Development of a Gene Therapy approach to treat A-T
Research Project information
Principal researcher: Professor Samuel Young
Institute: University of North Carolina at Chapel Hill, USA
Cost: £249,128 in partnership with AEFAT (Spain) and BrAshA-T (Australia)
Start Date: 1st of September 2024 over 36 months
What are the researchers proposing to do?
Although A-T is a multisystem disease, one of the most devastating symptoms is the progressive degeneration of the cerebellum. The cerebellum is part of the brain that helps coordinate and regulate a wide range of functions and processes in both the brain and body. The degeneration of the cerebellum in A-T causes severe movement problems and results in children becoming full time wheelchair users by around the age of 10. Currently there is no clinically approved therapy to treat A-T cerebellar degeneration. Therefore, the goal of this project is to develop a therapeutic approach that treats the root cause of A-T induced cerebellar degeneration.
Why?
No clinically approved therapy that restores ATM expression in the cerebellum exists. ATM is the protein that does not function properly or is missing in children and adults with A-T. Some cells that are in the cerebellum don’t function well without ATM and gradually die off causing degeneration. Therefore, development of therapeutics to stop cerebellar degeneration is critical.
How will the research be done?
Gene therapy is a way to treat or prevent a specific disease by introducing normal functioning genes into cells in place of missing or defective ones to correct genetic disorders. A common way that researchers have found to accomplish this is by using a vector. Vectors are essentially vehicles designed to deliver therapeutic genetic material, such as a working gene, directly into a cell.
The researchers will use Helper Dependent Adenoviral vectors (HdAd). These vectors have improved safety profiles and have a large capacity to deliver genetic material. HdAd provides long-term gene expression without toxicity after a single administration in multiple preclinical animal models. Due to these features, HdAd has extraordinary promise to treat A-T. Currently, its use in the cerebellum has not been explored as current HdAd vectors do not work for Purkinje Cells (large neurons found in the cerebellum that are affected in people with A-T). Therefore, a knowledge gap exists in developing HdAd gene therapy approaches to treat A-T cerebellar degeneration.
Building on the lab’s decade of experience developing and using HdAd vectors in the central nervous system, the team have created a novel HdAd vector that transduces Purkinje cells and other cerebellar cell types in a mouse model. They will now carry out work to overcome the major limitations preventing the use of HdAd in the cerebellum and their objective is to develop an HdAd approach that delivers therapeutic levels of ATM and characterize their efficacy in restoring ATM function in Purkinje cells. They will use their novel viral vectors, to develop approaches for long-term expression and restoration of ATM function in Purkinje cells and other cerebellar cell types.
How could it make a difference in the lives of those affected by A-T?
This research represents the first steps towards establishing a therapeutic approach that treats the root cause of A-T induced cerebellar degeneration. Ultimately, the team hope their findings will lead to new gene therapy to treat all A-T induced neurological disorders and potentially in other organs.
