Periodic Reporting for period 1 - NATURE-ETN (Nucleic Acids for Future Gene Editing, Immunotherapy and Epigenetic Sequence Modification)
Berichtszeitraum: 2020-04-01 bis 2022-03-31
The NATURE-ETN project has forged a new integrated network of 10 industry-academia partners, which trains 15 early-stage researchers (ESRs) using cutting-edge resources at leading research facilities, universities, and biopharmaceutical enterprises throughout the EU. Our research programme involves world-leading chemists in combination with high-tech/biotech companies and small and medium-sized enterprises. In the NATURE-ETN project there are three main objectives:
1. To provide training excellence and expertise to 15 ESRs in cutting-edge research areas of nucleic acid chemistry, bioinorganic chemistry, biological chemistry, gene editing, X-ray crystallography, cancer immunotherapy, epigenetic base manipulation and DNA sequencing. The ESRs within NATURE-ETN will undertake two, independent, secondment periods to industry and cross-disciplinary academia. Our joint aim is to foster collaborative relationships, creativity, and confidence to enhance the training experience, productivity, scientific excellence, and cooperation of all 15 fellows.
2. To generate a deep skillset in scientific and transferable skills training and the translation of basic research into high-functioning commercial nucleic acid therapies in breakthrough research areas of gene therapy and epigenetic base manipulation.
3. Research within NATURE-ETN is centred on: (a.) New types of gene editing technologies that differ from the current state-of-art; (b.) New approaches to probing prebiotic origins of life and in the development of cell-based cancer immunotherapy by employing therapeutic oligonucleotides, and; (c.) Novel sequencing, imaging, and profiling technologies for epigenetic base detection and manipulation.
NATURE-ETN’s ESRs are being trained to address some of the most important scientific questions while also engaging with societal needs. Given the rapid expansion in gene-targeted technologies, vaccines, and therapeutics, there is an urgent need for Europe to train new experts in nucleic acids, biotechnology, and biopharmaceutical industries. We need experts not only to fill high-functioning industry jobs but also to maintain and grow Europe’s competitiveness for R&D excellence. We expect that NATURE-ETN will develop the next generation of pioneering scientific leaders in Europe where they will grow our commercial need for disruptive technologies in 21st-century medicine.
1. To provide training excellence and expertise to 15 ESRs in cutting-edge research areas of nucleic acid chemistry, bioinorganic chemistry, biological chemistry, gene editing, X-ray crystallography, cancer immunotherapy, epigenetic base manipulation and DNA sequencing. The ESRs within NATURE-ETN will undertake two, independent, secondment periods to industry and cross-disciplinary academia. Our joint aim is to foster collaborative relationships, creativity, and confidence to enhance the training experience, productivity, scientific excellence, and cooperation of all 15 fellows.
2. To generate a deep skillset in scientific and transferable skills training and the translation of basic research into high-functioning commercial nucleic acid therapies in breakthrough research areas of gene therapy and epigenetic base manipulation.
3. Research within NATURE-ETN is centred on: (a.) New types of gene editing technologies that differ from the current state-of-art; (b.) New approaches to probing prebiotic origins of life and in the development of cell-based cancer immunotherapy by employing therapeutic oligonucleotides, and; (c.) Novel sequencing, imaging, and profiling technologies for epigenetic base detection and manipulation.
NATURE-ETN’s ESRs are being trained to address some of the most important scientific questions while also engaging with societal needs. Given the rapid expansion in gene-targeted technologies, vaccines, and therapeutics, there is an urgent need for Europe to train new experts in nucleic acids, biotechnology, and biopharmaceutical industries. We need experts not only to fill high-functioning industry jobs but also to maintain and grow Europe’s competitiveness for R&D excellence. We expect that NATURE-ETN will develop the next generation of pioneering scientific leaders in Europe where they will grow our commercial need for disruptive technologies in 21st-century medicine.
