Recent Advances in Therapy for the Neurodegenerative Disorder Ataxia-Telangiectasia

At present, there is no cure for the human genetic disorder ataxia-telangiectasia (A-T), which is managed by supportive care. This disorder arises due to mutations in the ATM (ataxia-telangiectasia mutated) gene and is characterised by a defect in the response to DNA damage, oxidative stress, mitochondrial dysfunction and immune deficiency. The ATM protein is activated by DNA damage, reactive oxygen species (ROS), and a variety of other stimuli, which leads to the phosphorylation or altered cellular localisation of multiple protein substrates that participate in cellular defence pathways. ATM plays a central role in orchestrating cellular defence against stress, which forms a focal point for approaches to treating the symptoms in this disorder. These strategies involve boosting mitochondrial function and dampening the inflammatory response. A more direct approach to treatment is gene therapy, yet the leading method using Adeno-Associated Virus (AAV) is hampered by the large size of the ATM gene itself. The use of antisense oligonucleotides (ASO) as an alternative gene therapeutic approach to treat patients has been increasingly utilised. However, only certain mutations fit the criteria for ASO-based intervention, which encourages rescue through readthrough of premature truncation mutations. For this reason, small-molecule-based therapies addressing the multi-system nature of the disease are urgently required. We address these different approaches to therapy and the outcome of numerous recent clinical trials with A-T patients, as well as ongoing research that has potential to lead to therapy.