The Snow Foundation Confidently Creates
Hope Through Collaboration.
Hey there! Did you know that The Snow Foundation is working tirelessly to find a cure for Wolfram syndrome? We believe that your support can go a long way in helping us achieve our goal. Let’s unite and catch the cure together by 2024!
This year, we are funding four projects worth almost $400,000.
Please donate today to support our community. Your gift will make a significant difference and help us achieve our goal.
Please read below to learn about our projects.
1. Novel experimental therapies to treat blindness in Wolfram syndrome- Eye gene therapy for restoring WFS1 gene function in Wolfram mice
Dr. Vania Broccoli
San Raffaele Hospital/CNR-Institute of Neuroscience, Milan Italy
Eye gene therapy for restoring WFS1 gene function in Wolfram mice
AAV-based gene therapy is based on intra-vitreal injections of AAV vector expressing a therapeutic gene. This strategy is already in clinical use for treating Leber hereditary optic neuropathy (LHON) and clinical trials performed in multiple centers have reached beneficial effects without any troublesome side-effects. Strong advantages of this approach areå the ease of the surgical intervention, the efficacy of the AAV infection and the durable expression of the therapeutic genes for many years if not forever. Thus, we are developing an AAV-based replacement gene therapy to express a functional copy of the Wfs1 in retinal tissue to eb tested in Wolfram mice. However, our recent results indicate that Wolframin is significantly more expressed in glial cells where it controls MCT1 protein levels and its inactivation leads to RGC death through a non-cell autonomous mechanism of energy deprivation. These results clearly implicate that restoring Wfs1 gene expression only in RGCs might not be sufficient to protect from progressive visual loss. Our previous results indicate that both astrocytes in the retina and oligodendrocytes in the optic nerve play a crucial role in supplying energetic molecules to RGCs and this function is affected when Wolframin is inactivate in these cells. Thus, the question is in which cells the reintroduction of Wfs1 will have the best therapeutic effects in promoting RGC survival and functions. To answer to this question and to establish the most efficient strategy of gene therapy, we have been generating 4 different AAV vectors where the WFS1 gene is under the control of different promoters that combined with a specific delivery route will allow the expression of the therapeutic WFS1 gene copy in either only RGCs, optic nerve oligodendrocytes, retinal astrocytes, both glial cell types or all these type together. We will produce in our lab the AAV viral particles for intra-vitreal injections in the Wolfram mice.
This study will determine the best AAV gene therapy method considering both the ease of the administration route and its beneficial effects on visual functions. These results will pave the way to the clinical exploitation of this approach in Wolfram patients for establishing the first neuroprotective approach to arrest RGC loss in the disease.
Understanding the molecular role of WFS1
and how mutations in this protein cause Wolfram syndrome.
Filippo Mancia, Ph.D. Columbia University, USA
Dr. Rosemary Cater, University of Queensland, Australia
Wolfram syndrome manifests as a genetic disorder marked by early-onset diabetes, progressive optic atrophy, and hearing loss. In addition to these defining symptoms, some individuals may also experience neurological complications, including motor impairments, neurological disorders, and deficits in memory and learning. Tragically, Wolfram syndrome carries a high mortality rate, and currently, there are no therapeutic interventions available to halt or slow its progression. This lack of effective treatment stems, in part, from our incomplete understanding of the disease’s underlying mechanisms.
While it is known that Wolfram syndrome is caused by mutations inthe WFS1 gene, the precise role of the WFS1 protein in healthy individuals remains elusive, as does the link between its various mutations and Wolfram Syndrome.Our research is focused on understanding the molecular function of the protein encoded by WFS1, and what this protein looks like on an atomic level. By gaining these molecular insights into the normal WFS1protein, we will be able to understand how mutations in this protein disrupt its activity and cause Wolfram syndrome.
Through a collaborative effort with Prof Vania Broccoli (San Raffaele Hospital and CNR-Institute of Neuroscience in Milan) and Prof Filippo Mancia (Columbia University, USA), we have preliminary results that are already helping us understand what this protein looks like and are enthusiastic about furthering this research to fill this gap in knowledge within the field, and ultimately contribute to the development of effective treatments for Wolfram syndrome.
