Development of next-generation gene therapy vectors for the treatment of epilepsy

Project: Research

Project Details


It is well established that the protein Tau regulates post-synaptic signaling pathways that mediate neuronal hyperexcitation (='excitotoxicity') in several diseases, including Alzheimer's disease, epileptic seizures, and stroke. We have recently demonstrated that these post-synaptic, tau-associated pathways are regulated by the activity of the neuronal p38gamma MAP kinase, revealing a novel target for therapeutic intervention in these disorders. Building on these discoveries, we have developed a novel gene therapy vector for targeted increase of neuronal p38gamma kinase activity. In our recently published work, we demonstrated that treating various mouse models of epilepsy (both childhood epilepsy and temporal lobe epilepsy models) with this gene therapy significantly prolongs survival, improves behavioural deficits and prevents acute and reoccurring seizures. With this proposal, we aim to extend on these findings to establish p38gamma-targeting gene therapy as a novel treatment for epileptic conditions, which we hypothesize will target underlying disease mechanisms for significant, prolonged clinical outcomes. This is particularly important as up to 30% of clinical epilepsy is therapy resistant with poor clinical outcomes. Firstly, we aim to test our novel gene therapy in a more physiologically relevant human setting by using patient-derived 3D stem cell culture models (organoids), to further clinical translation. Secondly, to address concerns surrounding potential impacts associated with long-term gene overexpression in patients, we aim to establish several new, regulatable gene therapy vectors for the temporal control of gene expression in neurons, which will have broad therapeutic value to a vast range of neurological conditions. These aims will also include critical experiments to establish the safety and toxicity profiles of our novel vectors, which essential for clinical translation. Together, these aims will help pave the way towards clinical testing.
AcronymIDEAS 23
Effective start/end date1/01/2431/12/26