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Dear friends and colleagues,
I hope everyone is keeping OK and have managed to have some time relaxing over the Summer. I wanted to provide some updates from our research teams here in Birmingham.
Firstly, the TREATWOLFRAM trial is continuing in the follow-up phase. Some participants have completed their involvement, and the remaining people are being seen every 6 months for an eye test, and every 12 months for more detailed assessments including MRI scans. Our trials unit team, Amy Lamb and Lewis James, are working hard to check all the information that participants have kindly supplied, ready to be analysed when the trial closes in October 2024. I am pleased to say that we have secure drug supplies to the end of the trial, and over 80% completion rates for the tests that we need to look at to see if the intervention works to slow down the progress of the condition. I’ll update further as we get nearer the end of the trial.
Secondly, our laboratory team, led by Dr Sovan Sarkar, has been very busy: Dr Malgosia Zatyka has been working on cell models of Wolfram, and her research has led to publication of a really interesting paper in the science journal “Stem Cell Reports”. The report is titled: “Depletion of WFS1 compromised mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome”. Essentially, mitochondria are the power houses of cells, generating the energy needed by cells to grow. Mitochondria operate closely with another part of the cell, the endoplasmic reticulum, to keep cells healthy. We’ve known for some time that the endoplasmic reticulum does not work properly in Wolfram syndrome. Malgosia has shown that in her Wolfram cell models, the mitochondria are also affected. This seems to relate to the way mitochondria interact with the endoplasmic reticulum. Her work implicates mitochondria in the disease processes that cause Wolfram, and suggests new targets for developing treatments for the condition.
Thirdly, my clinical consultant colleague Dr Renuka Dias has been investigating puberty and hormones in people affected by Wolfram syndrome. She has looked at a series of children and young people with Wolfram who have completed puberty. She and her team found that puberty was delayed or not completed in 40% of young men, and there were menstrual irregularities in 50% of young women. Testosterone supplements were effective in helping young men complete puberty, and there are treatments for young women to help make periods more regular. Dr Dias is presenting her findings at the European Society for Paediatric Endocrinology, so this study will reach a wide audience and help inform doctors to offer better treatments to people affected by Wolfram.
Finally, all our study team owes a big thank you to Wolfram syndrome UK as always for their generous support.
Sincerely
Tim Barrett
Have a Car to show off? Register today for the 3rd Annual Car Show presented by Westside Automation. All makes, models and years are welcome. Free for all spectators, pre-register your car by Sept. 25th and receive a cool T-shirt. Car show to benefit The Snow Foundation. https://www.tickettailor.com/events/thesnowfoundation/928089
August 30, 2023
Dear Friends,
Thank you so much for continually believing in and supporting me. I deeply appreciate it! Your encouragement has been such a driving force in our journey. Excitingly, we’re making significant strides in our therapeutic development for Wolfram syndrome. I can’t wait to fill you in on all the details. Let’s dive right into an update about our current clinical trial.
Ongoing clinical trial
We’re genuinely excited about the positive strides being made in Wolfram syndrome treatments. In collaboration with our partners at Amylyx Pharmaceuticals, we’re actively advancing the development of AMX0035, an innovative oral medication designed to halt the progression of Wolfram syndrome. Interested in understanding how AMX0035 addresses endoplasmic reticulum stress and mitochondrial dysfunction? We invite you to explore our latest article here: https://insight.jci.org/articles/view/156549.
In 2020, the US FDA granted AMX0035 orphan drug status for Wolfram syndrome. Using previous study data, we developed a safety and effectiveness protocol for AMX0035, which has been approved by the US FDA and the Institutional Review Board at Washington University Medical Center:
We’ve started a phase 2 clinical trial for adult Wolfram syndrome patients:
https://wolframsyndrome.wustl.edu/items/a-phase-ii-study-of-safety-and-efficacy-of-amx0035-in- adult-patients-with-wolfram-syndrome/.
Our first participant was dosed in April 2023: https://www.amylyx.com/news/amylyx- pharmaceuticals-announces-first-participant-dosed-in-phase-2-study-of-amx0035-for-the- treatment-of-wolfram-syndrome.
