Therapeutic oligonucleotides (Th-ONs) are short chemical analogues of RNA or DNA molecules that can be used to inhibit disease development at the RNA level. They are emerging as a powerful therapeutic option for combating severe life-limiting diseases where small molecule approaches fail, by targeting the disease’s genetic makeup and altering it to change cell behaviours.
It has been suggested that Th-ONs have potential to reduce the chemotherapy and radiotherapy resistance of cancer and improve the specificity of treatment. Currently six Th-ON treatments are approved for clinical use, but their development has been limited due to cost, potential toxicity risks and an inability to cross cellular membranes to reach a target.
Recent CRUK Oxford Centre Development Fund award winners Dr Ysobel Baker and Prof Tom Brown, from the Dept of Chemistry, have launched a new project aimed at overcoming the issue of endosomal entrapment – whereby the Th-ONs are collected up by a cells ‘waste-disposal’ system and ejected back out the cell. Alongside the Vallis group at the Department of Oncology, the team will be investigating specific designs that will help to ensure more effective treatments are made.
Thus far, early data suggests that the teams new Th-ON ‘backbones’ have potential to improve target affinity and cellular uptake rates. It is hoped that, by determining the effect of varying the chemistry of these molecules that the team will be able to develop new precision cancer therapies that target the DNA or RNA of specific tumour subtypes.
The next stage of this project is to take this closer to the clinic, using new equipment, which allows the researchers to quickly construct the different Th-ON designs for evaluation as therapeutics.
Prof Tom Brown, Principle Investigator, says:
We are delighted to be awarded this grant. It will allow us to purchase an item of equipment that is essential for our study to improve therapeutic oligonucleotide delivery. This is a major problem that is encountered by all who are working in this growing field.
About the researchers
Professor Tom Brown, Department of Chemistry & Deptartment of Oncology, investigates the applications of nucleic acid chemistry. His research group, including Dr Ysobel Baker, have developed rapid methods for the identification of mutations in the human genome such as Scorpions, which are used to analyse genomic DNA at single base resolution. Developed in collaboration with AstraZeneca, Scorpions were commercialised and have led to the clinical use of cancer therapies, which were previously rejected on the basis of limited efficacy by tailoring the therapy to the individual patient (Personalised medicine). He also focuses on the synthesis of DNA and RNA analogues and their applications as potential diagnostic and therapeutic tools.