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Orthogonal Ligase Enzymes for Assembly of Modified Nucleic Acids

Project description

Greener production of next-generation medicines

Modified nucleic acids used as therapeutics and mRNA vaccines offer a new, powerful way to treat various diseases including cancer, neurological disorders and infections. However, current manufacturing methods are slow, costly and require extensive resources. Moreover, they are difficult to scale, limiting wider access to these treatments. With the support of the Marie Skłodowska-Curie Actions programme, the OLIGNA project aims to develop a cleaner and more flexible enzymatic method for building modified nucleic acids. Instead of relying on traditional chemical synthesis, researchers will engineer specialised enzymes that assemble nucleic acids with high precision and add medically important chemical modifications. This approach has the potential to improve sustainability and lower production costs of nucleic acid therapeutics.

Objective

Modified nucleic acids including antisense oligonucleotides and siRNAs are set to transform medicine. Currently there are 18 approved drugs, and over 150 modified nucleic acid therapeutics currently in clinical trials for the treatment of cancer, cardiovascular, and neurodegenerative conditions as well as other diseases. The mRNA vaccines used to combat COVID-19 and related cancer vaccines also comprise of modified mRNA with alternative nucleobases. In addition, modified nucleic acids are widely used in basic research (structure-function studies). Currently, nucleic acids are mainly produced by outdated solid-phase synthesis (SPS), which requires many steps per cycle and is highly atom inefficient, using expensive monomers, deleterious reagents and large amounts of organic solvents. Such methods are very difficult to scale up and create a huge amount of waste which has hampered drug production. Longer modified mRNA vaccines can be produced using template-dependant polymerase enzymes, but this limits the extent to which modifications can be included. In OLIGNA I aim to overcome these limitations and deliver an alternative template independent enzymatic approach for the synthesis of modified nucleic acids which is more sustainable than SPS, in addition to being more versatile than existing enzymatic approaches. The project is comprised of three work packages: WP1 aims to engineer orthogonal ligases enzymes to insert modified nucleotide monomers between two RNA strands to generate longer site-specifically labelled RNAs for structure-functional studies; WP2 will explore developing the orthogonal ligases for the iterative assembly of native RNA; WP3 aims to further engineer the ligases to accept modified nucleotide and dinucleotide precursors including the common 2´-sugar modifications required for the production of nucleic acid therapeutics. OLIGNA will deliver game-changing technology to transform nucleic acid synthesis, providing new research tools and medicines.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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(opens in new window) HORIZON-MSCA-2025-PF

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Coordinator

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 260 347,92
Address
SOUTH KENSINGTON CAMPUS EXHIBITION ROAD
SW7 2AZ London
United Kingdom

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Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
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Total cost

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