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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
MRC INDUSTRIAL CASE STUDENTSHIPS 2025
Designed to nurture the academic entrepreneurs of the future, the Enterprise studentship programme offers a stimulating educational experience as part of the Oxford-MRC DTP cohort, with the additional benefit of working closely with an industrial partner. This will provide entrepreneurial training opportunities and an insight into how commercial science is conducted alongside a superb academic base within the University. Students will work for at least 3 months in the associated company.
ELIGIBILITY
They are open to both UK and non-UK nationals and will follow the UKRI student eligibility requirements. UKRI will normally limit the proportion of international students appointed each year through individual training grants to 30% of the total intake each year.
FUNDING PACKAGE
Each iCASE studentship is fully-funded – it includes four years of stipend at the UKRI stipend level + £2,500 p.a., course fees, and a generous research training support grant.
APPLICATIONS DEADLINE
Applications must be received by 12 noon (UK time) Tuesday 3 December 2024. Details on entry requirements and how to apply can be found below.
For details of entry requirements please go to the Oxford-MRC DTP iCASE 2025 Projects page.
HOW TO APPLY
Before applying for this project we recommend you contact the lead supervisors for informal discussion.
To make a formal application, please complete the University’s online application form for the DPhil course specified under the project description above. Please indicate the iCASE project clearly by inserting ‘iCASE’ before the project title and by using the reference code iCASE. You will need to provide a personal statement (500 words max if applying for a project hosted by one of Medical Sciences departments – please note that this limit might be different if a project is hosted by one of MPLS departments in which case follow their requirement) detailing your interest and fit for the studentship. Note that no project proposal is required for the iCASE studentship applications.
If you wish to apply for a combination of iCASE and other projects within the hosting department, this can be done on the same application form (max number of projects you can apply for on one application depends on the department you wish to apply to). If you wish to apply for iCASE projects within different departments, you will have to make separate applications directly through those departments.
If you have any queries about the iCASE application process (questions about the project should be directed to the lead supervisor), please email mrc@medsci.ox.ac.uk.
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