Project information
PRECISION-AT: A next-generation precision therapy development platform for splice-modulating ASO therapies in AT, advanced by novel therapeutic targets and chemistry.
Principal researcher(s): Professor Matthis Synofzik
Institute: Hertie-institute for clinical brain research and centre of neurology, Germany
Funding partner(s): The AT Society, Action for A-T (UK), AEFAT (Spain) and BrAshA-T (Australia)
What are the researchers proposing to do?
Professor Synofzik and his team are working to develop and improve a new type of personalised genetic medicine for children with AT, called antisense oligonucleotides (ASOs). These are tiny, custom-made chemical nucleic acid molecules that can correct the faulty genetic messages caused by certain mutations in the ATM gene, which causes AT.
Two children with AT have already received individually tailored ASO treatments with some initial encouraging preliminary clinical treatment results. The team now want to develop their work by: (1) extending the treatment so it can help a larger group of AT patients whose specific ATM mutations could not be targeted before; (2) testing new, improved chemical designs for ASOs, so that this invasive treatment can be delivered with better effect and less often; and (3) combining these advances to achieve the strongest possible effect for the hardest-to-treat gene faults.
Why?
ASO therapies offer real hope to people affected by AT. ASO’s can in principle be tailored to a person’s own individual gene fault by allowing for a treatment right upstream at the origin of the disease cascade (rather than only downstream, at certain signal pathways like other current treatments for AT). However, right now this novel, highly innovative treatment approach can only help a limited number of AT patients, as it can only be applied to a very infrequent ATM mutation class (cryptic splice mutations), and treatment needs to be given often, requiring repeated invasive hospital procedures. This project aims to widen the type of ATM mutations eligible to this novel individualised treatment option, and thus the number of children who could benefit from this kind of personalised treatment. It also aims to make this unique treatment pathway for AT more powerful and longer lasting, easing the burden on children and their families.
How will the research be done?
All of the research will be carried out in the laboratory, using cells donated by children with AT and their family members. The project has three connected parts:
1. The team will design and test new ASOs aimed at a type of the ATM mutations that could not be targeted before (=splice-disrupting mutations), to see whether they can restore the missing ATM protein;
2. They will test three newly developed chemical formulations of ASOs, to find out whether any of them work better and last longer than the ASOs currently used, without causing side effects;
3. They will combine the most promising new ASO ATM gene-targeting approach with the most promising new chemical formulation they have identified, to test whether combining them gives an even stronger treatment effect for these hard-to-treat ATM mutations.
Throughout the project, the team will use well-established laboratory tests to measure how well the treatments restore the missing protein, and to check that they remain safe.
How could this make a difference to the lives of those affected by AT
If successful, this project could take an important step towards making personalised ASO treatment a realistic future option for substantially more ATM mutations and, over time, for more children with AT whose specific gene faults cannot currently be targeted. It could also lay the groundwork for more effective and longer-lasting approaches that may eventually need to be given far less often, helping to reduce the number of invasive hospital procedures children must undergo and easing the burden on children, families and healthcare teams.
In the longer term, this early-stage work could contribute to building a sustainable framework for delivering personalised genetic medicines to children with AT, moving the field closer to therapies that could help slow disease progression by targeting its underlying genetic cause. The methods developed could also open new avenues of research for other rare genetic diseases, extending the hope and potential impact of this work beyond AT alone.