The NATURE-ETN started in April 2020 and recruited 15 ESRs across 10 beneficiary host organisations. All ESRs are acquiring training in state-of-art research facilities and to date, our research has focused on developing new gene-editing technologies, designing therapeutic oligonucleotides that modulate immune-responses required for treating cancer, exploring prebiotic chemistry to probe the origin of life, and the development of new DNA sequencing reagents for epigenetic base detection.
The research connected with therapeutic oligonucleotides has branched out to take advantage of i.) emerging prebiotic model systems and ii.) the urgent need to develop new antiviral Covid-19 treatments. The scientific results obtained so far, are disseminated in the form of peer-reviewed scientific publications (including Nature, Organometallics, Journal of Biological Inorganic Chemistry, Nature Communications, Nucleic Acids Research, Molecules) with several other papers either under review or at advanced draft stages.
A personal career development plan (PCDP) was completed by each ESR under the guidance of their PIs. NATURE-ETN ESRs have attended, and presented, their work at scientific conferences throughout Europe, as well as at our online scientific meetings and the Project Check meeting held in October 2021. In addition, two training weeks have been delivered (June 2021, September 2021) which included high-quality scientific lectures, experimental techniques, workshops on Scientific Writing & Publishing by Nature Publishing Group, soft skills workshops, and several industry-focused workshops. In line with the dissemination strategy proposed, over the previous 24 months, a dedicated website (https://www.nature-etn.eu) was created along with a Twitter account (@ETN_NATURE), and an Instagram account (nature.etn) to ensure the maximum outreach to four main stakeholder groups; scientific community, industry, healthcare actors and the general public.
The research connected with therapeutic oligonucleotides has branched out to take advantage of i.) emerging prebiotic model systems and ii.) the urgent need to develop new antiviral Covid-19 treatments. The scientific results obtained so far, are disseminated in the form of peer-reviewed scientific publications (including Nature, Organometallics, Journal of Biological Inorganic Chemistry, Nature Communications, Nucleic Acids Research, Molecules) with several other papers either under review or at advanced draft stages.
A personal career development plan (PCDP) was completed by each ESR under the guidance of their PIs. NATURE-ETN ESRs have attended, and presented, their work at scientific conferences throughout Europe, as well as at our online scientific meetings and the Project Check meeting held in October 2021. In addition, two training weeks have been delivered (June 2021, September 2021) which included high-quality scientific lectures, experimental techniques, workshops on Scientific Writing & Publishing by Nature Publishing Group, soft skills workshops, and several industry-focused workshops. In line with the dissemination strategy proposed, over the previous 24 months, a dedicated website (https://www.nature-etn.eu) was created along with a Twitter account (@ETN_NATURE), and an Instagram account (nature.etn) to ensure the maximum outreach to four main stakeholder groups; scientific community, industry, healthcare actors and the general public.
NATURE-ETN’s scientific and technological progress beyond the state-of-the-art focuses on:
1. Developing new methods for artificial gene editing. We have contributed to this field by developing a click chemistry strategy for producing DNA-damaging metallodrugs. Currently, our work aims to generate a radical class of advanced hybrid biomaterials with sequence-specific gene targeting properties. The ESRs are progressing steadily, as the goal is quite advanced. The research involved is on the development of artificial gene-editing systems using triplex-forming oligonucleotide-M+ hybrids that can be light and chemically activated - a field that is actively explored by the Gasser group. We also aim to crystallise and structurally characterise these hybrid systems using DNA X-ray crystallography. Here, expertise from the Cardin group will help to establish an efficient high-throughput methodology. The successful outcome of these projects will not only be a major milestone for the project, but it will also benefit and assist the establishment of a gene-editing technology for exploitation.
