Nature–ETN: Nucleic Acids for Future Gene Editing, Immunotherapy and Epigenetic Sequence Modification
Website: https://www.nature-etn.eu/
Budget: €4.04M
Challenge:
Nucleic acid (NA) therapeutics are expected to yield major advances in the treatment of human diseases, especially cancer. This new and fast-growing field underpins Europe’s biotechnology and pharmaceutical industries and requires highly qualified experts in nucleic acid chemistry, biomaterials development and chemical biology. The challenge is to develop researchers with the necessary knowledge and skillset for high-functioning industry jobs, but also to maintain and advance Ireland’s and Europe’s competitiveness and innovation capacity.
Solution
NAs behave in a fundamentally different way than the small molecules traditionally forming the backbone of drug formulation. NATURE-ETN (funded by Horizon 2020 – budget of €4.04M) will leverage recent breakthrough discoveries in epigenetic manipulation, gene editing, small molecule DNA targeting, and rapid gene/transgene detection to extend the boundaries of molecular medicine and provide new tools for treating cancer and monogenetic diseases. Co-ordinated by SSPC investigator and Dublin City University (DCU) Professor, Andrew Kellett, this award offers fifteen early-stage researchers (ESRs) a unique PhD experience with multidisciplinary scientific, business, and transferable skills training and the chance to build a pan-European network with leading scientists in Europe. Training takes place across a network composed of ten beneficiaries and eight partner organisations from eight European countries, including ten leading research institutions, five cutting-edge SMEs and three multinationals. ESRs will complete secondments in both industry and research organisations across Europe with emphasis on the 3 I’s, International, Inter-sectoral and Inter-disciplinary.
The scientific work being undertaken by the ESRs is divided into three work packages (WP):
WP 1. – Extending the boundaries of gene editing technologies: CRISPR sgRNA strands are being engineered for light-controlled activation and live-cell imaging. A new route to gene editing using TFO hybrids is being pioneered and studied by X-ray crystallography.
WP2. Developing therapeutic oligonucleotides for cancer immunotherapy: Manipulation of T-cells for CAR-T immunotherapy is being undertaken with cGAMP and therapeutic mRNAs; recent discoveries with engineered polymerases are being applied.
WP3. Sequencing and imaging of epigenetic bases: new methods for epigenetic base oxidation are being applied to mainstream sequencing technologies.
Impact
This award is ongoing. The programme commenced in 2020 and is expected to conclude in 2024.
Outputs: Publications emanating from NATURE ETN:
McStay, N., Slator, C., Singh, V., Gibney, A., Westerlund, F., Kellett, A. Click and Cut: a click chemistry approach to developing oxidative DNA damaging agents, Nucleic Acids Research, Vol. 49, Issue 18: 10289–10308 (2021).
Banasiak, A., Zuin Fantoni, N., Kellett, A., Colleran, J. Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors. Molecules, 27(3): 645 (2022).
Galdino, A.C.M., Viganor, L., Pereira, M.M., Devereux, M., McCann, M., Branquinha, M.H., Molphy, Z., O’Carroll, S., Bain, C., Menounou, G., Kellett, A., Dos Santos, A.L.S. Copper(II) and silver(I)-1,10-phenanthroline-5,6-dione complexes interact with double-stranded DNA: further evidence of their apparent multi-modal activity towards Pseudomonas aeruginosa. J Biol Inorg Chem (2022).
Searle, B., Müller, M., Carell, T., and Kellett, A. Third Generation Sequencing of Epigenetic DNA. Angew. Chem. Int. Ed. (2022).
Traube, F.R., Özdemir, D., Sahin, H., Müller, M., Carell, T. et al. Redirected nuclear glutamate dehydrogenase supplies Tet3 with α-ketoglutarate in neurons. Nature Communications, 12, 4100. (2021).
Schoch, S., Iacopini, D., Dalla Pozza, M., Di Pietro, S., Degano, I., Gasser, G., Di Bussolo, V., and Marchetti, F. Tethering Carbohydrates to the Vinyliminium Ligand of Antiproliferative Organometallic Diiron Complexes. Organometallics (2022).
Müller, F., Escobar, L., Xu, F., Wegrzyn, E., Nainyte, M., Amatov, T., Chan, C.-Y., Pichler, A., and Carell, T. A prebiotically plausible scenario of an RNA–peptide world. Nature 605, 279–284 (2022).
Dalla Pozza, M., Abdullrahman, A., Cardin, C.J., Gasser, G., and Hall, J. Three’s a crowd – stabilisation, structure, and applications of DNA triplexes. Chemical Science (2022).
Schönegger, E.S., Crisp, A., Müller, M., Fertl, J., Serdjukow, S., Croce, S., Kollaschinski, M., Carell, T., and Frischmuth, T. Click Chemistry Enables Rapid Amplification of Full-Length Reverse Transcripts for Long-Read Third Generation Sequencing. Bioconjugate Chemistry (2022).
Enslin, L.E, Purkait, K., Dalla Pozza, M., Saubamea, B., Mesdom, P., Visser, H.G., Gasser, G., and Schutte-Smith, M. Rhenium(I) Tricarbonyl Complexes of 1,10 Phenanthroline Derivatives with Unexpectedly High Cytotoxicity. Inorganic Chemistry (2023).
Partnership: The fifteen ESRs will be supervised and co-supervised by academic partners in 6 countries. Namely, Ireland, Dublin City University, University College Dublin via NIBRT (National Institute for Bioprocessing Research and Training), the UK ( University of Oxford, University of Reading), Germany (Ludwig-Maximilians-Universität München), France University PSL (Paris Sciences & Lettres University), Poland (University of Warsaw) and Czech Republic (Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic, Charles University). With industrial partners including ATDbio, Ltd., Nature Research Ltd., and Diamond Light Sources Ltd. (all UK), Baseclick GmbH (Germany), Accelopment Switzerland Ltd. (Switzerland), MSD Ltd (Ireland) and ThermoFisher Scientific (Lithuania).
