Wolfram Syndrome Patient Registry Update
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We are currently partnering with the National Organization for Rare Disorders “NORD” to implement the first-ever WS global patient owned registry, a priority in the field of rare disease.
Please help us improve patient care, strengthen our voice, and improve the chance for quicker drug development. Support The Snow Foundation’s vision of “a world without Wolfram syndrome.”
The registry should be up and running by March 2022. Sign up today to receive critical information about treatment, research, resources, and other initiatives. We will contact you once the registry is live to sign up officially. If you have any questions, please email Pat Gibilisco, pat@thesnowfoundation.org.
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Research Supported by The Snow Foundation
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Dr. Benjamin Delprat
University of Montpellier, France
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My projects are focused on elucidating Wolfram syndrome molecular mechanisms and more particularly to study the role of the alterations of communication between two intracellular organelles named the endoplasmic reticulum (ER) and mitochondria, one of the key pathways in the disease. Based on this impairment, we are developing two therapeutical strategies to stop the progression of Wolfram syndrome. Associated with a prompt diagnosis, we are optimistic that the manifestations of the disease can be halted in a timely manner, decreasing the probability to develop neurological and sensorineural symptoms.
Our first strategy is a pharmacological approach. We identified a strong and potent target expressed at the ER-mitochondria junction that interacts with Wolframin, the protein responsible for WS. Its activation restored the cellular alterations in patients’ fibroblasts and the altered behaviors observed in mouse and zebrafish models. Using a phenotypic screening in zebrafish, we already identified novel chemical entities that bind to our relevant target. Following these encouraging results, we are optimizing the molecules that will be tested in cells and in our different animal models. A multi-system screening method (zebrafish and mouse models) approach will be used to screen the panel of molecules and highlight compound that can eventually be used to treat WS patients.
We are also developing an innovative gene therapy. Based on recent studies in the lab, we have envisioned a different approach from what is currently developed. We decided to express a partner protein of Wolframin but not Wolframin itself. The size of this protein allowed us to use viral transfection using a virus already proven efficient in other disorders. By developing a unique gene therapy, which will be delivered systemically, we are hoping to stop the progression of the disease, body-wise, contrarily to the currently explored strategies. Our preliminary data in both zebrafish and mouse models of the disease are very encouraging. We are currently testing the long-lasting effects of the gene therapy as well as its impacts on the different symptoms of the syndrome.
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Dr. Cecile Delettre
Neuroscience Institute of Montpellier, France
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Our team’s goal is to discover, test and develop treatments in order to prevent or limit visual impairment and to improve the autonomy and the quality of life of patients with Wolfram syndrome.
For the last 20 years, our group together with Pr Christian Hamel has made highly significant contributions concerning the clinics, genetics and pathophysiology of autosomal inherited optic neuropathies, by identifying the genes involved in these diseases, analyzing mouse models reproducing human pathologic mutations, deciphering the basic function of the uncharacterized genes and start therapy projects in this field.
Wolfram syndrome is a devastating multisystemic disorder and despite decades of intense research, no curative therapies are currently available. All aspects of this disease reinforce our commitment to elaborate a therapeutic strategy for Wolfram patients.
Our team are working on two axes:
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Development and testing of new therapeutic drugs
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Use gene therapy delivering WFS1 to treat Wolfram syndrome
Recently we have identified a family of molecules with the capacity to
stimulate significantly the growth of retinal ganglion cells in vitro in a model
of optic atrophy. These molecules appear to represent interesting
therapeutic candidates for the disease. Our project is to test the efficacy of
these molecules in a previously established mouse model of Wolfram
syndrome.
Gene therapy has exciting potential. For several reasons, gene therapy will have considerable therapeutic potential in this monogenic disorder. In our first gene therapy studies in a mouse model of Wolfram syndrome, we have demonstrated that it is possible to rescue visual function using overexpression of WFS1 when it is administrated into the vitreous. To go further, we hypothesized that a systemic delivery of WFS1 could restore WFS1 expression and function in both retinal ganglion cells and other organs. Our project will evaluate functional evidence that WFS1 expression by systemic gene transfer in a Wolfram model greatly mitigates the development of the phenotype.
Our projects represent a first step in acquiring the proof of principle necessary for carrying out clinical trial in human. Our link with the reference center for genetic sensory diseases Maolya in Montpellier will help us to improve preclinical to clinical translation.
