Development of antisense oligonucleotide and base editing therapeutics for neurodevelopmental haploinsufficiency disorders
This project is part of the Therapeutic Genomics Centre, a multidisciplinary programme of innovative approaches to treating rare genetic disorders and providing an enhanced training experience for DPhil applicants.
Academic Supervisors: Dr. Thomas Roberts, Prof. Matthew P.A Wood
Other Supervisors: Dr. Dhanu Gupta
Host Dept: Paediatrics, Oxford
Neurodevelopmental disorders constitute a group of diseases in which the normal development of the nervous system is disrupted and for which treatment options are currently very limited. As such, neurodevelopmental disorders constitute a major unmet and neglected clinical need. Many neurodevelopmental disorders are caused by low levels of expression of the disease-causing gene (i.e. haploinsufficiency) and so gene activation strategies are desirable.
This proposal aims to generate therapeutics that can activate gene expression at the level of translation in order to treat or manage specific neurodevelopmental disorders by compensating for haploinsufficiency. We have identified upstream open reading frames (uORFs) as gene regulatory elements that are possible targets for therapeutic intervention. uORFs act to repress the translation of their associated protein coding sequences, and so disrupting their function can lead to targeted protein upregulation. Importantly, many genes associated with neurodevelopmental disorders contain predicted uORF sequences. More than 10 such targetable neurodevelopmental genes have been identified in initial computational screens, and the Therapeutic Genomics Centre will expand this list. Here we propose to experimentally validate these targets, and then screen molecular medicine drugs intended to upregulate them. We will utilise both antisense oligonucleotide and CRISPR-Cas9 base editing approaches for targeted uORF disruption. The proposed work has the potential to identify lead candidate molecules for multiple currently untreatable neurodevelopmental diseases.
Studentship code: MRCTGCORE2024005
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