8th International Wolfram Symposium Presentation Fumihiko Urano, MD, PhD, Samuel E. Schechter Professor of Medicine, Washington University School of Medicine, St. Louis, USA
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).