University of Oxford — Nuffield Department of Clinical Neurosciences
Assoc Prof Kanmin Xue, Dr Dhanu Gupta, Prof Stephen Hyde
Tuesday, December 01, 2026
Funded PhD Project (UK Students Only)
About the Project
Genetic eye diseases are leading causes of blindness in children and young adults, yet treatment options remain extremely limited. This DPhil project aims to develop a scalable next-generation genome editing approach to treat genetic eye disease using choroideremia - a severe inherited retinal degeneration – as an exemplar. The student will design and evaluate genome editing strategies alongside novel delivery technologies to enable safe and efficient targeting of retinal cells. The project combines genome engineering, nanomedicine and translational ophthalmology, with evaluation in state-of-the-art laboratory and preclinical models to contribute towards regulatory approval. Working within a multidisciplinary team, the student will gain expertise in cutting-edge genomic technologies while contributing to the creation of transformative therapies for inherited blindness. The technologies developed have the potential to be applied to a wide range of eye diseases.
Project Objectives
- Design a CRISPR-based gene correction strategy for the CHM gene locus - Design guide RNAs and donor DNA templates to target the CHM locus.
- Validate the CRISPR construct in vitro - On-target gene editing/integration efficiency of the CRISPR construct will be assessed and quantified in cell-based models, including retinal pigment epithelium (RPE) cells.
- Assess restoration of REP1 expression and function - Edited cells will be evaluated for REP1 mRNA and protein expression. Functional rescue will be assessed using existing disease-relevant assays.
- Optimise delivery using lipid nanoparticle (LNP) or hybrid systems - Delivery strategies will compare LNP-mediated versus viral vector-mediated methods. These approaches will be evaluated for in vivo editing rates, retinal toxicity, and immune response, to inform clinical feasibility.
- Pre-clinical evaluation of the gene therapy vector in an animal model - With the support of established collaborators, the CRISPR construct and delivery method will be tested in a translationally relevant animal model to assess retinal delivery, tissue tropism, editing feasibility, REP1 protein expression, biodistribution and safety. This will enable subsequent evaluation in a clinical trial.
Research Methodologies
- Molecular cloning: CRISPR guide RNA and donor DNA design
- Tissue culture: in vitro validation of genome editing efficiency in cell lines and human iPSC-derived retinal pigment epithelium (RPE) cells
- Biochemistry: quantification of REP1 mRNA and protein expression, and protein function assays
- Gene therapy vector production: development and comparison of lipid nanoparticles and viral vectors for retinal gene editing
- Preclinical evaluation in a clinically relevant large animal model to assess retinal delivery, ON- and OFF-targets, biodistribution, and immune response
Potential Project Impact
If succesful, this project will provide a novel CRISPR-based genome editing strategy to treat choroideremia. Establishing a non-viral delivery platform alongside the disease focus will offer a cost-effective, modular approach that can be applied to a wide range of genetic eye diseases in the future, where transgene durability and immunogenicity limit current adeno-associated viral (AAV) vector-based approaches. Large animal study will generate clinically relevant translational data on safety, route of administration, and biodistribution. This information will be critical to enable first-in-human trial design for an Investigational New Drug (IND), reducing risk for subsequent clinical translation.
Proposed Project Timelines
- CRISPR construct design and testing: Months 1 - 12 Key deliverable - Select CRISPR guide RNAs; design DNA template, test constructs in cell lines
- LNP and AAV vector production and optimisation: Months 12 - 26 Key deliverable - Lead construct packaged into LNP and AAV vectors for initial in vitro testing in human RPE cells to confirm ON-target genome correction rate; assess protein expression and function
- Animal study: Months 26 - 42 Key deliverable - In vivo delivery, imaging, tissue analysis for ON- and OFF-targets, feasibility, surgical delivery and safety assessment
- Data analysis, paper and thesis writing & submissions: Months 40 - 48 Key deliverable - Draft, submission, revisions
Potential Internship/Exceptional Training Opportunities
This project will provide the DPhil candidate training in pre-clinical development of advanced therapies, including state-of-the-art CRISPR genome editing tools, viral and non-viral vectors, and methods of pre-clinical testing in clinically relevant models (human iPSC-derived retinal cells and large animal).
Opportunities for student participation in PPIE
The student will join an established PPIE programme within the Oxford Eye Hospital and the Oxford Eye Research Group (ERGO), working alongside vision charity partners from Fight for Sight, Retina UK, to Choroideremia Foundation. The student will have the opportunity to engage with patients through contributing to ongoing retinal gene therapy trials (including the opportunity to gain GCP training), as well as the chance to present their work to the public through patient-focused events, meetings and conferences.
For application queries, please contact NDCN Graduate studies graduate@ndcn.ox.ac.uk
For questions about the MRC CoRE in Therapeutic Genomics programme, please contact mrccoretg@paediatrics.ox.ac.uk
For further information about the project, please contact the listed supervisors.
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 or other 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.
Code: CoRE-TG 2026-003