Enzymatic methods for assembly of nucleic acid therapeutic agents

Lead Research Organisation: University of Manchester
Department Name: Chemistry


Modified nucleic acids have emerged as a powerful new class of therapeutic agents for the prevention and treatment of a range of diseases (e.g. Inclisiran, a revolutionary cholesterol lowering drug. Over 150 clinical trials are also ongoing using the main types of nucleic acid drugs, antisense oligonucleotides (ASOs) or small interfering RNAs (siRNA), for cancer, cardiovascular, neurodegenerative and infectious diseases etc. ASOs are short single stranded nucleic acids (oligonucleotides) that hybridise with messenger RNA (mRNA), modulating gene expression by blocking progression of the ribosome or inducing cleavage of the mRNA through recruitment of a ribonuclease enzyme (RNaseH). siRNA are short double stranded RNA molecules that bind to specific proteins in the cell to form a complex (RISC) which can cleave complementary mRNA targets. Despite their massive potential the production of these 'magic bullets' is extremely challenging, as extensive modification is required to evade nuclease degradation and to improve affinity for the mRNA target. In addition, their cellular uptake can be problematic, which often requires conjugation with other molecules to aid delivery. Currently solid phase synthesis is used to assemble ASOs and siRNAs. However, this requires an excess of costly precursors (monomers), toxic reagents, deleterious solvents and is very difficult to scale up, making treatments expensive and preventing development of new drugs. In this project we will develop more sustainable and scalable enzymatic methods (industrial biotechnology) to deliver essential ASO and siRNA medicines under mild conditions, in water, utilising more benign enzymes and renewable precursors. (see application form for further details).


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/T008725/1 01/10/2020 30/09/2028
2777796 Studentship BB/T008725/1 01/10/2022 30/09/2026 Louis Adamson