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Wolfram Syndrome Research Updates
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February 2022
Hello Friends,
It is always nice to “see” you. Although I have not met with most of you in person, I always feel your support, trust, and faith in me. My research program is 120% functional, and I keep on doing my best to provide the best clinical care and develop safe and effective treatments for patients with Wolfram syndrome. Here are my updates, and I am upbeat.
Upcoming clinical trial
In the past, I looked for existing drugs that could be beneficial for patients with Wolfram syndrome. This effort led to a few clinical trials, but a repurposed drug could be just a band-aid for Wolfram, and we need a new medication for Wolfram syndrome. I have been focusing my efforts on developing a new drug, AMX0035, for the treatment of Wolfram syndrome in collaboration with Amylyx Pharmaceuticals in Cambridge, Massachusetts. AMX0035 targets endoplasmic reticulum stress (a molecular mechanism of Wolfram) and mitochondrial dysfunction. A recent clinical trial of AMX0035 in patients with ALS, an adult-onset neurodegenerative disorder, was successful (https://www.nytimes.com/2020/10/16/health/ALS-treatment.html). Our pre-clinical study using cell and rodent models of Wolfram syndrome was positive. We have deposited the data to the public server (https://www.biorxiv.org/content/10.1101/2021.11.07.467657v1) and plan to publish it in a medical research journal soon.
US FDA granted an orphan drug designation of AMX0035 for the treatment of Wolfram syndrome in October 2020. We submitted our clinical trial plan to the US FDA and received their feedback in the late summer of 2020. We have examined our longitudinal study data and dantrolene clinical trial data extensively and have created an innovative clinical trial protocol to ensure the safety of our patients and assess the efficacy of AMX0035 accurately. I spend a certain amount of time every single day on this project with medical officers at Amylyx and my colleagues at Washington University. We have been communicating with US FDA and hope to start a trial late summer of 2021. Please stay tuned.
Regenerative Gene Therapy for Optic Nerve Atrophy
My strategy is to stop/delay the progression of Wolfram syndrome using oral medications and restore functions of retinal ganglion cells, brain cells, and insulin-producing cells by regenerative gene therapy. Our first target is vision. We have been trying to improve visual acuity using viral vectors expressing a healthy Wolfram gene (WFS1) and a regenerative factor called MANF in cell and rodent models of Wolfram syndrome. Our preliminary results are encouraging. Dr. Venu Gurrum has recently joined my lab to accelerate the progress of this project. He is an expert in gene therapy for inherited optic nerve atrophy. My goal is to start a gene therapy trial in the next 3-7 years.
Gene-editing and Base-editing Therapy
The best way to treat genetic disorders is gene-editing or base-editing-based therapy. We have been working with Dr. David Liu’s team at Harvard University/Broad Institute and Dr. Catherine Verfaillie’s team at the Katholieke Universiteit Leuven to develop a novel gene therapy using base editing. This technology uses some components from CRISPR systems together with other enzymes to directly replace the abnormal WFS1 gene with the normal WFS1 gene. We are making steady progress, and I hope that we can bring this technology to our patients in the next 3-7 years.
Genotype-Phenotype relationship and a new drug target
We are pleased to announce that Dr. Saumel Ahmadi, a pediatric neurology resident at Washington University Medical Center, is joining my research team and will be developing a new method to study the genotype-phenotype relationship in Wolfram syndrome. He will also use the same method for identifying new drug targets for the treatment of Wolfram syndrome. Please read his blog in this newsletter!
Clinical service
To improve the clinical care for patients with Wolfram syndrome and Wolfram-related disorders, I have been running the WFS1 clinic at the Center for Advanced Medicine, Washington University Medical Center. This clinic has been incredibly successful, and I see patients from different states and countries almost every week. The Snow Foundation, the Ellie White Foundation, the Unravel Wolfram Syndrome, and the FB groups related to Wolfram syndrome have referred patients to my clinic, which I really appreciate. We offer genetic evaluations, education, and counseling for patients and family members of all ages with or suspected to have Wolfram syndrome and WFS1-related disorders. We also provide personalized management plans based on the type of gene variants our patients have in collaboration with other specialists at our medical center. We accept international patients via our international patient care office. We also accept out-of-state patients. To make an appointment, please call +1-314-273-3780. US patients can call 314-362-3500 (this is a new number) to make an appointment. Our medical center has been selected as a Rare Disease Center of Excellence, and we have excellent specialists.
Thank you for supporting the Snow Foundation. We will work as one team and make a difference together.
