Project Information

Data-driven drug discovery for AT – interrogation of dysfunctional pathways at single-cell resolution in cerebellar organoids

Principal researcher: Dr Sam Nayler

Institute: QIMR Berghofer Medical Research Institute, Queensland, Australia

Cost: £149,690.39 co-funding in partnership with Action for A-T (UK), AEFAT (Spain) and BrAshA-T(Australia)

Start Date: 1st of December 2022

Completion Date: 1st of February 2026

Project Overview

This study used cutting edge stem cell technology to create “mini brains” from AT patients, allowing researchers to study the disease in human cells for the first time at single cell resolution. By analysing more than 20,000 cells, the team uncovered major problems in energy production, immune responses, and glutamate handling caused by loss of the ATM gene. They also added microglia to model neuro immune interactions and tested drugs such as Riluzole and 4 aminopyridine, which showed early signs of restoring normal cell function. The project produced a powerful new platform for understanding AT and identifying promising treatment strategies.

Research Methods and Outcome

Dr Nayler and his team used advanced stem cell technology to grow cerebellar organoids, or “mini brains,” from AT patients, healthy individuals, and gene corrected cells. They analysed more than 20,000 cells using single cell RNA sequencing, allowing them to see how each cell type behaves when the ATM gene is missing. They examined the makeup of these mini-brains one cell at a time, in high numbers and also generated microglia, the brain’s immune cells, and integrated them into the organoids to study neuro immune interactions. Additional laboratory methods measured inflammation, energy metabolism, iron handling, and neural activity, including high throughput calcium imaging.
The study revealed major disruptions in energy production, immune responses, and glutamate handling across multiple brain cell types in AT. Purkinje neurons showed abnormal electrical activity, and AT microglia displayed weakened immune responses and metabolic stress. Although iron related genes were altered, iron levels themselves were unchanged.
Drug testing identified several promising candidates. Riluzole improved glutamate uptake, and 4 aminopyridine enhanced neural activity in AT organoids, suggesting potential therapeutic benefit. The project produced a publicly accessible dataset and a powerful new platform for future AT drug discovery.

What Next?

Thanks to this project, researchers now have one of the most advanced human models of AT ever created — and this opens the door to several exciting next steps. The team will continue testing the most promising drugs, including Riluzole and 4 aminopyridine, to confirm whether they can safely restore healthier brain cell activity. They are also expanding their work on energy boosting therapies, after discovering that AT cells struggle to produce and use energy efficiently. New collaborations have been established to explore immune targeting treatments and next generation compounds that stabilise the firing of Purkinje neurons — the cells most affected in AT. At the same time, the researchers will keep improving their “mini brain” models and sharing their data with scientists worldwide.

This project has created a powerful foundation for future breakthroughs. With continued support, the discoveries made by the team can be transformed into real therapeutic opportunities for people living with AT.

Publications

The team will complete the next phase of their study before any publications are created. You can learn more about this new work by visiting https://actionforat.org/data-driven-drug-discovery-for-a-t/