May 2018 Update from Dr. Urano

Fumihiko “Fumi” Urano, MDDear Friends,

First of all, I would like to express my gratitude to you for coming to see me today. Thank you so much for following my mission & vision and being the kindest person. I think about patients with Wolfram syndrome and their families and friends every morning. That’s one of the first things I do every day at 4:30 am. I would like to support, help, and save them. I would like to know their challenges and help them overcome these challenges. Three things are always on my mind: 1. Improve Clinical Care, 2. Raise Awareness, and 3. Provide a Cure. We are clearly making progress in #1 and #2. How about #3? Is it possible? If so, how long?

Here is my answer. “We are making progress. We are this close.”

This close = my head size. I have all the strategies and ideas for developing cutting-edge treatments for Wolfram syndrome in my head. My challenge is to realize these ideas. There are technical roadblocks for developing gene therapy. There are regulatory issues to bring new drugs from bench (lab) to bedside (patients). There are financial constraints. These are not so easy to overcome, but these are much smaller challenges than those our patients have been experiencing. I would like to articulate my strategies again. There are three steps. Step 1: Drug Therapy for halting progression. Step 2: Regenerative therapy for protecting and regrow remaining eye and brain cells. Step 3: Gene therapy for replacing pathogenic genes. To achieve these goals and accelerate our progress, I have started creating three new animal models (mice and rats) carrying human Wolfram gene mutations. They are humanized Wolfram mice and rats. I plan to use these animals to test gene therapy and regenerative therapy.

In addition, I have been developing “genetic testing” for screening Wolfram syndrome and Wolfram-related diseases. I believe that Wolfram syndrome is an underdiagnosed disease. Using a single tube of blood, I would like to provide an accurate diagnosis. An accurate diagnosis serves as a basis for targeted therapy. An accurate diagnosis provides a sense of relief. 

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. Our potential is limitless. We have superpower to overcome this challenge.

With passion, hope, and gratitude,

Fumi Urano

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Wolfram Research Clinic Update – May 2018 – Tamara Hershey, PhD

 Washington-University-Wolfram-Study-group Washington-University-School-of-MedicineWashington University School of Medicine

Wolfram Research Clinic Update- Tamara Hershey, PhD

The main activity in our lab right now is the furious planning process for the 2018 Wolfram Research Clinic! However, we also have some other progress to report. First, in the past month, we have submitted two new papers on Wolfram Syndrome for review, both based on data from previous research clinics. One of the papers is on the very important topic of urological symptoms. The paper reports on the common urological issues in Wolfram Syndrome, possible explanations for these issues and makes some recommendations for interventions. The second paper is on sleep, using the overnight sleep apnea monitoring data collected during the last few years of the research clinic. This paper describes the high rate of obstructive apnea that we observed and discusses the potential importance of detecting and treating this symptom. A third paper is almost ready to be submitted; this one is on hearing impairment and how it changes over time in Wolfram Syndrome. Once these papers are peer reviewed and approved for publication we will certainly share them with all who are interested.
Second, Dr. Marshall and I are planning our trip to Paris for the International Wolfram meeting. I will be presenting on change in brain structures over time in Wolfram Syndrome, again using our Wolfram research clinic data. We are excited to learn from our Wolfram Syndrome research colleagues and see what progress the entire field has made since we last convened.
Finally, we have been talking with The Snow Foundation about submitting a grant to the NIH to fund a family/scientific conference on Wolfram Syndrome. The idea would be to bring in researchers and clinicians with relevant expertise on Wolfram Syndrome and present the latest information to other researchers, clinicians and families. As we start planning for this, we will be interested in hearing what families might be interested in learning at such a conference.
Thank you all for your interest and support.

Tamara Hershey, PhD
Professor, Psychiatry & Radiology Departments
Lab Chief, Neuroimaging Labs (NIL) @ MIR
Co-Director, Neuroscience PhD Program, DBBS
Washington University School of Medicine
Email: tammy@wustl.edu

Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu 

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Paint Party Fundraiser

Paint Party Fundraiser

 

Paint Party Fundraiser in honor of Joe Mirra, Jr. is Friday, July 13 at Hubcap, 128 Center Street, Wallingford at 6pm.

 

Please contact Christine Mirra for more information jemirra@comcast.net or to donate  visit www.thesnowfoundation.org/donate

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Derby de Mayo 2018

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Prof Tim Barrett Clinical Trial Update-Birmingham, England

Rebecca Storey and Shazia Ahmed, our senior and junior trials coordinators respectively, have been busy writing all the regulatory documents needed for the trial to go ahead. These were submitted to the Health Regulatory Authority in early January. The ethics committee met in early February. This was in Glasgow, but we were allowed to join by telephone conference. the committee was very sympathetic and had only minor requests. Rebecca and I are writing the response, which has to be back with them by Wed. We cannot get complete regulatory sign-off until we have evidence that the study medicine is stable outside it’s manufacturer’s packaging.

