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.

Outline

Introduction and Presentation Overview

• Benjamin Delprat introduces himself and his team, mentioning his role as a Research Director at Inserm in Montpellier, France.
• Benjamin Delprat provides a brief history of Wolfram syndrome, describing its symptoms and the lack of available treatments.
• He explains the focus of his research on the endoplasmic reticulum and the role of the WFS1 protein in cellular function.

Research Methods and Findings

• Benjamin Delprat describes the use of yeast to screen for proteins interacting with WFS1, identifying NCS1 as a key partner.
• He explains the role of NCS1 in neurotransmitter release and cell survival, and its potential as a target for treatment.
• Benjamin Delprat discusses the interaction between NCS1 and IP3R, a calcium channel crucial for cellular energy production.
• He presents a metaphor to explain the role of the endoplasmic reticulum and mitochondria in cellular energy production.

Gene Therapy and Pharmacological Therapy

• Benjamin Delprat outlines the goal of developing a gene therapy targeting NCS1 to restore cellular function in Wolfram syndrome patients.
• He describes the use of self-complementary AAV9 vectors for gene therapy, aiming for systemic administration to transduce multiple organs.
• Benjamin Delprat explains the second part of his research, focusing on developing a pharmacological therapy targeting the sigma-1 receptor.
• He discusses the potential of sigma-1 receptor agonists and antagonists in modulating cellular function and their clinical relevance.

Zebrafish Model and Experimental Results

• Benjamin Delprat introduces the use of zebrafish as a model for Wolfram syndrome, highlighting their rapid development and cost-effectiveness.
• He describes the phenotyping of zebrafish larvae to measure swimming capacity and assess the impact of WFS1 mutations.
• Benjamin Delprat presents results showing that overexpression of NCS1 in zebrafish larvae corrects hyperlocomotion and mitochondrial impairment.
• He discusses the use of pharmacological agents to activate the sigma-1 receptor and improve zebrafish larvae phenotypes.

Conclusion and Future Directions

• Benjamin Delprat concludes by summarizing the proof of concept obtained in zebrafish and the ongoing work in mouse models.
• He mentions the collaboration with the laboratories of innovation in therapeutic research to identify new sigma-1 receptor agonists.
• Benjamin Delprat expresses hope that the research will lead to effective treatments for Wolfram syndrome.
• The webinar continues with questions and discussions from the participants.