Qiu, Yichen; (2023) Transcriptional upregulation as novel gene therapy strategy for neurological disorder. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Epilepsy remains one of the commonest serious neurological diseases. 30% of people with epilepsy are refractory to pharmacological treatment, and surgical resection of the focal brain area remains the best option. Gene therapy is currently the most promising candidate replacement for surgical treatment of pharmaco-resistant focal epilepsy. Gene therapy targets carried by adeno-associated virus (AAV) offer high-efficiency delivery without significant aversive effects. This project aims to test the possibility of using novel anti-epileptic gene therapy strategies with potential clinical translation. We carefully analysed the available gene therapy strategies and identified key issues that need to be addressed. Gene therapies that modulate neuronal excitability cannot discriminate between neurons involved in pathological circuits and the healthy ‘bystanders’. We proposed a novel activity-dependent gene therapy strategy using inducible promoters to drive potassium channels overexpression in hyperactive neurons. We showed that this therapy successfully rescued pathological activities in epilepsy models. A second strategy we have investigated used CRISPR-activation (clustered regularly interspaced short palindromic repeats) system to transcriptionally modulate endogenous potassium channel expression at rescued epilepsy activities in animal epilepsy models. In conclusion, this thesis describes two novel gene therapy strategies that have great potential in treating neurological disorders.

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