Regarding the study medicine, we have been in weekly contact with the pharmacy manufacturing unit at Guy’s and Thomas’s Hospital in London. They have outsourced the testing of the medicine to a commercial contract company, Butterworth’s. So, the problem is that the study medicine comes in foil blister packs. The manufacturer only guarantees the quality of the tablets while they are in their own packaging. For the clinical trial, Guy’s and Thomas’s Pharmacy have to take the tablets out of the manufacturer’s packaging and put them into white polypropylene containers, so that they can be masked (blinded) with the placebo tablets. Unfortunately, these study tablets absorb moisture from the atmosphere when taken out of their foil packaging, which in theory may affect the stability of the active component. Guy’s and Thomas’s hospital have been trying to test some tablets that they have kept in typical study bottles; but without success. They then outsourced this job to Butterworth’s, who found a non-standard method to measure drug stability. However, when they tried to convert this to an approved method, they could not get the measurements to work. This is turning into a major headache, and is the reason the study has been held up. We are having a telephone conference on Monday with the pharmacy team to get an update and plan what we do next.

We have appointed a new study team member, Heather Rose, who will look after the MRI scans for the trial, and do the measurements to see if the study drug is slowing down the brain changes. She is getting the scanners set up in Birmingham for both children and adults to take part.

Rebecca has been in touch with the international sites, in Almeria, Montpellier, Paris and Lodz, to start getting them set up.

Finally, I have been asked to speak with the French families in Paris on March 17th to explain to them where the trial is at.

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Dr. Urano’s April Update

Dear Friends,Fumihiko “Fumi” Urano, MD

Thank you so much for “coming to see me” today. It is always my pleasure and privilege to see you and talk to you. I feel your support and encouragement, and I am grateful for everything you have done for me, the Snow Foundation, patients, and their families and friends. Just reading this blog is helping me because I can feel your support, which makes me feel stronger and committed.

I would like to share my ideas on how to provide a cure for Wolfram with you today as our first clinical trial is ongoing and we are making steady progress in the development of new drugs, regenerative therapy, and gene therapy. I have been thinking and presenting my strategy for therapeutic development of Wolfram syndrome, CURE4WOLFRAM, since 2002. My current version, 4.0, is the following.

1. Stop Progression

ER Calcium Stabilizers
One of the common molecular pathways altered in patients with Wolfram syndrome and diabetes patients is imbalanced cellular calcium homeostasis. More specifically, endoplasmic reticulum (ER) calcium levels are lower in patients with Wolfram syndrome, leading to cell dysfunction and death. To overcome this challenge, we are currently testing if an ER calcium stabilizer, dantrolene sodium, can delay the progression of Wolfram syndrome. Dantrolene sodium is a FDA-approved drug for the treatment of muscle spasticity and high fever induced by anesthesia. We previously reported that dantrolene sodium stabilizes ER calcium levels and prevents cell death in cell and mouse models of Wolfram syndrome. We are currently conducting a clinical trial of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. In collaboration with NIH/NCATS, we are also developing novel ER calcium stabilizers (i.e., second generation dantrolene) for the treatment of Wolfram syndrome.

Molecular Prosthetics
Another common issue in patients with Wolfram syndrome is ER stress caused by the expression of mutant Wolfram protein produced in patients’ cells. To resolve this issue, we have been developing molecular prosthetics that can optimize the structure of mutant Wolfram protein together with NIH/NCATS and Amylyx, a biotech company in Cambridge, MA.

2. Protect and Regrow Remaining Tissue

Our second step towards a cure for Wolfram syndrome is to protect and regrow remaining tissue using regenerative therapy. We have discovered a naturally produced molecule in our body that can activate the proliferation of damaged beta cells and brain cells. Expression levels of this molecule, MANF, are usually low in our body. We are developing a method to enhance the activity of MANF using a pill that can mimic the functions of MANF and gene therapy (i.e., produce safe virus expressing MANF).

3. Replace Pathogenic Genes

Towards a cure for Wolfram syndrome, a genetic condition, we need to target the root cause of the disease, which is the loss of function of Wolfram syndrome gene, WFS1. Using CRISPR/CAS9 technology, we are attempting to replace a pathogenic Wolfram gene (WFS1 gene) with a healthy Wolfram gene. We are also trying to introduce safe virus expressing normal WFS1 gene into patients’ cells.

Thank you so much for being with me today. Good things happen to people who do good things. I am always hopeful.

With grace and gratitude,
Fumi Urano

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The British Journal of Occupational Therapy

“Understanding activity participation among individuals with Wolfram Syndrome”

2018 has brought another publication from the Wolfram Research Group! This article, titled “Understanding activity participation among individuals with Wolfram Syndrome”, was recently accepted to the British Journal of Occupational Therapy.

