From the Desk of Dr. Sarah Gladstone

Chief Medical and Scientific Officer

From the Desk of the Dr. Sarah Gladstone, CMO/CSO

As we enter 2026 and look back on 2025, it’s remarkable how much progress has been made in such a short time.Scientific research can be challenging—there are periods when progress feels slow and frustrating, and answers seem just out of reach. Then there are moments when things finally come together: the data start to make sense, key questions are answered, and important milestones are achieved. We are now in a time of data coming together. What follows is a look back at the progress made in 2025, and an exciting look ahead at the possibilities now opening up for the year to come. Treating Wolfram syndrome is not a one-size-fits-all approach. The condition itself is not the same for everyone. Each person with Wolfram syndrome has a unique combination of symptoms based on their specific genetic variation and individual biology. Because of this, treatment may differ from person to person depending on age, genetic findings, and which symptoms are most prominent. Even though treatments may differ, the overall treatment strategy follows a clear and consistent path. The goals remain the same:

  • First, to slow the progression of cell stress and dysfunction;
  • Second, to prevent ongoing cell death;
  • Ultimately, to replace damaged cells with new, healthy cells.

Based on the expressed needs of the Wolfram syndrome community, current treatment efforts focus on the central nervous system (including the brain, retina, vision, and hearing), the pancreas (diabetes), and bowel and bladder function, while also addressing other associated symptoms. It has been an incredibly busy and fulfilling year…. and decade! We are profoundly thankful to our donors and supporters—you are the reason this work happens. Your generosity fuels every step forward, and we are so grateful to have you as part of this community. Because of you, we are moving forward with energy, hope, and momentum. The year ahead is shaping up to be an exciting one, and we can’t wait to celebrate and share our progress with you in 2026!

— Dr.Sarah Gladstone

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TREATWolfram — What’s next? – Virtual Global Research and Trial Updates

Overview

Professor Timothy Barrett presented updates on the Treat Wolfram trial, focusing on the use of sodium valproate for Wolfram syndrome. The trial, involving 42 valproate-treated and 21 placebo-treated patients, aimed to assess vision loss over 36 months. Despite a younger, healthier placebo group, valproate showed trends towards stabilizing HbA1c and insulin-adjusted HbA1c, and increasing C-peptide levels. However, no statistically significant reduction in visual acuity was observed. Future plans include reanalyzing data with a better-matched placebo group and exploring new treatments. The trial’s natural history data will inform future trial designs.
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Amylyx HELIOS Trial Week 48 Results and Updates – Virtual Global Research and Trial Updates

Overview

Jamie Timmons from Amylyx presented the HELIOS trial results for Week 48, focusing on the investigational therapy AMX 35 (sodium phenylbutyrate and ursodil) for Wolfram syndrome. The trial, involving 12 participants, showed improvements in pancreatic beta cell function, insulin secretion, and glycemic control, with a significant reduction in hemoglobin A1c levels. The therapy was generally well-tolerated, with diarrhea being the most common side effect. The phase three trial is planned for the second half of next year, with a larger participant pool and potential inclusion of younger patients and those with single-allele mutations. Use is not currently available due to drug supply limitations.
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Virtual Global Research and Trial Updates

Overview

Vania Broccoli presented on Wolfram syndrome, highlighting the role of the WFS1 gene and its protein, Wolframin, in protein synthesis and folding. She discussed the impact of WFS1 mutations on retinal ganglion cells, leading to optic atrophy and vision loss. Broccoli’s research involved gene replacement therapy using adeno-associated viral vectors to restore Wolframin function in both glial cells and retinal ganglion cells in mice. Preliminary results showed improved visual activity and reduced retinal ganglion cell loss in treated mice. The discussion also covered ongoing clinical trials with amalex and the challenges of obtaining GLP-1 agonists in the UK.
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Restoring Sight: Therapeutic Perspectives in Wolfram disease – Virtual Global Research and Trial Updates

