The Snow Foundation (TSF) has the ability to change the outcome of Wolfram Syndrome and save patients around the world. For the last seven years, TSF has been faithful to its mission, with a proven track record of working toward a cure for WS. TSF has accomplished more on a limited budget than some of the world’s top non-profit organizations. We now need to fund the projects that will improve vision and the management of diabetes. I am keenly aware that an overwhelming and intimidating dream was placed in my heart. But my faith in God, and my compassion and empathy for the patients and families who suffer daily, allow me to hold my head up high, have a spring in my step, and remain confident and secure that this dream will come to pass.
TSF 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.
As this is the first time to see you in 2018, I would like to begin by thanking all of you for your continued support and encouragement. I appreciate it immensely. I am so grateful to have such supportive friends. I would like to update you about our latest developments as usual.
Our drug-repurposing clinical trial of dantrolene sodium is ongoing. The trial began in January 2017. Twenty-two patients with Wolfram syndrome enrolled. Two patients decided to leave the study due to personal reasons and one patient could not start the study because of medical reasons. So nineteen patients started taking dantrolene sodium. As of today, fifteen of them have been taking dantrolene for more than 6 months. At this stage, my team has found few side effects and has identified safe dosage levels in adult and pediatric patients. I saw some beneficial effects on remaining beta cell functions, visual acuity, and neurological functions in some patients, but did not see any beneficial effects in other patients. Because all the participants are taking dantrolene, we cannot conclude that any effects are due to dantrolene. Nevertheless, I have sent the data of fifteen patients to statisticians who have not been involved in our Wolfram studies (myself and my colleagues are biased as you can imagine). We will find out more about the outcome of this study in the next several months.
I thought a lot about our therapeutic development for Wolfram syndrome during the holiday season. I feel that drug-repurposing may not be good enough. I firmly believe that we need a breakthrough therapy for Wolfram syndrome. This year, I would like to spend more time for developing regenerative gene therapy, especially for visual impairment. In parallel, I would like to develop a second-generation dantrolene which is more potent and safe. These are my two goals in 2018.
I feel that something new and wonderful will happen to us this year. I feel that we will go into a new stage. Thank you again for your continued support. I am hopeful and grateful.
Saturday 7th October 2017 saw the 6th Wolfram Syndrome conference being held with many affected individuals and families attending along with the doctors from our WS clinic and visiting clinicians. We had presentations from Prof Tim Barrett and the Lead Research Statistician, Kristian Brock, giving us updates on the UK clinical drug trial, Mr Patrick Yu Wai Man on WS and the eye, Mrs Stephanie Gebel, founder of The Snow Foundation, had flown over to give us an update on the work and trial being carried out by Dr Fumi Urano of Washington University and we also had Dr. Malcolm Lewis, a Urology Consultant fly over from Dublin, Ireland to give us a presentation about the Bladder & WS. This talk was greatly received as it is one area we have struggled with in getting a speaker. In the afternoon we held various workshops which included a session with all the clinicians & those only affected by WS giving them a chance to speak freely about any concerns without the worry of upsetting a family member. We had sports taster sessions running throughout the day as well giving people the chance to have a goat VI Boccia, Handball & tennis.
Thank you to all the Wolfram families who participated in TSF’s Year-End Holiday Campaign. We raised over $40,000, and we had six families who participated. With more than 80 known families who have WS, imagine what we could achieve if each family participated! As Dr. Seuss says in Oh the Places You’ll Go, “You have the brains in your head. You have the feet in your shoes. You can steer yourself any direction you choose.” Patient organizations such as TSF don’t solely focus on the disease; they also look to the future, with hopes of raising the necessary funding for research, disease awareness, collaboration and support.
We need to be a community of impassioned doers. Reach out to family, friends, and colleagues today and ask them to support The Snow Foundation.
The Importance of Finding a Bio-Marker for
Wolfram Syndrome
What are biomarkers and why are they important?
