Therapeutic Genomics Centre, DPhil Programme

We are looking for outstanding applicants for 3 to 4-year, fully funded DPhil/PhD positions at the University of Oxford to apply skills in computational biology and/or translational science to enable cutting-edge therapies to treat genetic disorders.

REad on for Details of the eight proposals and guidance on how to apply.

We are excited to recruit these inaugural DPhil students into our new Therapeutic Genomics Centre. This Centre provides a coordinated, multidisciplinary environment that will address major scientific questions to enable the development of genome-targeted therapies for rare genetic disorders. It will provide an enhanced training experience to recruit and empower the next generation of leaders in this emerging field.

What are rare genetic disorders? About 5,000 different disorders are caused by a genetic variant at a single location in the genome. Many of these impact a single gene, for example, a mutation to a single base of DNA that impairs the function of the encoded protein. These disorders are often very severe resulting in strong selective pressure so that the variants are not passed on to subsequent generations. Although this selective pressure ensures that the disorders are rare, collectively these disorders affect millions of individuals since there are so many vulnerable genes. With whole-genome sequencing, these specific variants are now routinely diagnosed; the UK is a world leader in the genetic diagnosis through the NHS Genomic Medicine Service (https://www.england.nhs.uk/genomics/nhs-genomic-med-service/) and Genomics England (https://www.genomicsengland.co.uk).

What is genome-targeted therapy? With recent technological advances, many rare genetic disorders are now potentially treatable. A new class of therapeutic compounds use genetic sequence to target a specific region of DNA or RNA. These include CRISPR-based reagents that can edit DNA and antisense oligonucleotides (ASOs) that modify RNA stability or splicing. These genome-targeted therapies have unrivalled potential for specificity since 16 nucleotides are sufficient to target most of the genome uniquely (4¹⁶ > 3.3 billion); additional nucleotides provide robust genome-wide specificity. Many disease-causing variants can already be targeted and, furthermore, altering just the nucleotide hybridizing sequence can ‘reprogram’ one successful therapy to a new disorder, e.g., by changing just the guide RNA (sgRNA). These therapies could be used as a ‘platform’ to rapidly adapt to treating multiple disorders.

What is Therapeutic Genomics? To realise the potential of genome-targeted therapies we need to accumulate and share the data and knowledge to predict how changing the targeting sequencing will influence behavior. The term ‘genomics’ describes the use of genome-wide technologies; these, combined with large-scale collaboration and data sharing, have enabled the revolution in the diagnosis of rare disease. ‘Functional genomics’ uses these technologies and principles to add genome-wide insight into gene regulation, including epigenetics and RNA. Therefore, we use the term ‘Therapeutic Genomics’ to describe the application of the principles, approaches, and technologies used in genomics to accelerate the development of effective and safe genome-targeted therapies.

What is the Therapeutic Genomics Centre? To realize the potential of Therapeutic Genomics, a team of over twenty laboratories are working together to generate the necessary knowledge and experience. These laboratories are based at the University of Oxford, Newcastle University, University College London (UCL), the University of California (including the Innovative Genomics Institute at Berkeley and UCSF), and the Karolinska Institute. In addition, we are assisted by several commercial and non-commercial partners.

How will this benefit your DPhil experience? Students in the Therapeutic Genomics Centre will receive all the benefits of a DPhil studentship in the Oxford University-MRC Doctoral Training Partnership, including funding, training opportunities, and student wellbeing initiatives (https://www.medsci.ox.ac.uk/study/graduateschool/mrcdtp/training). In addition, students in the Centre will work within a multidisciplinary team with expertise across the complete range of therapeutic development from target selection and vector delivery to clinical design and regulatory science. An individual ‘Training Needs Analysis’ will create a customized training plan for you to make the best use of this environment. Furthermore, internships with industry partners will provide trainees with experience of both academic and non-academic career paths. We are committed to promoting best practices in equality, diversity and inclusivity. Applications are competitive, with the best applicants receiving the funded positions.

What projects are available? There are eight project proposals via the Oxford-MRC Doctoral Training Partnership portal. The eight proposals are:

1. Pioneering genomics approaches to develop targeted antisense oligonucleotides for treatment of patients with rare neurological disorders. Supervisors: Prof. Jenny Taylor, Prof. Carlo Rinaldi. This project will identify tractable variants in whole-genome sequencing data and develop antisense oligonucleotides for therapy. 
2. Predicting the therapeutic potential of all single gene disorders. Supervisors: Prof. Stephan Sanders, Assoc. Prof. James Davies. This project will use genomic data and machine learning to build a classifier to assess the potential to treat specific variants with CRISPR, antisense oligonucleotides, or small molecules. 
3. Addressing the health economic challenges of evaluating the full costs and effects of genome-targeted therapies. Supervisors: Prof. Sarah Wordsworth, Assoc. Prof. Nicky Whiffin. This project will use genetic and clinical data from Genomics England to assess the economic impact of genetic disorders and models of reimbursement for therapies.
4. Targeting enhancers to treat neurological diseases. Supervisors: Assoc. Prof. Carlo Rinaldi, Prof. Stephan Sanders. This project will identify non-coding enhancer elements to develop CRISPR gene-editing and antisense oligonucleotide therapies. 
5. Development of antisense oligonucleotide and base editing therapeutics for neurodevelopmental haploinsufficiency disorders. Supervisors: Dr. Thomas Roberts, Prof. Matthew P.A. Wood. This project will develop therapies targeting upstream open reading frames of neurodevelopmental disorders. 
6. In vivo reprogramming of extracellular vesicles for targeted drug delivery of genome editors to the central nervous system. Supervisors: Prof. Matthew P.A. Wood, Prof. Stephen Hyde. This project will develop a cutting-edge approach to reliver CRISPR reagents to cells in the brain. 
7. Directed evolution of targeting strategies for precise delivery of genome editors to haematopoietic stem cells using extracellular vesicles and lipid nanoparticles. Supervisors: Prof. Matthew P.A. Wood, Assoc. Prof. James Davies. This project will develop nanobody-targeted vectors to deliver CRISPR reagents to treat immune and blood disorders. 
8. Peptide-mediated delivery of CRISPR-Cas genome editors in the eye. Supervisors: Assoc. Prof. Jasmina Cehajic-Kapetanovic, Assoc. Prof. Kanmin Xue, Prof. Robert E MacLaren. This project will use cell-penetrating peptides coupled with ribonucleoprotein (RNP) complexes to deliver CRISPR reagents to treat retinal blindness.

Please read these guidance notes for detail on how to apply

Click here to apply: IPP login screen (ox.ac.uk)

For more information on DPhil in Paediatrics: DPhil in Paediatrics | University of Oxford

For more information about our MRC-Oxford Doctoral Training Programme see: https://www.medsci.ox.ac.uk/study/graduateschool/mrcdtp