Developing a Precision RNA Editing Platform for Therapeutic Applications

About the project

About the Project RNA editing is a natural and widespread post-transcriptional modification in mammalian cells, primarily involving adenosine to inosine (A-to-I) conversions mediated by ADAR enzymes, and cytosine to uridine (C-to-U) conversions facilitated by APOBECs. These modifications are crucial for regulating gene expression, splicing, and other cellular processes. Recent developments in programmable RNA editing, especially those leveraging ADARs, have opened new possibilities for correcting pathogenic mutations with high specificity and reversibility, offering advantages over permanent DNA editing approaches. Current therapeutic RNA editing strategies focus on delivery of recombinant enzymes and guide RNAs or use of highly chemically modified antisense oligonucleotides (ASO); while demonstrating proof-of-concept in correcting disease-causing mutations in vivo , they face challenges such as low efficacy, hurdles with the delivery of large payloads, and off-target effects. These limitations highlight the need for more effective, targeted delivery systems to unlock the full therapeutic potential of RNA editing. Combining the precision of ASOs with the targeted delivery capabilities of ASO conjugates, here we aim to develop a new class of therapeutics with high specificity, safety and potency which has the potential to open up hundreds of therapeutic targets. Project Objectives Mining available databases (e.g., ClinVar, Genomics England) to identify disease-causing mutations that are amenable to RNA editing Conjugate antisense oligonucleotides with moieties targeting endogenous RNA editors to identify the most effective combinations Test ASO conjugates in reporter cell lines and disease models (iPSC-derived neurons) Deliver lead ASO conjugates in mice (optional) Research Methodologies Molecular Cloning and Protein Engineering: Designing and constructing expression vectors Engineering and optimizing linker sequences and protein modifications Protein expression, purification, and characterization (e.g., ELISA) Nucleic Acid Synthesis and Modification Cell Culture and Transfection RNA Editing and Gene Expression Analysis (i.e., RT-PCR, and sequencing to assess editing outcomes) Bioinformatics & Data Analysis (i.e., Analysing sequencing data for editing efficiency and off-target effects). Potential Project Impact This project has the potential to create a new class of highly specific, safe, and reversible RNA-based therapeutics. By harnessing antisense oligonucleotide conjugates, it could enable the correction or modulation of a wide range of genetic disorders, including those that are currently not amenable to standard ASO therapy. Additionally, the project holds significant potential for intellectual property generation, with opportunities to develop novel patents that can propel further commercialization and clinical translation. Proposed Project Timelines Year 1: Concept Development & Design Conduct literature review on RNA editing and oligonucleotides conjugates Establish protocols for protein expression, purification, and binding Begin preliminary in vitro studies Year 2: Optimization & In Vitro Validation Develop and test ASO conjugates Assess RNA editing efficiency and specificity in mammalian cell models Year 3: Preclinical Evaluation & In Vivo Studies Select lead conjugates Evaluate therapeutic efficacy in relevant disease models Refine delivery methods Year 4: Validation, Translation & Preparation for Clinical Development Confirm therapeutic benefits and safety in in vivo studies Prepare detailed data for publication Potential Internship/Exceptional Training Opportunities During the first Year of the DPhil, the candidate will have the opportunity to gain insight into the process of protein generation by visiting the dedicated Discovery Platform at the Rosalind Franklin Institute, in Harwell (Oxfordshire), with whom this project will be developed in collaboration. Opportunities for student participation in PPIE Once a disease suitable for this RNA editing technology has been identified, we will actively liaise with affected family groups and patient organizations. We plan to organize activities such as informational sessions, workshops, and public engagement events to explain the therapeutic strategy, its potential benefits, and the research process. This collaboration aims to foster understanding, gather feedback, and build trust with the community. Engaging patients and families early will also help tailor the research to real-world needs, ensuring that the development of this innovative therapy aligns with patient priorities and expectations. MRC CoRE-TG Scholarships Applicants to MRC CoRE-TG projects may be nominated for a CoRE-TG DPhil scholarship, which involves a second interview following the departmental interview. Due to UKRI limits on international student recruitment, only UK home students are eligible for these MRC CoRE-TG DPhil scholarships. For information on home student eligibility, please refer to UKRI training grants: standard terms and conditions of training grant sections TGC 5.2.4 & TGC 5.2.5. The MRC CoRE-TG DPhil scholarship provides funding for: Course fees for the duration of fee liability. A living stipend at the UKRI rate, paid for four years. A £20,000 Research Training Support Grant (RTSG) to support research and training costs. A £1,200 travel allowance to support research-related travel and development opportunities. The stipend rate is reviewed annually by UKRI/MRC. Overseas applicants are still welcome to apply for MRC CoRE-TG projects. They may be considered for other funding opportunities available through the relevant department and may also apply for external scholarship funding independently to support their DPhil. Ready to join us? Applications are competitive and will be assessed according to the admissions requirements of the relevant host department or university. For questions about the MRC CoRE in Therapeutic Genomics programme , please contact mrccoretg@paediatrics.ox.ac.uk Scholarship Code: CoRE-TG 2026-005

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