We apply our knowledge of viral RNA structure and function to a number of specific problems in the prevention and treatment of disease.
Every RNA virus uses RNA structure to perform additional functions aside from simply coding for viral proteins. These functions which are often highly conserved, making them attractive targets for antiviral therapy. We use our knowledge of RNA structure and function (and its role in pathogenicity) to explore practical applications our research and work closely with the Crick’s Translation Team.
Programmable antiviral therapy
Therapeutic options are limited for recently-emerged viruses and those for which no vaccine remains available. Small-molecule antiviral drugs against a given RNA virus may be available, but resistance mutations are often quick to emerge. Such viral mutation effectively “resets” the drug development pipeline, necessitating repeated screening, synthesis strategies, and testing.
Antisense oligonucleotides (ASO) are RNA-targeting therapeutic agents, and can directly target the viral RNA genome and its structure as antiviral agents. Unlike conventional small-molecule antivirals, only the viral reference genome sequence is needed for their design, and standard ASO synthesis permits rapid development and subsequent adaptation of the antiviral agent in response to viral evolution or mutation. We currently work with collaborators at the University of Oxford, the UKRI-funded Nucleic Acid Therapeutics Accelerator, and commercial partners to develop antiviral therapies using this approach.
Segmented viruses can reassort their genome segments to generate new strains. For influenza viruses, this ‘mixing and matching’ between established human viruses and influenza viruses harboured in the animal reservoir (e.g. swine, avian) can lead to the emergence of pandemic influenza strains to which there is little pre-existing immunity in the human population. While we know that RNA:RNA interactions between different segments can drive reassortment, we do not know what makes one particular interaction more important than another, nor how they act in concert. We work with the Worldwide Influenza Centre at the Crick (one of six global WHO Collaborating Centres) to map RNA structure within circulating influenza strains and analyse this in context with their reassortment potential, with the aim to refine existing models for pandemic strain emergence.
Influenza vaccine optimisation
While influenza virus reassortment can happen in nature, it is also exploited as a lab-based tool for the production of influenza virus vaccines. In such cases, the two antigenic genome segments of a circulating virus to which we wish to generate immunity are reassorted with six standardised ‘backbone’ genome segments. These backbone segments come from a virus that is adapted to grow well in eggs or laboratory culture (in the case of the inactivated influenza virus vaccine) or a virus that is has been adapted to be attenuated in humans (in the case of the live attenuated influenza virus vaccine, which is given in the UK each year to children as part of the standard immunisation programme). We work with scientists from AstraZeneca and Seqirus to study RNA:RNA interactions between vaccine backbones and their antigenic segments, with the aim of optimising vaccine design and speeding up the generation of vaccine candidates each year.