Predicting the therapeutic potential of all single gene disorders

Academic Supervisors: Prof. Stephan Sanders, Assoc. Prof. James Davies

Other Supervisors: Dr. Vanessa Almendro (Danaher), Dr. Petros Giannikopoulos (Innovative Genomics Institute, University of California, Berkeley)

Host Dept: Paediatrics, Oxford

Over 4,000 single gene disorders have been identified, affecting multiple tissues and biological processes. Emerging genetic therapies, including antisense oligonucleotides (ASOs), CRISPR genome-editing, and gene replacement are capable of restoring gene function and treating some of these disorders. Where simple biological endpoints exist, small molecule screens can also yield therapies. Through work in the Therapeutic Genomics Centre, we have begun to develop tools to predict which of these therapies are appropriate for different disorders. Some of these methods are simple (e.g., cDNA size limit for AAV gene replacement) while others are complex (e.g., poison exons with ASOs).

Experiments underway using in vitro genomic screens will augment these approaches further, identifying therapeutic targets at scale. This project aims to integrate these data, yielding a ‘classifier’ to determine the potential for different approaches based on current knowledge and to share this result through a web interface. This project is primarily computational, however, if desired, the project could include high-throughput lab-based CRISPR screens of clinical genome editing approaches to train and validate the classifier; these approaches are well established in the Davies laboratory.

Studentship code: MRCTGCORE2024002

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