Sincerely yours,
Fumi
Fumihiko Urano, MD, PhD, FACMG
Professor of Medicine and Pathology & Immunology
Samuel E. Schechter Endowed Professor in Medicine
Director, Wolfram Syndrome/WFS1-related disorders Registry & Clinical Study and WFS1 clinic at BJC HealthCare
Washington University School of Medicine
https://wolframsyndrome.wustl.edu/
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Dr. Timothy Barrett’s Update
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Dear friends and colleagues,
Hello to you all from this side of the pond, and hope you and your families are OK and keeping safe in these Covid times.
Stephanie asked me to give you an update on the TREATWOLFRAM clinical trial. As you know, this is an international, randomised controlled trial of sodium valproate to delay or prevent the progression of vision loss in Wolfram.
I am really pleased to say that we reached the recruitment target for the TREATWOLFRAM clinical trial on 1st Nov 2021. 75 children, young people and adults kindly consented to take part in the trial. Some people were sadly not able to take part for medical or logistical reasons. We closed recruitment to the study with 63 participants.
These include 25 children and adults recruited in Birmingham UK, 15 children and adults in Paris and Montpellier, France, 18 children and adults in Almeria, Spain, and 5 children in Lodz, Poland. The youngest participant is 8 years, and the oldest, 61 years. We have a good spread of participants from white UK, and other ethnic groups. Dr Heather Rose and Prof Andrew Peet have build an imaging pipeline, so that we have now received brain MRI scans from all sites, following the protocol kindly shared by Prof Tamara Hershey.
This is fantastic support from the whole European community, especially Dr Renuka Dias, Dr Ben Wright, Prof Christophe Orssaud, Prof Agathe Roubertie, Dr Gema Esteban, and Prof Wojciech Mlynarski, the site investigators. Wolfram Syndrome UK are generously supporting UK participants to travel to Birmingham. The support from Snow Foundation, Eye Hope Foundation and French Wolfram Association has really helped the collection of research samples with consent for sharing with the global research community.
This is the first international trial of a treatment for Wolfram. Most importantly, we have the right number of participants to give a definite answer to the question: does sodium valproate treatment slow disease progression in Wolfram?
I know I can say on behalf of all the clinical trial team that we really appreciate the time and effort that people are making to take part in this study. This is a lengthy process and can be frustrating. However, by having a gold standard clinical trial, we will have really strong evidence to support the adoption of the treatment into the clinic, if it works.
We have an independent Data Monitoring Committee that meet every 6 months. They look at all the data and know who is taking the treatment and who is taking the placebo. If that group see either a really strong signal that the medicine has stopped the disease process, or alternatively that there is no evidence that it works, they can stop the trial immediately.
Realistically I expect the trial to run to Autumn 2024, and for us to have results to share then.
I hope we can meet soon, perhaps by teleconference at your family meeting
With best wishes to all
Timothy Barrett
Chief Investigator TreatWolfram clinical trial
On behalf of all investigators and Cancer Research UK Clinical Trials Unit
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Dr. Saumel Ahmadi Blog Update
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It was a fine Thursday morning, in the summer of 2021, when I was walking from my apartment to St. Louis Children’s Hospital, where I work. As a part of my routine, I was checking the new patient list from overnight, and I saw a patient with “Wolfram syndrome” who was admitted with a disabling headache. This was the first time I was directly responsible for taking care of a patient with this genetic condition. On reviewing the chart, patient had a plethora of other conditions including diabetes, optic atrophy, recurrent headaches, to name a few. I entered the patient room, and I had my first conversation with this patient and her mom. Unlike many of my other families with rare genetic conditions, both mom and patient were very much up to date in terms of Wolfram syndrome, and even the ongoing unpublished clinical trials. The conversation was intriguing to say the least, and after I left the room, I looked up literature to see what is known at the molecular level for this disease. What got me excited further was the fact that this clinical condition is caused by the way certain human cells handles calcium. Given my background in precision medicine in rare diseases, I looked up if it was possible to help my patient by developing a personalized drug discovery platform. Talking about this idea with my division Chief, Dr. Christina Gurnett, who felt the excitement, she quickly directed me to Dr. Fumi Urano who is the Director of the Wolfram syndrome study at the Washington University. I met with Dr. Urano the very next week, and since then we have worked together to develop a personalized drug discovery platform for Wolfram syndrome, by establishing local and international collaborations. Together we hope to not just better understand the disease process, but also collaboratively work to improve the lives of patients and families with this condition.