Our trial is progressing smoothly and more patients have been dosed, and we are already mapping out our subsequent steps. Stay tuned for updates.
Gene Editing Therapy
As you are all aware, Wolfram syndrome is a medical condition caused by issues in a gene named WFS1. When this gene isn’t functioning right, it can lead to multiple health problems, including optic nerve atrophy, diabetes mellitus, and neurodegeneration. Our current focus and priority is to safeguard the retinal ganglion cells. Why? Because these cells play a crucial role in preventing damage to the optic nerve and maintaining vision.
To address this, we’ve joined hands with distinguished scientists: Dr. Catherine Verfaillie, Dr. Lies De Groef, and Dr. Lieve Moons from Katholieke Universiteit Leuven in Belgium. Together, we’re applying a pioneering technique named “Base Editing” to make corrections in the problematic gene changes. Using iPS cells derived from Wolfram syndrome patients, we’ve seen promising results with this method. Our next step is to test this approach on a mouse model that simulates the human condition of Wolfram syndrome.
Besides “Base Editing,” we’re diving deep into an even newer method called “Prime Editing.” This is cutting-edge technology in gene correction. For this endeavor, we’re collaborating with Dr. David Liu and his team from Harvard/MIT, who are at the forefront of this field.
Ultimately, our heartfelt goal is to harness these innovative techniques to bring relief to those living with Wolfram syndrome.
Regenerative Therapy for Optic Nerve Atrophy – Gene Therapy and Mesenchymal Stem Cell Transplantation
We’re looking into new ways to heal and even reverse damage to the optic nerve, which is the nerve in our eyes that helps us see. We’ve come up with two main ideas.
First, we’re trying to introduce a special regenerative factor, called MANF, into the eyes of patients with Wolfram syndrome. We use a virus (a safe one!) to help deliver this factor. MANF helps protect retinal ganglion cells and encourages them to grow.
Secondly, we’re testing the use of special cells, called mesenchymal stem cells, which we can get from fat tissues or bone marrow. In previous tests with animals, these cells have been shown to help eye nerve cells survive and grow back after damage.
Right now, we’re doing more tests using MANF in rodent models of Wolfram syndrome developed in our lab. If everything goes well, we hope to test these methods on actual patients in the next 3- 7 years.
Clinical service
At the Washington University Medical Center’s Center for Advanced Medicine, we have established the Wolfram Syndrome and Related Disorders Clinic program, aimed at improving clinical care for patients with Wolfram syndrome and related disorders, including WFS1-related deafness and optic nerve atrophy.
Our program provides genetic evaluations, education, and counseling services to patients and family members of all ages who have either been diagnosed with Wolfram syndrome, are suspected of having it, or have WFS1-related disorders.
Our team collaborates with other specialists, including neurologists, neuro-ophthalmologists, urologists, medical geneticists, and endocrinologists at our medical center, to provide personalized management plans. We strive to see patients either on the same day or within two consecutive days. Our services are available to both pediatric and adult 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
So many things are happening in the world of Wolfram syndrome. Let’s keep the momentum going! Our team’s dedication to therapeutic development for Wolfram syndrome shines bright, and it’s deeply inspired by the resilience of patients and families facing this condition. The positive results we’re seeing are truly uplifting and fuel our hope for the future. While challenges remain, rest assured, we’re wholeheartedly committed to driving breakthroughs that could transform the lives of those with Wolfram syndrome. Stay tuned for more updates, and a huge thank you for being our rock-solid support!
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
Washington University School of Medicine
https://wolframsyndrome.wustl.edu/
8th International Wolfram Symposium Presentation Liiv M1, Vaarmann A1, Kuum M1, Gupta-Blixt R1, Janickova L1, Hodurova Z1, Cagalinec M1, Zeb A1, Choubey V1, Hickey MA1, Safiulina D1, Yi-Long H2, Gogichaisvili N1, Mandel M1, Plaas M1, Vasar E1, Loncke J3, Vervliet T3, Tsai T-F2, Bultynck G3, Veksler V4, Kaasik A1.1Departments of Pharmacology and Physiology, University of Tartu, Estonia. 2Department of Life Sciences, National Yang Ming Chiao Tung University, Taiwan 3Laboratory of Molecular and Cellular Signaling, KU Leuven, Belgium. 4INSERM UMR-S 1180, University Paris-Saclay, France.