Tim Barrett
Leonard Parsons Professor of Paediatrics
Institute of Cancer and Genomic Sciences
College of Medical and Dental Sciences
University of Birmingham
Centre for Rare Disease Studies, Birmingham
Centre for Endocrinology, Diabetes, and Metabolism
January 2018
One of the global health priorities of the International Rare Diseases Research Consortium (IRDiRC, www.irdirc.com) is on to find new treatments for the 80% of rare diseases that currently have no cure or means to treat. We know of over 8,000 rare diseases, so this is a really big challenge. As everyone knows, it is a huge task to come up with a treatment, then get it approved so that patients can have it in the clinic. Once you have come up with a treatment, people ask: ‘how do you know it will work?’.
The best example I can think of is anaemia. You may be feeling tired and pale with a lack of energy, and go to your doctor – she takes a blood test, tells you that you are anaemic, and prescribes you some iron medicine. You take the medicine, and after a few weeks you feel better so your doctor invites you back for another blood test, says your blood count has come up, and you can stop the medicine. That blood count is what we call a ‘biomarker’ – something that we can measure to see if a treatment has worked. The doctor needs it to decide when to tell you to stop taking your medicine. Without it, she doesn’t know whether you feel better because the medicine worked, or because you are eating better, or just because the sun has come out!
A biomarker is anything that we can measure, to see if a treatment is working. If the treatment is to help you lose weight, the biomarker is your weight. If you have a metabolic problem where a toxin builds up in your blood, then the biomarker is the level of toxin in your blood. It can even be a change seen on X-ray or brain imaging scan.
Biomarkers become especially important when you are treating a disease that takes months or years to progress- if you start taking a treatment, you want to know it is helping you, without waiting for years to find out if you are going to develop any complications of the disease.
When we study a medicine to see if it will treat a disease like Wolfram, it may take at least two years, or probably longer, to tell if the medicine has stopped the disease getting worse. If after 2 years, the person’s disease is still getting worse, then the medicine has not worked, and he/she has to start the process from the beginning with another treatment.
You might ask – why not try several different treatments at once? That’s a good question but there are two problems: firstly, the treatments may not work; or only one of them may work and the others are unnecessary; and then every treatment has side effects, which may get worse when you mix them with other medicines.
So why might biomarkers help? Well, to use the example of anaemia again: if you have something that you can measure, like a blood count in anaemia, you can quickly find out if the treatment is working, even before the person who was anaemic feels any better.
In Wolfram, if we ask people to take a treatment for the disease, we want something we can measure that will tell us quickly whether the treatment is working or not, without having to wait 2 or more years to tell if the disease has stabilised.
Biomarkers become really useful in clinical trials of a treatment: we really need a biomarker that will tell us whether the treatment is working within 6 months; so that if it is not, we can stop the trial, and switch to another treatment.
This is why we will be asking people to donate blood samples during our upcoming clinical trial. We want to make the samples available for the wider research community, and support the international effort to find biomarkers to measure the effectiveness of treatments in Wolfram.
The consortium
Left : prof. Timothy Barrett,
Right, 1st line: prof. Melanie Calvert, Dr Kristian Brock, Dr Zsuzsanna Nagy
Right, 2nd
line : prof. Richard Sinnott, Dr Anita Slade, Dr Ben Wright
The National Institutes of Health will launch an effort aimed at removing barriers that slow the adoption of genome editing for treating patients. This program, Somatic Cell Genome Editing, plans to award researchers approximately $190 million over six years beginning this year, pending availability of funds. These researchers will collaborate to improve the delivery mechanisms for targeting gene editing tools in patients, develop new and improved genome editors, develop assays for testing the safety and efficacy of the genome editing tools in animal and human cells, and assemble a genome editing toolkit containing the resulting knowledge, methods, and tools to be shared with the scientific community. The program is funded by NIH’s Common Fund.
“Genome editing technologies such as CRISPR/Cas9 are revolutionizing biomedical research,” said NIH Director Francis S. Collins, M.D., Ph.D. “The focus of the Somatic Cell Genome Editing program is to dramatically accelerate the translation of these technologies to the clinic for treatment of as many genetic diseases as possible.”
Many rare diseases, as well as some common disorders, are caused by changes in a person’s DNA, either through changes inherited from parents or those that occur during a person’s lifetime. Advances in genome editing made over the past decade now make it possible to precisely change the DNA code inside living cells. Despite widespread interest and investment in this field, many challenges remain preventing broad adoption of this technology in the clinic.
