Project description
Using off-target gene editing to advantage
Gene editing relies on making a targeted double-strand break in a sequence of interest. ‘Programmable nucleases’ found in microbes do just this. They can degrade the DNA of viruses that infect microbes (phages), while leaving microbial DNA intact. There are thousands of programmable nucleases in microbial genomes, but too little is known about their actions. The lack of ‘guide-target parity’ (cutting only fully matched target genome sites) is a significant concern. The ERC-funded PROTEGE project aims to turn this into an advantage. The team will use high-throughput biochemistry to profile nucleases for the specificity of guide-target parity, create a toolset to assess this, and test whether purposefully ‘misprogramming’ nucleases can direct specific repair outcomes.
Objective
Programmable nucleases reside at the nexus of advanced gene editing and microbial defense. These nucleases degrade phage DNA but avoid genomic DNA to provide the microbe with adaptive immunity. The standard-bearer, CRISPR-Cas9, relies on a guide RNA (gRNA) – its program – to precisely cut a complimentary genetic sequence – its target – for precision gene editing. These programmable nucleases deliver cure for genetic diseases like anemia, blindness, and cancer; quick disease model development; and diagnostics for viruses like SARS-CoV-2.
Hunts across microbial genomes have exposed thousands of programmable nucleases. Each could be another valuable tool for genome engineers, but we know just too little about them to use them safely. Even Cas9 does not have guide-target parity: It cuts partially matched ‘off-target’ genome sites, which can lead to dangerous side effects. Though we work hard to avoid off-targets, partial matching may have a bright side. What if we leverage it, using it to make gene editing more predictable?
Using high-throughput biochemistry, we will Profile nucleases and Repurpose Off-Targets to Expand Gene Editing. The PROTÉGÉ research program will profile guide-target parity – specificity – across promising, newly discovered programmable nucleases. It will deliver a toolset for assessing this critical safety feature rapidly and broadly. Finally, we will test the hypothesis that purposefully misprogramming nucleases can direct specific repair outcomes. We intended to benefit Europe and the world community with safer and more diverse gene editing tools for achieving its Horizon Europe health, technology and environmental goals.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been validated by the project's team.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been validated by the project's team.
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2022-STG
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01513 Vilnius
Lithuania
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