Our primary focus is to discover preclinical Liraglutide and other GLP1 receptor agonists available on the market to help slow the progression of Wolfram syndrome. Additionally, we are exploring a new generation of GLP1 and GIP co-agonists for the same reason. We are also developing gene therapy against WS-associated neurodegeneration.
4. 2024 International Research Symposium
Windsor, England
The Wolfram Syndrome International Symposium, an event facilitating collaborative efforts to advance medical knowledge for over 13 years, is all set to take place from October 22-24, 2024, in Windsor, England. This invite-only conference, hosted by The Snow Foundation and Wolfram Syndrome UK, is expected to be attended by over 35 leading research scientists. These meetings have proved indispensable in driving medical advancement, improving patient care, and developing new treatments and therapies for patients afflicted with Wolfram syndrome.
Earlier in February 2024, Amylyx Pharmaceuticals announced that enrollment was completed in the Phase 2 HELIOS clinical trial of AMX0035 (sodium phenylbutyrate and taurursodiol) for the treatment of Wolfram syndrome.
HELIOS is a 48-week exploratory, open-label proof of biology study assessing the effect of AMX0035 on a number of measures, including pancreatic function (mainly pertaining to diabetes), visual function, and Wolfram syndrome disease rating instruments.
The study, being conducted at Washington University in St. Louis, has enrolled 12 adult participants living with Wolfram syndrome, and preliminary results are anticipated in the second half of 2024. Data from this initial study will play an important role in giving Amylyx information needed to make decisions for potential future trials. Amylyx looks forward to sharing the results with the community, including at scientific meetings, when they are available.
I hope everyone is keeping OK and are keeping warm enough in this cold weather. Our research teams have kept busy and I would like to use this letter to keep you updated on our progress.
The TREATWOLFRAM trial is now in its final year. It has been a long journey to get here, navigating medicine manufacture problems, BREXIT, Covid, and supply issues. Thank you to all the participants who have supported the trial with their involvement. Our trials unit team, Amy Lamb, Lewis James Victoria Homer and Darren Barton, are working hard to make sure all the information that participants have kindly supplied, will be ready to be analyzed when the trial ends in October 2024. There has been an update from the UK Medicines Regulator (MHRA) to remind patients and the public about the safety precautions we all need to follow for people taking sodium valproate. Anyone female under 55 years who may be taking sodium valproate, needs to have a safety check with their doctor each year. It is important that sodium valproate should not be taken by women who may be pregnant, as there is a risk of significant harm to the baby. There is helpful information on this UK Government website: https://www.gov.uk/guidance/valproate-use-by-women-and-girls .
Our laboratory team, led by Dr Sovan Sarkar, with Dr Malgosia Zatyka, and their colleagues, have been finding new biological pathways in cells that are important in developing Wolfram syndrome. Some of these pathways relate to the ways that cells clear unwanted by-products. Sovan’s team have studied these pathways to look for new treatments to correct the defects. They have some candidate medicines and have applied to research funders to test if these medicines work in cell models. Sovan’s team presented at a major conference hosted in Birmingham at the end of the Summer, and one of his team members won the prize for best presentation.
Finally, our team has been approached by researchers in Europe and North America, to support their work on Wolfram syndrome. The team in North America are looking at changes in DNA that silence or activate genes and how these affect symptoms in Wolfram syndrome. The team in Europe are hoping to set up a new clinical trial of a treatment for Wolfram, and we are sharing our expertise, data and samples to help push this research forward
All our study team owes a big thank you to Wolfram syndrome UK for their generous support, and for bringing the Wolfram community of families, researchers and health care professionals together.
In my lab, we are developing concomitantly two therapeutic strategies: a pharmacological approach and a gene therapy. To achieve these goals, we are working with suited animal models: two transgenic mouse lines and one zebrafish line. One mouse model and the zebrafish line are deficient for Wolframin, the protein responsible for Wolfram syndrome type 1. The other mouse model has been genetically engineered to mimic a human mutation, recapitulating sensorial deficits (vision and hearing loss) and diabetes. We are hoping to treat vision and hearing, as well as central neurodegeneration.