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On November 10th of 2021, we lost one of the brightest stars in our Wolfram community, Lauren Gibilisco. Lauren was beautiful inside and out. She always had a smile on her face and a joke to share. Lauren was one of The Snow Foundation’s most prominent advocates, always willing to share her story and fight for the younger generation. When she spoke at our events, she always said, “I don’t want the younger generation to have to suffer the way I have.” Even though WS was stripping her of all her faculties, she always had a positive attitude and a gleam in her eyes. Lauren’s unshakeable faith in God was truly remarkable. She would spend most of her time praying for others rather than worrying about herself. There is no hurting, no suffering, and no pain in Heaven. While we grieve her physical loss, we are comforted by the fact that she is in a far better place now. We will miss you, Lauren!
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Rare Disease Day
February 28, 2022
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Please consider supporting The Snow Foundation this February 28, 2022 for Rare Disease Day by making a donation. Your contribution helps support a worthy cause.
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Classic Car Show
July 23, 2022
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West Side Automation, Inc and West County Auto Body & Repair presents the 2nd annual Classic Car Show benefitting The Snow Foundation on Saturday, July 23, 2022 from 11 am to 3pm at Pond Athletic Association. Registration/donation is $30 and is available from 11 am to 1 pm. Pre-registration is available by July 16th for only $25 and receive a free t-shirt.
All makes, models, and years welcome. Trophies awarded for Best Paint, Best Survivor, Best Engine, People’s Choice, and Best of Show.
The event will feature live music, plus beer and concessions. This event is free for spectators.
For more information, please contact Bob Kraemer at 314-323-1314 or bobkraemer@charter.net OR Barclay Gebel at 314-422-1035 or barclaygebel@gmail.com.
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The Snow Foundation Golf Shootout
August 29, 2022
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Join us for a great event on August 29, 2022 at the Bogey Hills Country Club to support the Snow Foundation.
The day will feature golf, 14 Par 3 holes with unique hole in one contests, 4 Par 5 Long Drive holes, a $100,000 Shootout for 18 golfers.
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Wolfram Syndrome Awareness Day
October 1, 2022
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Last year all known WS groups were invited to a virtual meeting to discuss the idea of creating a global awareness day for Wolfram Syndrome (WSGAD). The meeting was attended by 7 WS groups from 5 different countries. We have Rare Disease Day which encompasses all rare diseases once year but as we are a smaller condition we tend to get overlooked. Other rare conditions have their own specific awareness days throughout the year, so it was thought that this was something we could do as well.
It was decided to have 1st October as the awareness day as this was the date that a paper was published by the late Dr Alan Permut and his team at Washington University Hospital on the discovery of the WSf1 gene back in 1998. This date therefore holds some significance to the WS Community.
The groups discussed who we were going to contact and how. It was decided for this first year that we would target clinicians and groups in the countries where we had contacts as well as global organisations in the fields of Ophthalmology, Diabetes and Endocrinology. A logo was created as well as a website specifically for the awareness day, www.globalwsday.org, with the information that was sent out, information about WS in general, details of doctors around the world that see patients with WS as well as all the WS groups.
We also contacted you, our WS community to get involved where you could. We asked if you could help with raising awareness by contacting your local press and tv news stations to publish your story about living with WS, if you wanted to fundraise for your WS organisation this was a good opportunity and, on the day, we asked you all to join in with a global social media relay event that started at 10.00am in New Zealand and moved across the world with people posting and sharing at 10.00am in each country.
This year we intend to target the sending of information and raising of awareness to Neurologists and Geneticists globally. Wolfram Syndrome UK (WSUK) will also be holding their face-to-face families conference on this date, which seemed appropriate. We would love for you all to become more involved with this so that it becomes bigger each year and raises the awareness of our syndrome and invite interest from clinicians and researchers into finding out more. This in turn could help make diagnosis quicker and help their patients. It could help to spark interest into areas of research already being carried out that could also help those affected by WS.
Updates on this event will be posted on social media as well as newsletters. If you would like to know more or how to get involved you can contact Tracy Lynch at WSUK – tracylynch@wolframsyndrome.co.uk. You are welcome to share the WSGAD website with your clinicians or care teams as well – www.globalwsday.org.
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If you’ve supported TSF in the past, you know that your donations help us advance Wolfram syndrome research and programs that support patients and their families. Consider donating today and imagine how much more impact we can make together in 2022.
Mobile Donations, Text snowfoundation to 41444
Online Donations https://thesnowfoundation.org/donate/
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