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.

Action Items

• Publish the details of the AMX 35 clinical trial results.
• Report the results of the investigation into the use of GLP-1 receptor agonists in Wolfram syndrome patients by the end of the year.
• Continue preclinical studies on gene-editing therapies for Wolfram syndrome, including testing engineered virus-like particles to deliver the gene-editing components.

Overview of Wolfram Syndrome

Introduction and Presentation Overview

• Dr. Urano provides an overview of Wolfram Syndrome, a rare genetic disorder with juvenile onset.
• Key symptoms include optic nerve atrophy, deafness, central diabetes, and neurodegeneration.
• The disorder is caused by mutations in the WFS1 and WFS2 genes, with most patients having Wolfram Syndrome Type 1.
• Wolfram Syndrome is an autosomal recessive disorder, with a prevalence of 1 in 250,000 to 700,000.

Multidisciplinary Approach and Clinical Studies

• Dr. Urano discusses the multidisciplinary Wolfram Syndrome clinic at Washington University Medical Center.
• The clinic is designated as a center of excellence by the National Organization for Rare Disorders.
• Participation in registry and natural history studies is encouraged to understand the clinical manifestations.
• Blood samples from patients are crucial for identifying new biomarkers and understanding the genetic severity categorization system.

Case Study: Mild Manifestations in Wolfram Syndrome

• Dr. Urano shares a case study of a patient with mild manifestations of Wolfram Syndrome.
• The patient was diagnosed with gestational diabetes and type 2 diabetes at older ages, despite being lean and antibody negative.
• The patient carries a common WFS1 gene variant common in Ashkenazi Jewish populations, associated with mild manifestations.
• The study aims to understand why some patients have milder manifestations and the stability of certain gene variations.

Therapeutic Development: Oral Medications and Gene Editing

• Dr. Urano outlines a three-step formula to cure Wolfram Syndrome: slowing progression with oral medications, stopping progression with gene editing therapy, and reviving tissues with regenerative therapy.
• The focus of the talk is on gene editing therapy, targeting the upstream problem of pathogenic variations in the WFS1 gene.
• The goal is to prevent downstream consequences such as diabetes, optic nerve atrophy, and brain problems.
• AMX 35, a combination of two chemical chaperones, is identified as a promising molecule to mitigate endoplasmic reticulum stress.

Clinical Trial of AMX 35

• Dr. Urano discusses the clinical trial of AMX 35, which started in 2023 and completed its 48-week timepoint.
• The trial enrolled 12 patients, with outcomes measured in diabetes-related, eye-related, and neurological functions.
• The trial showed improved C-peptide response, decreased hemoglobin A1C levels, and stabilized visual acuity.
• The therapy is well-tolerated and safe, with the next step being a phase three clinical trial using patient-oriented outcome measures.

GLP-1 Receptor Agonists and Patient Data

• Dr. Urano addresses common questions from patients about GLP-1 receptor agonists like semaglutide, dulaglutide, and tazepatide.
• A registry of 378 patients with Wolfram Syndrome is used to gather data on the use of GLP-1 receptor agonists.
• The data shows that 84 patients have insulin-dependent diabetes, with 54 patients only on insulin.
• The study aims to determine the effectiveness and side effects of different GLP-1 receptor agonists.

Gene Editing Therapy: Proof of Concept and Preclinical Studies

• Dr. Urano explains the concept of gene editing therapy to replace misspellings with correct spellings.
• Proof of concept studies in beta cells showed restored insulin production after gene correction.
• Collaboration with Dr. Samavia’s group at Boston University is ongoing to replicate the success in other organ systems.
• The base editing system is preferred over CRISPR Cas9 to avoid double-stranded DNA breaks and increase target efficiency.

Preclinical Studies and Future Directions

• Preclinical studies are conducted targeting three mutations in Wolfram Syndrome patients.
• The base editing system is tested in patient-derived neural progenitor cells, cortical neurons, and insulin-producing beta cells.
• Engineered virus-like particles are used to deliver the base editor and guide RNA to cells.
• The goal is to correct mutations and improve cellular functions, with ongoing experiments to assess the efficacy of the treatments.