– Update –
* We have explored the impact of the absence of Wolframin or the presence of an abnormal protein in the neurons of our mouse models (neurons of the hippocampus and cortex) as well as in patients’ fibroblast (cells cultured from the skin). Our findings suggest considering the use of the same therapeutic targets in both cases, thus opening treatment perspectives for patients carrying a mutation leading to an abnormal protein (Wolfram-like syndrome).
* Using our zebrafish model of the disease, we have validated our gene therapy strategy. Based on these encouraging results, we are now investigating the outcomes of this approach in our mouse models.
Our gene therapy approach corrected the memory deficit and locomotor coordination alteration at least one month after the injection of the virus. In addition, the virus is efficiently transducing the affected brain structure such as cerebellum, hippocampus, or cortex and lasting in time.
We are now exploring vision and hearing loss of our preclinical models, following the injection of the virus.
I want to take a moment to express my deep gratitude for your unwavering belief in and support of our mission to find a cure for Wolfram syndrome. Your enduring encouragement has been a beacon of hope guiding us on this remarkable journey. As we embark on the year 2024, filled with hope and determination to inch closer to our goal of finding a cure, I would like to provide a summary of our progress in the battle against Wolfram syndrome.
Rare Disease Day at NIH 2024
Before I delve into our progress update, I’m excited to share some fantastic news with you. I’ve received an invitation to present our research on Wolfram Syndrome at the Rare Disease Day event held at the National Institutes of Health on February 29, 2024. This event is widely regarded as one of the most prestigious gatherings for rare diseases, offering an excellent platform for us to raise awareness about Wolfram Syndrome. Even if you can’t attend in person, you can still participate by watching my presentation remotely. Here is the link to access it: https://ncats.nih.gov/news-events/events/rdd
Ongoing clinical trial
In partnership with Amylyx Pharmaceuticals, we are actively advancing the development of AMX0035, an innovative oral medication designed to slow or halt the progression of Wolfram syndrome. In 2020, the US FDA granted AMX0035 orphan drug status for Wolfram syndrome. Using data from previous clinical studies, we have developed a protocol to assess the safety and effectiveness of AMX0035. This protocol has been approved by both the US FDA and the Institutional Review Board at Washington University Medical Center. We have initiated a phase 2 clinical trial for adult patients with Wolfram syndrome at Washington University Medical Center, with the first participant starting AMX0035 treatment in April 2023.
Our trial is proceeding smoothly, and we are currently planning our next steps. We have received numerous inquiries about including children in the trial, as well as patients without diabetes and patients with WFS1-related disorders (those who have hearing loss and optic nerve atrophy due to having one pathogenic copy of WFS1). We appreciate your interest and feedback, and we plan to make a formal announcement later this year. Please stay tuned for further updates.
Regenerative Therapy for Optic Nerve Atrophy
Our primary objective is to halt and reverse the progression of low vision resulting from optic nerve atrophy in individuals with Wolfram syndrome. We are pursuing this goal through regenerative medicine. Our current strategy involves the administration of a regenerative factor called MANF into the eyes of Wolfram syndrome patients using a viral vector. As you may be aware, our brain naturally produces certain neurotrophic factors like BDNF and CDNF to maintain brain health. MANF is also a neurotrophic factor, but it stands out because it offers protection against Endoplasmic Reticulum (ER) stress, a key molecular mechanism involved in Wolfram syndrome. Additionally, MANF aids in boosting the growth of ER-stressed cells. We are presently conducting preclinical studies using cell and rodent models specifically designed to mimic Wolfram syndrome, in order to evaluate the effectiveness of MANF in addressing optic nerve atrophy. Promising results have emerged from our humanized mouse model of Wolfram syndrome, indicating the potential of this innovative approach to treat other causes of low vision as well. While there are undoubtedly several challenges ahead, our ultimate aim is to initiate a regenerative therapy trial for optic nerve atrophy within the next 3 to 7 years.
Gene Editing Therapy
The primary cause of Wolfram syndrome stems from a pathogenic alteration within the WFS1 gene. Consequently, the most effective approach to treating Wolfram syndrome involves rectifying these gene mutations. To ensure safety, we have transitioned from using CRISPR to utilizing the more advanced Base Editing (2nd generation) and Prime Editing (3rd generation) techniques to correct the pathogenic changes in the WFS1 gene associated with Wolfram syndrome. These cutting-edge gene editing technologies are currently considered the most advanced methods available. To evaluate the efficacy of this technology, we have generated rodent models featuring pathogenic mutations in the Wfs1 gene that closely mimic those observed in our patients. Our ultimate objective is to apply this therapeutic approach to benefit our patients within the next 5-10 years.