Pharmacological targets to correct deficient ER-mitochondrial Ca2+ homeostasis in the neuronal models of Wolfram Syndrome
Abstract: Wolfram syndrome (WS) is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in WS involves poor endoplasmic reticulum (ER) Ca2+ handling, but how this disturbance leads to the disease is not known. Although the clinical symptoms of WS resemble mitochondrial diseases and WFS1 or CISD2 deficiency leads to mitochondrial abnormalities, no causal link has been established between the ER defects, mitochondrial dysfunction and cell metabolic disturbances. The current study, performed in primary isolated neurons, the most affected and disease-relevant cells, involving both WS genes explains how the disturbed ER Ca2+ handling compromises mitochondrial function and in turn affects neuronal health. Loss of ER Ca2+ content in the axons of the WFS1 or CISD2 deficient neurons is associated with lower IP3R3-mediated Ca2+ transfer from ER to mitochondria leading to decreased mitochondrial Ca2+ uptake. In turn, reduction in mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased axoplasmic NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress further compromise the neurons health. Our work also identifies pharmacological targets and compounds that potentially may restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal function.
Points noted:
• Compounds affecting ER and mitochondrial Ca2+ could improve mitochondrial function and neuronal health.
• WS serves as an important disease prototype for ER and mitochondrial dysfunction.
• Hope to publish findings soon.
8th International Wolfram Symposium Presentation Fumihiko Urano, MD, PhD, Samuel E. Schechter Professor of Medicine, Washington University School of Medicine, St. Louis, USA
Novel Therapies for Wolfram Syndrome
Abstract: Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision and progress on developing novel treatments and achieving a cure for Wolfram syndrome. Our approach entails utilizing oral pharmacotherapy aimed at modulating endoplasmic reticulum and mitochondrial functions to impede the progression of the disease, followed by the implementation of gene therapy to arrest its advancement, ultimately culminating in the application of regenerative therapy using a unique neurotrophic factor, MANF, and iPSC-derived tissues for the repair of any damaged tissues, especially retinal ganglion cells and brain cells. Our proposed approach has the potential to not only alleviate the symptoms of Wolfram syndrome, but it may also lead to a potential cure for medical conditions commonly seen in Wolfram syndrome, including diabetes, vision loss, and neurodegeneration. This is due to the innovative nature of our strategy, which targets the root cause of Wolfram syndrome, thereby offering a universal solution for a wide range of human chronic disorders.
Points noted:
• Dr Urano is working with many collaborators. The team have medical records for +250 patients (2009-present) and long-term data for +50 patients (2011- present).
• There is an increased understanding of this rare disease.
Look to identify patient cohorts for clinical trials and the best outcome measures.
• Previous dantrolene clinical study showed improved beta cell function in a subset of patients. Patients with greatest increase tended to have visual acuity and less severe disease.
• AMX-0035 – preclinical studies have confirmed that this combination therapy performs better than a single agent (e.g. reduced cell death and improved mitochondrial function). First clinical trial initiated in April 2023 with C-peptide as the primary outcome measure.
• S1R agonist (Pridopidine) is being tested in pre-clinical models (through collaboration with Prilenia).
• Working with an industry partner on gene therapies and gene editing with Prof Catherine Verfaillie. Willing to share protocol for iPSCs models with other researchers.
• Shared WS mutant rodent (rat and mice) models with other researchers and is willing to share with additional researchers who would like them.
• For entrepreneurship, need industry partners, which are also needed in Europe (current industry collaborators are US companies).
8th International Wolfram Symposium Presentation Prof Timothy Barrett, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK, on behalf of the TREATWOLFRAM investigators (Dr Renuka Dias, Dr Ben Wright (UK), Dr Gema Esteban Bueno (Spain), Prof Wojciech Mlynarski (Poland), Dr Christophe Orssaud, Prof Agathe Roubertie (France)
Sodium Valproate efficacy and safety in WFS1 Spectrum Disorder (TREATWOLFRAM). Update on phase II pivotal international multicentre, double-masked, randomised controlled trial.
