Modelling Ataxia Telangiectasia pathogenesis and therapeutics using human pluripotent stem cells and genetic engineering.

Principal researcher:  Dr Núria Montserrat
Institute:  Institute for Bioengineering of Catalonia, Spain
Cost: €150.000 over 24 months in partnership with AEFAT (Spain) and BrAshA-T (Australia)
Start Date: Jan 2024

What are the researchers proposing to do and why?

A-T is caused by mutations in the ATM gene. The most debilitating symptom of the condition is the progressive neurodegeneration of the cerebellum. Those with A-T also have a higher chance of developing cancer. The molecular mechanisms driving neuro degeneration and cancer susceptibility remain unclear, due to limitations of current disease models. The team aim to generate ATM-defective human pluripotent stem cell lines (hPSCs) via CRISPR/Cas9* as a disease model for A-T. They will also carry out work to validate their model as a drug-screening platform by identifying several compounds that improve cell survival of ATM-defective hPSCs and differentiated products whilst also looking to identify predictive biomarkers for A-T patients. In summary, this project aims to explore the impact of ATM mutations by testing ATM protein expression in patient cells. This will be crucial for the generation of unique cellular models capturing A-T genetic backgrounds via genetic engineering in human pluripotent stem cells and organoids.

* CRISPR/Cas9 is a gene-editing technology. It makes it possible to correct errors in the genome and turn on or off genes in cells and organisms quickly, cheaply and with relative ease.  CRISPR/Cas9 has potential to be used to treat genetic disorders caused by single gene mutations, like A-T.

How could it make a difference to the lives of those affected by A-T?
If successful, this will be a unique in vitro platform and will enable the team to study A-T cellular phenotypes and potential therapeutics. This is very early-stage research, but the aim is to understand how to mitigate and alleviate the effects of A-T to move to ultimately developing a curative option.