2. Synthesis and delivery of new therapeutics that promote cell-based cancer immunotherapy. NATURE-ETN ESRs are engaged in the development of geranylated nucleosides to anchor RNA to nanoparticles for transfection. Moreover, one ESR is focusing on establishing prebiotically plausible scenarios of an RNA–peptide world. Another NATURE-ETN’s ESR is progressing on investigating the stabilization effects of m6A in RNA constructs including guide-RNA in combination with dCas13-fused methyltransferases. Another project is dedicated to the design of antisense oligonucleotides containing artificial cleaving agents which have Cas13-like behaviour but without the protein component. The research outcome will have a major impact on cancer therapy since the approach here will both simultaneously reduce immunogenicity and enhance mRNA expression.
3. Generation of new reagents for high-sensitivity epigenetic base detection. Reading the epigenetic status of DNA bases encoded in the human genome gives us vital information related to gene expression. NATURE-ETN ESRs focus on sequencing the epigenome and addressing current limitations. ESRs working here, are currently developing breakthrough materials for epigenetic base oxidation for use in next-generation sequencing. Progress is made so far on establishing analytical methods for quantification of cAzadC and metabolites prepared using isotopically labelled compounds for metabolic assays. The successful development of such an analytical protocol will allow rapid and parallel monitoring of dC and metabolites that would revolutionise epigenetic monitoring and diagnostics. In parallel, novel Fe(IV)-oxo complexes are synthesized as agents able to oxidize 5mC and 5hmC to 5fC. In this Work Package, baseclick GmbH aims to exploit other important avenues for probe development through a click chemistry-based method for the generation and amplification of full-length cDNA libraries from total RNA for next-generation sequencing.
1. Developing new methods for artificial gene editing. We have contributed to this field by developing a click chemistry strategy for producing DNA-damaging metallodrugs. Currently, our work aims to generate a radical class of advanced hybrid biomaterials with sequence-specific gene targeting properties. The ESRs are progressing steadily, as the goal is quite advanced. The research involved is on the development of artificial gene-editing systems using triplex-forming oligonucleotide-M+ hybrids that can be light and chemically activated - a field that is actively explored by the Gasser group. We also aim to crystallise and structurally characterise these hybrid systems using DNA X-ray crystallography. Here, expertise from the Cardin group will help to establish an efficient high-throughput methodology. The successful outcome of these projects will not only be a major milestone for the project, but it will also benefit and assist the establishment of a gene-editing technology for exploitation.
2. Synthesis and delivery of new therapeutics that promote cell-based cancer immunotherapy. NATURE-ETN ESRs are engaged in the development of geranylated nucleosides to anchor RNA to nanoparticles for transfection. Moreover, one ESR is focusing on establishing prebiotically plausible scenarios of an RNA–peptide world. Another NATURE-ETN’s ESR is progressing on investigating the stabilization effects of m6A in RNA constructs including guide-RNA in combination with dCas13-fused methyltransferases. Another project is dedicated to the design of antisense oligonucleotides containing artificial cleaving agents which have Cas13-like behaviour but without the protein component. The research outcome will have a major impact on cancer therapy since the approach here will both simultaneously reduce immunogenicity and enhance mRNA expression.
3. Generation of new reagents for high-sensitivity epigenetic base detection. Reading the epigenetic status of DNA bases encoded in the human genome gives us vital information related to gene expression. NATURE-ETN ESRs focus on sequencing the epigenome and addressing current limitations. ESRs working here, are currently developing breakthrough materials for epigenetic base oxidation for use in next-generation sequencing. Progress is made so far on establishing analytical methods for quantification of cAzadC and metabolites prepared using isotopically labelled compounds for metabolic assays. The successful development of such an analytical protocol will allow rapid and parallel monitoring of dC and metabolites that would revolutionise epigenetic monitoring and diagnostics. In parallel, novel Fe(IV)-oxo complexes are synthesized as agents able to oxidize 5mC and 5hmC to 5fC. In this Work Package, baseclick GmbH aims to exploit other important avenues for probe development through a click chemistry-based method for the generation and amplification of full-length cDNA libraries from total RNA for next-generation sequencing.