ABSTRACT: Introduction
WFS1 spectrum disorder (WFS1-SD) comprises a classic form of progressive neurodegenerative disorder, formerly known as Wolfram syndrome, and non-classic forms including low-frequency sensorineural hearing loss. This is the commonest monogenic syndrome of diabetes and vision impairment, affecting 1:500,000 in the UK. Despite this, there are no licensed pharmacological therapies for WFS1-SD. Sodium valproate (VPA) is an anti-convulsant approved for use for the treatment of epilepsy and bipolar disorder. VPA has been shown to reduce Endoplasmic Reticulum (ER) stress, is known to exert neuroprotective effects in models of neurodegeneration, and in the context of WFS1-SD, VPA is thought to mediate its effect via alteration of cell cycle kinetics, increase in p21cip1 expression levels or nuclear translocation and reduction in apoptosis, and increase in Wolfram protein expression. There is currently a lack of prospective controlled studies investigating therapeutic candidates in people with WFS1-SD.
Methods
TREATWOLFRAM is a phase II, pivotal, international multi-centre, double-masked, placebo-controlled, randomised clinical trial designed to investigate whether a 36 month treatment with up to 800mg/day of VPA in children aged 6-12 years, or up to 1600mg/day for those aged 12 years of over, will slow the rate of change in visual acuity as assessed by corrected visual acuity in each eye, using standardised charts, in participants with WFS1-SD. Children aged 6 years or more and adults with genetically confirmed WFS1-SD and visual acuity with LogMAR score of 1.6 or better on an EDTRS chart, were assessed for eligibility at 6 recruitment centres in Europe. Patients who satisfied the eligibility criteria were randomly assigned (2:1) to receive twice daily tablets of either VPA or VPA-placebo (control). Analysing visual acuity outcomes using longitudinal hierarchical models, and using data on a cohort of 26 patients with Wolfram syndrome kindly provided by Prof Tamara Hershey, (significance level 0.05, power 0.90), and accounting for an estimated 15% withdrawal rate, we estimated a target sample size of 70 patients, so that a minimum of 21 participants were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable participants achieving a decline in the rate of progression of vision loss between baseline and after 36 months of treatment. Visual acuity progression will be defined as the change in LogMAR units over time as measured on EDTRS charts.
Ethics and dissemination
The protocol was designed with assistance from the EU Committee for Medicinal Products for Human Use (CHMP) and approved by The West of Scotland Research Ethics Service (18/WS/0020) and The Medicines and Healthcare Products Regulatory Agency (EudraCT 2017-001215-37; ISRCTN 10176118). Recruitment into TREATWOLFRAM started in January 2019 and ended in October 2021, with 63 patients randomised. The treatment follow-up of TREATWOLFRAM patients is currently ongoing and due to finish in October 2024. The findings of this trial will be disseminated through peer-reviewed publications.
Trial registration: Clinicaltrials.gov NCT03717909 Points noted:
• Visual acuity is the primary endpoint of TreatWolfram. A number of secondary endpoints are also included.
• Sodium valproate targets the final part of the treatment pathway. This drug has decades of use, has been shown to be neuroprotective and as it is off- patent – there is freedom to operate in clinical trials and ongoing licensing.
• TreatWolfram received 2014 orphan drug designation by EMA and FDA. Regulators may not require a gold standard double blind randomised controlled trial today.
• The trial was delayed by a range of issues – as a result some patients were unable to participate as their vision had deteriorated while awaiting trial commencement.
• If starting the study today, Milan would be included as a study site (this group has been developing a clinical trial centre).
• University of Birmingham now has an established clinical trial unit for delivering pivotal trials in rare disease and a network of trial sites that would like to be included in future WS clinical trials in Europe.
• The study clearly highlighted that Brexit has been damaging for rare disease research.
• Better biomarkers are needed that can demonstrate efficacy in around 6 months that are relevant for patients. Researchers need to be able to identify responders to potential treatments in a much shorter timeframe.
• With better biomarkers, new clinical trials could be designed to report in a shorter timeframe (and should therefore be less expensive). This could help attract more commercial partners into WS clinical research.
• It was noted patient samples will be available to help assist in developing biomarkers, including placebo data from clinical trials.
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