Understanding and optimising RNA therapeutic delivery, efficacy, and toxicity with chemical biology

Chemically modified RNAs have recently emerged as a unique and powerful therapeutic approach since they can be designed to address almost any disease state by directly and specifically modulating gene expression. These molecules operate through a diverse range of mechanisms, and include antisense oligonucleotides (ASOs), small interfering RNA (siRNA), micro-RNA (miRNA), messenger RNA (mRNA) and RNA vaccines, and splice-switching oligonucleotides (SSOs).

However, these advanced therapeutics are currently limited by lack of understanding of mechanisms of uptake and delivery to target disease, whilst avoiding toxicity and non-specific delivery to off-target tissues.

In this project you will develop and apply a platform of chemical biology technologies to explore the interactome of any oligonucleotide therapeutic in living cells, combining synthetic oligonucleotide probes with quantitative proximity labelling proteomics. Your platform will be used to discover and explore the interacting partners of diverse oligonucleotide modalities, establishing mediators of delivery, uptake, and mechanisms of action in cells and in plasma.

You will then proceed to explore the impact of chemical modifications commonly used to modulate delivery, providing a framework for knowledge-led optimisation of next generation oligonucleotide therapies.

You will benefit from a unique supervision team and access to state-of-the-art facilities, including expertise in chemical biology and proteomics (Tate, Imperial/Crick), RNA biology and therapeutics (Vernia, MRC Laboratory of Medical Sciences), and RNA therapeutic discovery (Knerr, AstraZeneca Sweden).