Targeting Enhancers to Treat Neurological Diseases
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: Prof. Carlo Rinaldi, Prof. Stephan Sanders
Other Supervisors: Dr. Vanessa Almendro (Danaher), Prof. Nadav Ahituv (UCSF)
Host Dept: Paediatrics, Oxford
Enhancers are short DNA regulatory elements that regulate tissue-specific gene expression by recruiting the transcriptional machinery onto promoters of target genes. Enhancer RNAs (eRNAs) are non-coding RNAs transcribed from active enhancers, which are increasingly recognised as essential in forming the chromosome loop that brings the enhancers into close association with the promoters. Due to their fundamental role in various biological processes, enhancer-targeting approaches are rapidly emerging as promising therapies for both neurological and non-neurological conditions. This progress is highlighted by the recent seminal approval of the first gene-editing therapy, Casgevy (exagamglogene autotemcel), that works by targeting the erythroid-specific enhancer region of the BCL11A gene.
Using an approach that integrates both bioinformatics training available in the Sanders Group and newly generated large-scale single-cell datasets from human tissues to develop tools for accurate identification of eRNAs and wet lab training available in the Rinaldi Group which entails CRISPR gene-editing and antisense oligonucleotides (ASO) in iPSC-derived neurons, this project aims to develop and test enhancer-targeting therapies in a range of preclinical models of rare neurological diseases caused by mutations in transcription factors (i.e., AR, PACS2, TBP). Through the planned activity of the Therapeutic Genomics Centre, we plan to expand these approaches further, with the goal of identifying therapeutic targets at scale.
This work has the potential to open a new class of molecular targets to treat diseases, such as those caused by mutations in transcription factors, which have been challenging to address with traditional approaches.
Studentship code: MRCTGCORE2024004
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