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Development of a High-Throughput Sensor Library to Correct Over 60% of Known Pathogenic Variants in WS

Principal Investigator Dr. Samagya Banskota, Boston, USA

  • This project will attempt to make gene editing available to all WS patients who have a variant that involves a single base pair change (missense variant). Over 60% of people with WS with documented genotypes may benefit from this strategy.
  • This approach is important because a single attempt at gene editing for WS, right now, will only treat one patient/variant at a time.
  • This work by Dr. Banksota will attempt to create a “Platform” approach in which the basic gene-editing “machinery” will be the same, only the specific variant to be corrected will differ. In this way, the same drug/treatment could be used for over 60% of people with WS, regardless of their many different variants.
  • Such a platform approach will save many millions of dollars in drug development costs and many years of drug development time.
  • This project is very timely, given the gene editing preclinical data being generated now and in the near future by Drs. Urano, Banskota, and De Groef. If successful, this platform library will open the door to applying this same technique to all WS patients with missense variants concurrently in a potential gene editing/base editing clinical trial for WS.
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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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TREATWOLFRAM international clinical trial of sodium valproate in Wolfram syndrome: interim results

First results from the TREATWOLFRAM trial, sponsored by the University of Birmingham, find sodium valproate treatment does not slow vision loss in Wolfram syndrome.

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Long term clinical follow up of four patients with Wolfram syndrome and urodynamic abnormalities

Objectives: Wolfram syndrome is characterised by insulin-dependent diabetes (IDDM), diabetes insipidus (DI), optic atrophy, sensorineural deafness and neurocognitive disorders. The DIDMOAD acronym has been recently modified to DIDMOAUD suggesting the rising awareness of the prevalence of urinary tract dysfunction (UD). End stage renal disease is the commonest cause of mortality in Wolfram syndrome. We present a case series with main objective of long term follow up in four children having Wolfram syndrome with evaluation of their urodynamic profile.
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