We wanted to learn more about the use of Occupational Therapy (OT) services in people with Wolfram Syndrome (WFS), and how participation in daily activities could be affected due to WFS symptoms. Participation in daily activities means being able to do the things we want and need to do, which leads to more independence and improved quality of life. Knowing the activities that are most important to those with WFS can help us develop better and more patient-focused interventions and services.

We asked research clinic participants questions about 1) their use of OT services in the past and present, 2) which daily activities were most difficult for them to accomplish, how important these activities are to them and how satisfied they were with their performance and ability to do the activity, and 3) which WFS symptoms affected these daily activities.

Overall, we found that only 22% of participants have ever used OT services. These services were most often for fine motor coordination and low vision. In addition, we found that daily activities identified as important were self-care (personal care, mobility), productive (household management, going to school or work), and leisure (recreation and social) activities.

Overall, we found that people reported reduced participation in daily activities when compared to a non- WFS group. In addition, participation was more restricted over time as WFS neurological symptoms progressed. Adults had more difficulty with activities that were related to social activities and getting out in the community and children/teenagers had more difficulty with activities related to playing and school. Participation in daily activities was most restricted due to walking/balance problems and loss of vision.

These findings raise awareness of the impact of WFS symptoms on daily life and point to neurologic and vision symptoms as being the most limiting aspects of WFS. OT professionals can provide self-management techniques and strategies for low vision or balance issues. These approaches may be of help to those not already using OT services.

 

For more information, look for this publication in the near future: Bumpus E, Hershey T, Doty T, Ranck S, Gronski M, Urano F, & Foster E. Understanding activity participation among individuals with Wolfram Syndrome. British Journal of Occupational Therapy. (In Press).

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Washington University School of Medicine 2018 Wolfram Research Clinic Update

Washington-University-Wolfram-Study-group Washington-University-School-of-Medicine

Yes, we’re still waiting! No word yet on the final determination of funding for the 2018 Wolfram Research Clinic. But, as we said, we are proceeding with the planning. We wanted to share with you the final dates of the clinic and a couple of changes from previous clinics.

The official clinic dates are Wed., 7/11/18 thru Wed., 7/18/18. The way it will work is that we’ll have two groups thus two clinics; Clinic 1 and Clinic 2. Clinic 1 will be held Wed., 7/11/18 thru Sun., 7/15/18. Clinic 2 will be held Sat., 7/14/18 thru Wed., 7/18/18. Testing will take place on week days and the Wolfram Group meeting (formerly known as the “Saturday Session”) will be held on Saturday, 7/14/18. The change most frequently requested by the families on the post-clinic evaluations is more time built in to the schedule for families to socialize. In an effort to meet this request, we are working on setting up family socials at least one night during each clinic and one after the Wolfram Group meeting on Saturday. It will take a bit to find a space that fits our group but we want you to know that we heard your request and we’re working on it!

Dates to remember:

Clinic 1 – Wed., 7/11/18 – Sat., 7/14/18 Wolfram Group meeting & Family Social – Sat. 7/14

Clinic 2 – Sat., 7/14/18 – Wed., 7/18/18

If you have a preference of attending Clinic 1 or Clinic 2 please let Samantha know sooner rather than later!

Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu

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Wolfram Association-Georgia

Matsatso Khachapuridze from Georgia is the founder of a non-governmental organization called “Wolfram Syndrome – Georgia”. “Wolfram Syndrome – Georgia” was founded on November 29th, 2017. Matsatso decided to establish this organization because she has Wolfram Syndrome (WS). In Georgia, WS is not on the list of rare genetic diseases and there is no statistical data for this disease. The only data that is available is in the “Diabetic Child Protection Association”, where there are 20 people with WS (official data).

Matsatso met with the chairman of the Committee on Health and Social Issues of the Parliament of Georgia. She was asked why she needed WS to be on the list of rare genetic diseases since people with WS already receive free medication for diabetes insipidus, diabetes mellitus, and desmopressin. She explained to the chairman that there are other things that are desperately needed for these patients due to the many manifestations of this disease. For example, hearing devices.

There are no medical institutions or special programs in Georgia where patients with WS could get a consultation to discuss all the aspects and issues of WS. Wolfram Syndrome-Georgia is hoping to change this. For more information please contact;

Wolfram Syndrome-Georgia

wolframgeorgia@gmail.com

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The Snow Foundation to Start a Patient Registry

The-Snow-Foundation-to-Start-Patient-RegistryTSF is leading the charge to find a cure for Wolfram Syndrome. A major step in this fight is to assemble an international patient registry that will help with the funding and drug development process. TSF’s patient registry will be used prospectively to quickly identify patients eligible for a clinical trial, or retrospectively to analyze the effectiveness of an intervention. A foundation patient registry will also help patients receive more accurate advice and improve care pathways, which can lead to improved care and life expectancy, even in the absence of a cure.

This registry may also serve as a way for patients and families to connect with each other, as emotional support is an important part of the healing and treatment process.  TSF will be contacting families shortly.

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