Overview

Dr. Cécile Delettre-Criballet presented on therapeutic perspectives for Wolfram disease at a global virtual conference. Her team at the Institute for Neuroscience of Montpellier focuses on hereditary optic neuropathies and anterior segment diseases. They use genetic diagnostics, pathophysiological studies, and clinical trials to develop treatments. Key findings include the effectiveness of gene therapy in mouse models, showing improved visual acuity and reduced axonal damage. They also explored pharmacological approaches using synthetic polyamines, which enhanced retinal ganglion cell growth in zebrafish models. The discussion highlighted the potential of these therapies to address Wolfram syndrome’s optic atrophy and other symptoms.
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Wolfram Syndrome Clinical Trials: Advancing Treatments from Medications to Gene-Editing

Overview

Dr. Fumi Urano from Washington University discussed Wolfram Syndrome clinical trials, focusing on advancing treatments from oral medications to gene editing. Wolfram Syndrome, a rare genetic disorder with a median age of onset at 6 for diabetes and 11 for optic nerve atrophy, affects 1 in 250,000 to 700,000 people. Dr. Urano highlighted the severity categorization system (1-6) based on mutation types and shared a case study of a patient with mild manifestations due to a common Ashkenazi Jewish variant. The study on AMX 35, a drug to mitigate endoplasmic reticulum stress, showed improved insulin production and glycemic control in a 48-week clinical trial. Future steps include gene editing therapy and regenerative therapy.
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Wolfram syndrome: from physiopathology to therapy – Virtual Global Research and Trial Updates

Overview

The meeting discussed Wolfram syndrome, focusing on its physiopathology and potential therapies. Benjamin Delprat presented his research from Inserm, Montpellier, highlighting the role of the WFS1 protein and its interaction with NCS1 and IP3R in cellular calcium transfer. He proposed gene therapy using self-complementary AAV9 vectors to overexpress NCS1 and pharmacological therapy targeting the sigma-1 receptor. Preclinical studies in zebrafish showed that NCS1 overexpression corrected mitochondrial impairment, while sigma-1 receptor agonists improved hyperlocomotion. Future work includes validating these findings in mouse models and identifying new sigma-1 receptor modulators.
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Preliminary results on the Tirzepatide monotherapy in Wolfram syndrome trial – Virtual Global Research and Trial Updates

Overview

Dr. Giulio Frontino and Amelia Caretto presented preliminary results from a trial on Tirzepatide monotherapy for Wolfram syndrome. The trial, involving 17 patients (including children and adults), showed stabilization of C-peptide levels in half of the patients, with a median increase of 15% over two years. Tirzepatide improved beta-cell function and reduced inflammation markers. However, retinal nerve fiber layer thickness decreased in some patients, possibly due to pubertal hormonal changes. The trial also noted stable BMI and improved HbA1c levels. Side effects were mild and manageable, with no severe adverse events reported.
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A Hidden Diagnosis: Neurogenic Bladder Leading to Acute Kidney Failure in Wolfram Syndrome

Publication: cureus.com | Publication Date: 6 May 2025

Authors: Nadia Echcharii, Nabila Chekhlabi, Amal Haoudar, Nezha Dini

Abstract

Wolfram syndrome (WS) is a rare, autosomal recessive neurodegenerative disorder characterized by progressive multisystemic involvement, including diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural hearing loss, and urological dysfunction. While diabetes mellitus is typically the first clinical sign, atypical presentations can delay the diagnosis.

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A Rare Case of Wolfram Syndrome in a 27-Year-Old Male From Nepal

Publication: cureus.com | Publication Date: 25 October 2025

Authors: Tej P. Shah, Richard Sidlow, Prem K. Sah

Abstract

Wolfram syndrome is a rare autosomal recessive disorder characterized by diabetes mellitus, optic atrophy, and progressive neurodegeneration, often summarized by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We report a 27-year-old male with a history of diabetes mellitus, progressive visual loss leading to blindness, and bilateral sensorineural hearing loss. His family history was notable for diabetes-related mortalities and visual impairment in multiple members of the family. Clinical evaluation showed uncontrolled blood glucose level, optic atrophy, and high-frequency sensorineural hearing loss. A clinical diagnosis of Wolfram syndrome was made using the Euro-Wolfram, Alström, and Bardet-Biedl (WABB) criteria. Wolfram syndrome should be suspected in young patients with early-onset diabetes mellitus and visual or hearing impairment. This case report highlights the role of timely multidisciplinary management in preventing disease-related complications.

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