International Consortium
I’d like to present a significant idea to you. After extensive thought and discussions with senior advisers, I’ve made the decision to establish an international consortium focused on Wolfram Syndrome and Related Disorders and join the Rare Diseases Clinical Research Network (https://www.rarediseasesnetwork.org/). I intend to submit a substantial grant application to the National Institutes of Health. Through this consortium, my goals are as follows. I’m pleased to share that The Snow Foundation has graciously agreed to lead the patient organization group for objective #4.
1. Advance our understanding of the clinical manifestations of Wolfram syndrome and related disorders through collaborative clinical research.
3. Investigate genotype-phenotype correlations and identify drug targets.
4. Improve awareness among scientists, physicians, and the general public regarding the unique needs of patients with Wolfram syndrome and related disorders with patient organizations.
Clinical service
To improve the clinical care for patients with Wolfram syndrome and WFS1-related disorders, including WFS1-related deafness and optic nerve atrophy, we have been running the WFS1 clinic at the Center for Advanced Medicine, Washington University Medical Center. This clinic has been successful, and I see patients from different states and countries almost every week. I appreciate that the Snow Foundation, the Ellie White Foundation, the Unravel Wolfram Syndrome, and the FB groups related to Wolfram syndrome have referred patients to our clinic. 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 with other specialists at our medical center and beyond. We accept international patients via our international patient care office. We also accept out-of-state patients.
Patients in the US
If you’re in the US, please call Christine Manning, RN, Nurse Coordinator, at 314-747-7055 or 314-362-3500. Let her know that you or your family member has Wolfram syndrome or WFS1-related medical conditions and need to make an appointment. Once we review your medical records, Dr. Urano or his staff will contact you to discuss which specialists you may need to see.
Sending Medical Records via Fax
Please fax your medical records to 314-747-7065.
Referrals via Fax for both Missouri patients and out-of-state patients
Please fax your referral request to 314-747-7065.
International Patients
International patients are welcome to contact our international patient care office to schedule an appointment by calling +1-314-273-3780 or sending an email to Internationalpatients@wustl.edu.
Conclusion
The encouraging outcomes we’ve witnessed fill us with hope for the future, and we’re dedicated to forging ahead in our mission to bring about meaningful change. Thank you again for your unwavering support. Together, we will persist in our efforts and shine a beacon of hope for those affected by Wolfram syndrome. Here’s to a brighter future on the horizon!
With grace and gratitude,
Fumi
Fumihiko Urano, MD, PhD, FACMG
Professor of Medicine and of Pathology & Immunology
Samuel E. Schechter Endowed Professor in Medicine
Director, Wolfram Syndrome/WFS1-related disorders Registry & Clinical Study and WFS1 clinic at BJC HealthCare
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. We developed a zebrafish model with an optic atrophy and we have treated these fishes with one of these molecule. We used increasing doses of molecules to measure the toxicity and determine the most effective dose to protect the optic nerve. We have determined the dose with the best effect and confirmed that treatment with this molecule can prevent optic nerve developmental delay in vivo in our model of optic neuropathy. We are studding the mechanism of action of this molecule and using it in several model of Wolfram syndrome We look forward to a clear indication of the possibility of using this molecule in the future development of a treatment for Wolfram syndrome.
Gene therapy project using WFS1 is also important for us. We have synthetized a novel AAV2/9-WFS1 vector to treat all affected tissues in a previously established mouse model of Wolfram syndrome. After injection of the vector in young mice, we have checked that the vector could transduce all affected tissues including, eye, ear, brain and pancreas. We are now evaluating the efficacy of this gene transfer on visual and auditory function of our mouse model.
Thank you sincerely for your invaluable support of our collaborative study alongside Prilenia Therapeutics. As you are aware, our mission to find a cure for Wolfram syndrome involves three crucial steps:
Step 1: Slowing down the progression of the disease through the use of oral medications.
