Design, synthesis and optimisation of antisense oligonucleotide therapeutics for improved cellular uptake and efficacy

Lead supervisor:  Prof. Matthew Wood 

Co-supervisor: Dr. Jennifer Frommer

Commercial partner: ATDBio Ltd

Research and development of tailored oligonucleotide therapeutics for clinical usage has been in high demand in recent years for treating severe diseases endangering public health. The importance of nucleic acid therapeutics was recently honoured with the Nobel Prize in Medicine 2023 for the development of effective mRNA vaccines against COVID-19.
Yet, one of the main challenges of therapeutic oligonucleotides remains the effective intracellular delivery to the target site (only <2% reaches the cytosol) in correlation with the impact of defined chemical modifications to enable predictable pharmacokinetic and pharmacodynamic properties leading to an overall optimised cellular uptake.
A possible and universal way to obtain effective cell delivery to the target site is achievable by the covalent linkage of (bio-)conjugates e.g. cholesterol or glycoconjugates on the e.g. 5’ end of the antisense oligonucleotide (ASO). The usage of conjugates has been reported before, however, delivering enough ASO to the central nervous system (CNS), and to muscle tissues to induce a clinically relevant effect remains challenging. There is a need to establish effective intracellular delivery methods specifically for splice-switching oligonucleotide (SSO) therapeutics for treating neuromuscular diseases like DMD. Additionally, there is still a lack of understanding of the role of chemical modifications in cell-surface interaction and uptake.
Combining the usage of chemical modifications in the form of (bio-)conjugates with novel oligonucleotide designs to enable better intracellular delivery to the target site is a promising approach to overcome these challenges. Thus, we aim to utilise chemical modifications and tailored oligonucleotide designs along the ASO/SSO strand to generate the next generation of oligonucleotide therapeutics. Hence, the project includes designing and synthesising novel therapeutic oligonucleotides in collaboration with ATDBio, the UK’s leading oligonucleotide synthesis company. ATDBio has 20 years’ experience in synthesizing high quality, complex, modified oligonucleotides with a range of diverse chemistries for customers including some of the world’s biggest biotech and pharma companies. In recent years, ATDBio has invested in medium and large-scale synthesis capabilities, and now has 20 oligonucleotide synthesis instruments, covering the full range from small-scale (nmol) through to multi-gram (mmol) scale for preclinical applications, alongside state-of-the-art equipment for purification of analysis of oligonucleotides. ATDBio also has in-house small molecule synthesis capabilities for the synthesis of novel phosphoramidite building blocks. ATDBio works to the ISO 9001:2015 standard at its laboratories in Oxford and Southampton, and is regularly audited by customers and standards bodies. In addition to the available oligonucleotide synthesis in the Wood lab, ATDBio offers an excellent opportunity to explore a wider range of novel chemical modification patterns and conjugation chemistries at scale. ATDBio also has proprietary IP for oligonucleotide synthesis and ligation, including click chemistry for oligonucleotide ligation and a range of cleavable linkers. The highly modified ASO and SSO compounds will be evaluated in the Wood lab in disease-specific in vitro assays to identify hit compounds which will be further analysed in in vivo disease models. The screening criteria of the novel compounds are increased cellular uptake, low to no cell toxicity levels, enhanced nuclease resistance, high target binding affinity, and efficacy.

Apply using course: DPhil in Paediatrics