Generation and characterisation of cortical interneurons from human pluripotent stem cells (360G-Wellcome-099823_Z_12_A)

Inhibitory interneuron dysfunction is believed to lead to runaway excitation implicated in seizure­ based diseases, such as epilepsy. However, due to a lack of defined aetiology and causal mechanisms of the pathogenesis, there is currently no effective treatment for these conditions. The generation of neurons from pluripotent stem cells, either derived from patients carrying defined genetic variants, or engineered in culture with disease relevant genetic modifications, offer a unique path to investigate the underlying disease mechanisms. Moreover, exciting experimental cell therapy has shown that foetal-derived interneuron precursors can reverse seizure severity and reduce mortality in adult epileptic rodents. These proof-of-principle studies raise hope for potential interneuron-based transplantation therapies for treating epilepsy. Therefore, this PhD project aims to generate defined functional cortical interneurons from human pluripotent stem cells. The specific objectives are: 1, To establish an interneuron reporter cell line by genome editing in human ESCs; 2, To optimise interneuron production strategy and to perform phenotypic and functional characterisation of the derived human neurons; 3, To investigate the differentiation potential and functionality of hPSC-derived interneurons in vivo by transplantation. The anticipated outcome of this work will be the establishment of an improved inhibitory neuron differentiation regime and parameters for interneuron transplantation.