Step 2: Halting the progression via gene-editing therapy.
Step 3: Reviving damaged tissues with regenerative therapy.
Our current focus is on Step 1, specifically a clinical trial of AMX0035 in adult patients with Wolfram syndrome. This trial is designed to target endoplasmic reticulum stress (ER stress), a key mechanism underlying the syndrome. In many diseases, such as cancer, we have successfully employed combination therapies, utilizing multiple drugs that target various molecular pathways affected by the condition. We aspire to adopt a similar strategy for Wolfram syndrome in our efforts to slow its progression. To achieve this, we are exploring the potential of additional oral medications that target different pathways.
One promising candidate is the Sigma 1 receptor, and we have initiated a collaboration with Prilenia, a biotech company specializing in this field. Together, we are investigating the effects of a drug called pridopidine, which targets the Sigma 1 receptor, in cellular models of Wolfram syndrome. We are grateful to the Snow Foundation in collaboration with Ellie White Foundation for their generous donations, which enables us to conduct this crucial study using cells derived from Wolfram syndrome patients. The study is currently in progress as we explore various experimental conditions to assess the efficacy of pridopidine. We are committed to providing you with regular updates on our progress.
Once again, we extend our heartfelt thanks for your generous support, which is instrumental in advancing our mission to find a cure for Wolfram syndrome and bring hope to those affected by this condition.
With grace and gratitude,
Fumi
Fumihiko Urano, MD, PhD, FACMG
Professor of Medicine and of Pathology & Immunology
Samuel E. Schechter Endowed Professor in Medicine
Director, Wolfram Syndrome/WFS1-related disorders Registry & Clinical Study and WFS1 clinic at BJC HealthCare
The Snow Foundation and Wolfram Syndrome UK hosted the 8th International Wolfram Syndrome Symposium. The symposium was held at the Woodlands Park Hotel in Surrey England from April 16-18, 2023. There were over 30 researchers and scientist who attended.
For a full list of presentations and action items click here.
Wolfram Syndrome Global Patient Registy
Sign Up Today
Would you like to get involved in Wolfram Syndrome research? Contributing your data to a registry will help improve outcomes for our WS community. However, it will also tell us more about the current condition, which may positively impact patients taking part in international clinical trials.
A rare disease podcast series that shares the stories, experiences, knowledge, and voices of those living with Wolfram Syndrome and other rare diseases. Listen now.
Join our Wolfram syndrome community which offers support and companionship. This private Facebook site serves as a place to receive guidance and suggestions, such as the best questions to ask physicians, how to address symptoms that other families may have experienced, or you may join anonymously and learn from other families with older children who have had this diagnosis. These families get what it’s like to live in the rare disease lane and will help you navigate this journey.
GERMANY – “No one really expected such a sum of 2,650 euros,” explains Markus Kläsener from the pretzel bakers. The surprising auction of the giant pretzel caused a real surprise at the pretzel parade. The “Volle Kanne” bowling club was awarded the contract benefitting The Snow Foundation.
MISSOURI – McCarthy Fishing Tournament $13,445.00, McCarthy Building Company STL Warehouse/Yard’s Annual Dan Licari Memorial Fishing tournament supporting Alex Bieser family benefiting the Snow Foundation in the fight against Wolfram Syndrome.
PENNSYLVANIA – Fight for the Wolfram Syndrome Cure in honor of Danny Flexer-$978.65
CONNECTICUT – Pampered Chef Party in honor of Joe Mirra – $535.29
Thank you for your generous donations in honor and memory of your loved ones. Your kindness and support mean the world to us. Let’s take a moment to remember our Wolfram Warriors, who lost their battle in 2023. They will always hold a special place in our hearts.
Help us Build Awareness & Support Through Rare Disease Day on February 29th. Please help elevate the cause and shine a light on Wolfram syndrome patients and caregivers worldwide. Show your support, start putting together your social media campaigns now, and share the following link and QR Codes to raise money to support the research projects for 2024
We are immensely thankful for the unwavering support of our donors, who help us accelerate the research required to improve the lives of those suffering from Wolfram Syndrome. We strongly believe that by working together, we can achieve great things. Therefore, please donate today and join our journey towards a better tomorrow.
