Exploring Omaveloxolone efficacy in Ataxia-telangiectasia
Research Project information
Principal researcher: Professor Paola Giunti (pictured) and Dr Rosella Abeti
Institute: University College London (UCL), UK
Cost: £24,893 over 4 months
Completion Date: January 2025
Project Overview
One of the processes happening in people who have A-T is increased oxidative stress. Oxidative stress is an imbalance of free radicals and antioxidants in your body that leads to cell damage. The team at UCL proposed to study a drug called Omaveloxolone (Omav). This drug is known to defeat oxidative stress in patients with Fredreich’s Ataxia, and the team wanted to investigate whether it could help overcome the adverse effects of oxidative stress in A-T cells.
Research Methods and Outcome
The study achieved it’s 3 milestones over the 4-month period:
- Growing cells from AT and non-AT individuals
Skin cells (fibroblasts) were collected from both A-T patients and healthy individuals. These cells were then carefully grown and multiplied in the lab, creating a cell model to use in the next two stages of the research. - Testing the effect of Omav on cellular stress
Cells from A-T patients were found to produce higher-than-normal levels of harmful molecules called reactive oxygen species (ROS), which can damage cells. This suggests that A-T cells struggle to control oxidative stress. When treated with Omav, ROS levels in A-T cells dropped significantly, reaching levels similar to those found in healthy cells. This result shows that Omav is effective in reducing oxidative stress in the A-T fibroblasts. - Understanding Omav effect on the Nrf2 pathway
Western blot analysis, a technique used to measure protein levels, showed that A-T patient cells have lower-than-normal levels of Nrf2, a protein that helps cells fight oxidative stress. This deficiency may contribute to the increased oxidative damage observed in A-T.
When the cells were treated with Omav, Nrf2 levels increased and ROS, a potent toxin present in A-T cells, was reduced. This shows that the drug can activate the Nrf2 pathway, which plays a key role in antioxidant defence.
What next?
These initial findings show that A-T patient cells are highly vulnerable to oxidative stress due to defective Nrf2 signalling. However, treatment with Omav restores their antioxidant capacity, making it a potential therapeutic strategy for reducing oxidative damage in A-T. The team hope this could modulate disease progression. More in depth studies are now needed to bring this drug to clinical trials in humans. The team are planning to prepare a follow-on research application.
Publications
The team are currently working on a manuscript for publication.