Somatic cells are any of the non-reproductive cells of the body, i.e. the cells that do not pass DNA down to the next generation. By focusing on somatic cells, any changes to the DNA introduced by the genome editing therapeutics will not be inherited.
Funding opportunity announcements for this program are expected to be issued within a month. For more program information, please visit https://commonfund.nih.gov/editing. This program is supported by the NIH Common Fund and is managed by a trans-agency Working Group representing multiple NIH Institutes and Centers, led by the National Center for Advancing Translational Sciences (NCATS).
About the NIH Common Fund:
The NIH Common Fund encourages collaboration and supports a series of exceptionally high-impact, trans-NIH programs. Common Fund programs are managed by the Office of Strategic Coordination in the Division of Program Coordination, Planning, and Strategic Initiatives in the NIH Office of the Director in partnership with the NIH Institutes, Centers, and Offices. More information is available at the Common Fund website: https://commonfund.nih.gov.
About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation – the process by which interventions to improve health are developed and implemented – to enable more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visit https://ncats.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
WU 2018 Wolfram Research Clinic
Thoughts and Ideas
YEven though we are still waiting for the final confirmation of funding for the 2018 Wolfram Research Clinic, that has not stopped us from beginning the planning process. We anticipate the 2018 clinic to be our largest clinic yet! In order to accommodate an increase in the number of participants, we will be spreading the clinic over more days. The current dates under consideration for the 2018 clinic are Monday, 7/9/18 thru Wednesday, 7/18/17. The idea would be to bring patients in for 3-4 days of appointments at some point during that time. Of course it is very early and we will know more in the coming months. I would like any feedback you may have regarding this plan. If you have any preference or comments please e- mail me at rancks@npg.wustl.edu
. I would love to hear your thoughts!
Updates
Dr. Hershey was recently contacted by the National Organization of Rare Disorders (NORD) with a request to provide an updated report on Wolfram Syndrome. NORD maintains a database of reports on rare diseases written for patients and families. This database is often quoted in national, state and local media stories and is made available to students and others through subscribing medical schools, universities and public libraries. About 90% of the nearly one million visits made to NORD’s website each month go first to rare disease reports. You can view the full report written by Dr. Hershey and Dr. Marshall at: https://rarediseases.org/rare-diseases/wolfram- syndrome/
RESEARCH UPDATE
Dear Research Clinic Families:
I hope you are having a busy and productive fall! In the lab, we are working to describe how symptoms change over time in Wolfram Syndrome. This information is very helpful to physicians, families and in the planning of clinical trials, particularly after it has undergone peer- review at a scientific journals. After review and acceptance, the data have been thoroughly vetted by other scientists and can be found by anyone interested in Wolfram Syndrome. As one example, we recently published a paper on quality of life in Wolfram Syndrome (Doty, Foster, Marshall, Ranck and Hershey; The effects of disease-related symptoms on daily function in Wolfram Syndrome. Translational Science of Rare Diseases 2 (2017) 89–100).
Wolfram Syndrome affects many different physical and emotional functions. Our team wanted to know how these symptoms could affect individuals’ quality of life (QoL) and participation in activities they like to do.
As you may know, each year, study participants and parents in our Natural History Study fill out numerous questionnaires. One specifically asks about different symptoms that can impact QoL. Our analyses show that lower QoL is associated with greater severity of symptoms, in particular urinary problems and temperature regulation. We also found, surprisingly, that diabetes, hearing and vision loss, some of the most common symptoms in Wolfram Syndrome, did not relate to QoL.
In another questionnaire, we asked about participation in different activities. Participation in daily activities is important because it leads to more independence, productivity and life satisfaction. We found that both children and adults with Wolfram Syndrome are likely to restrict their activities because of performance difficulties associated with their symptoms.
Social functioning and physical activities were particularly challenging. We found that 50% of adults acknowledged that driving and being in a long term relationship are difficult for them, while 20% identified exercise/ fitness outdoors as difficult. For children, we found that over 30% reported difficulties with sport-related activities.
