Development of CRISPR/Cas Genome Editing as a Treatment for Ataxia Telangiectasia

Prof Yanez-Munoz

Research Project information

Principal researcher: Professor Rafael Yáñez-Muñoz
Institute:  Royal Holloway, University of London
Cost: £200,000 over 36 months
Project Completion Date: 30th June 2021

Project Overview
The aim of this project was to begin early research to explore the use of genome editing technology, known as CRISPR, to look at ways to permanently repair the ATM gene. The Royal Holloway based team hoped to use the technology to test ways to repair the faulty gene responsible for A-T (the ATM gene). Although the study offered much hope, it was widely acknowledged that the varied mutations in the disease could potentially make gene editing challenging.

Research Methods
Professor Rafael Yáñez-Muñoz and his team attempted to repair the faulty ATM gene using several different CRISPR genome editing strategies. They then tested these in human cells that are easy-to-grow in the lab. Next, they moved on to cells that have been derived from people affected by A-T, which harbour ATM gene mutations. Finally, they looked at genome editing approaches in human blood stem cells.

Project Outcome
The  first study objective was to attempt to replace the first or second half of the faulty gene dependent on where the ATM mutation was located. This was shown to be feasible but there was no evidence that the gene could be fixed. Work is ongoing to look at how this may be successfully achieved.

When they looked at repairing mutations relatively common in A-T using patient cell lines grown in the lab, they were able to detect correction of the ATM gene in a number of cases. Following this, changes in the cells suggest that there was successful fix of the gene.

There were some challenges with a lack of success with some of the repair templates used. Different vectors are now being explored in order to test the feasibility of achieving this (using Adeno-associated viral vectors). The group acknowledge that this was a technical challenge rather than a change of objective and their work in this field is ongoing with a master’s student.

Although the original study has now concluded, work continues as described above using AAV vectors and further gene editing using blood stem cells to test where the likely initial target for clinical application would be.

The team were very clear at the outset that this project involved very early research and unlikely to lead clinical applicability in the foreseeable future. There is a lot of work to be done to pave the way for a viable treatment option but with advances in CRISPR techniques and gene editing such research and the research that follows from it will be vital if gene editing in A-T is to be successful.

No publications are being proposed at this time.

What next?
Based on these early findings, the next stage of this project will focus on two approaches that have demonstrated as having potential.  We believe it is important to support ongoing work by this team to fully exploit and potentially benefit from this early research. Additional funding has therefore been provided for the additional strategies to be explored. Click here for more details.