Medicine)

February 21, 2014/by The Snow Foundation

Dr. Fumihiko Urano, Research, Social Media Posts

Patient-Based Therapeutics Part 2

Dr. Fumihiko Urano

Research Update from
Dr. Fumihiko Urano

Patient-Based Therapeutics Part 2

We are taking an unconventional approach to develop therapeutics for Wolfram syndrome. I would call it “patient-based therapeutics.” This implies a few things. One of these is the “mechanism-based treatment.” How can we achieve this component of “patient-based therapeutics” for Wolfram syndrome? Here are our current efforts.

1. Looking for FDA-approved drugs that can potentially halt progression of Wolfram syndrome (drug repurposing).
We looked for drugs that can protect cell death mediated by the leakage of calcium from the endoplasmic reticulum (ER) to the cytosol. We found four FDA approved drugs and one supplement so far. We are testing these drugs in Wolfram iPSC-derived neural progenitor cells and mouse models of Wolfram syndrome.

2. Looking for a new class of drugs that can protect cell death mediated by endoplasmic reticulum dysfunction.
We have developed a drug screening method to identify drugs that can protect cell death mediated by ER dysfunction. In collaboration with a non-profit organization, we are actively looking for a new class of drugs that can potentially halt the progression of Wolfram.

3. Testing if MANF (mesencephalic astrocyte-derived neurotrophic factor) can suppress the ER calcium leakage-mediated neuronal cell dysfunction in Wolfram iPSC-derived neural progenitor cells.

I will talk about more on MANF some other time. I thought that this was a good biomarker for Wolfram syndrome because expression of this molecule is increased by ER dysfunction. However, the increase of MANF might be an adaptive mechanism of our cells to cope with abnormal ER function.

Dr. Fumihiko Urano a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.

January 20, 2014/by Dr. Fumihiko Urano

Research

Research Update – Patient Based Therapeutics Part 1

Patient Based Therapeutics – Part 1

Dr. Fumihiko Urano

We are taking an unconventional approach to develop therapeutics for Wolfram syndrome. I would call it “patient-based therapeutics.” Our extensive molecular characterization of patient cells, especially iPSC-derived cells, has been providing us remarkable insights into the root cause of Wolfram syndrome. Based on these insights, I have been carefully choosing molecular targets and processes for developing therapeutics. These are the endoplasmic reticulum (ER) membrane integrity, ER calcium leakage, calpain-2, and WFS1 gene mutations.How we target WFS1 gene mutations? We have started testing genome editing to accomplish this. Genome editing is a process that involves cutting out pathogenic genetic material (i.e., mutations in the WFS1 gene) and replacing it with healthy genetic material. This is a molecular surgery. So I am becoming a molecular surgeon. In short, we are trying to repair a genetic defect in Wolfram syndrome.

Currently, we are repairing a genetic defect in iPS cells from patients with Wolfram syndrome to see if the molecular surgery can restore the normal function of neural progenitor cells derived from Wolfram iPS cells. This is an important step. When the transplantation of iPSC-derived retinal ganglion cells and beta cells are available in the clinic in the future, we need to repair the genetic defect before the transplantation.

Dr. Fumihiko Urano a renowned physician and scientist developing therapeutics and diagnostics for Wolfram syndrome and juvenile onset diabetes. His areas of expertise include Wolfram syndrome, type 1 diabetes, Pediatric pathology and genetics and Molecular Endocrinology. He is currently employed at the Washington University School of Medicine where he holds the Samuel E. Schechter Professor of Medicine, 2012 – present.

January 15, 2014/by The Snow Foundation

Research

2013 Wolfram Clinic

4th Annual Clinic on Wolfram Syndrome Held at St. Louis Children’s Hospital July 17-20th

The 2013 Wolfram Research Clinic was run over four days in mid July. A total of 22 patients, six of which were new, participated in MRI scans and many other measurements, totaling up to 326 individual appointments. This clinic is now truly international, with two families from outside of the US. Many researchers, clinicians, staff, volunteers and interpreters helped make this research clinic run smoothly and comfortably for the families. Highlights of the clinic include The Snow Foundation’s family dinner at The Wildflower Cafe and the Saturday research/clinical update for families. Speakers included Tamara Hershey, FumihikoUrano, Bess Marshal, and several other faculty members. For a look at the presentation that was given click on the link below.

2013 Wolfram Clinic Research Update