It is important to understand how Wolfram Syndrome affects people physically, as well as emotionally and functionally. Understanding which symptoms interfere most with which activities can help guide the development of interventions towards targets that are most meaningful for individuals.
One approach that may be helpful for managing the impact of symptoms on QoL is Occupational Therapy (OT). OT may help people learn methods to manage symptoms and improve their level of engagement in activities that they care about. For example, OT can help people manage fatigue, use adaptive equipment (like canes or walkers), and adapt school and work environment to the person’s needs.
We thank our participants and families for completing these long questionnaires! The information provided is very valuable guiding our and other labs’ future research.
Sincerely,
Tamara Hershey, Ph. D.
Scientific Director & Principal Investigator,
WU Wolfram Research Clinic
Suite 2203, East Bldg, 4525 Scott Avenue. St. Louis MO
We are excited to be planning the clinic for next summer. We have written a few letters for insurance, etc., and I hope they succeeded in getting what was needed! Please keep letting us know if you need letters or information about Wolfram for school, work, disability, insurance, etc.
I noticed an interesting article a few months ago from Dr. Andrew Hattersley’s group in Exeter, England, reporting a new syndrome caused by mutations in the Wolfram gene, WFS1. These mutations are dominant and the kids who have them develop diabetes in infancy and are born with deafness and cataracts. They found these mutations by sequencing all the genes in children who developed diabetes before age 6 months in their huge diabetes database in Exeter. Dr. Hattersley is an expert on diabetes in infancy. Our own Dr. Urano helped by doing studies to see what the mutations do to the protein made by the WFS1 gene. We have not really sorted out yet exactly why there is so much variation in what different body functions those WFS1 mutations affect, but information like this from Exeter added to all of Dr. Barrett’s and our information should eventually help figure that out.
All the best,
Bess Marshall, MD
Pediatric Endocrinologist & Research Clinic Medical Director
The full text Dr. Marshall is referring to can be located at: Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. De Franco E., Flanagan S.E., Yagi T., Abreu D., Mahadevan J., Johnson M.B., Jones G., Acosta F., Mulaudzi M., Lek N., Oh V., Caswell R., Ellard S., Urano F., Hattersley A.T. Diabetes. 2017 Jul;66(7):2044-2053. Doi: 10.2337/db16-1296. Epub 2017 May 3.
*Thanks to Marisel Ponton, Tasha Doty and Samantha Ranck for writing the QoL summary.
Need Help?
For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coordinator, Samantha Ranck.
*For more information about Wolfram Syndrome and the WU Wolfram Research Clinic go to: hersheylab.wustl.edu
*One way to interact with other Wolfram patients and their families, to learn more about fundraising activities and scientific developments in the US and UK as well as, links to helpful resources is to follow the “Wolfram Syndrome” page on Facebook (www.facebook.com)
A multidisciplinary clinic has been set up at Birmingham Children’s Hospital to provide reviews for children and young people with a suspected or confirmed diagnosis of Wolfram Syndrome.
During the clinic, they can access specialist advice for individual medical complications; educational support, emotional support and genetic testing.
They can also access support, advice, and information via the Wolfram Syndrome Family Coordinator, whose role it is to help families attend the clinic and support them on the day.
Adult Wolfram Clinics are run from the Centre for Rare Diseases in the Heritage Building at Queen Elizabeth Hospital, Birmingham and are taking place on the following days:
March 16th
May 25th
July 27th
September 28th
November 23rd
For more information please contact Debbie Gittins at Debbie.Gittens2@uhb.nhs.uk
The provisional dates for the Children’s Clinics (run from Birmingham Children’s Hospital) in 2018 are:
19th/20th Feb
30th April/1st May
16th/17th July
1st/2nd Oct
If you would like to be referred to a clinic, or have a child you would like to attend, please contact Jody or Tracy
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;
Would you consider helping The Snow Foundation by hosting an event in your local community? You can search the web for ‘fundraising event ideas’ and you’ll find plenty of useful resources to give you inspiration. In addition, look around to see what has already been successful in your local community. Please contact stephanie@thesnowfoundation.org if you are interested in helping with any events or would like to plan your own.
