Project description
Establishing tyrosine recombinases as advanced tools for genome editing
For safety and effectiveness, gene therapies often need to integrate a large therapeutic DNA cargo at precise genomic locations. In this case, DNA editors such as CRISPR technology are limited by nuclease-based mechanisms and cannot adequately handle large DNA insertions. Meanwhile, tyrosine recombinases are capable of rearranging large DNA segments without nuclease-based mechanisms. However, there is no current solution for rational reprogramming of their DNA specificities for binding non-native DNA targets. The ERC-funded EditYR project aims to create a rationally programmable tyrosine recombinase platform that enables efficient integration of large DNA cargo into precise genomic locations. It will extend recombinase engineering capabilities by leveraging recent advances in large-scale DNA synthesis and sequencing along with bioinformatics and protein design.
Objective
Gene therapies aim to cure genetic diseases by modifying the DNA blueprint. An ideal gene therapy should be durable, safe, and efficient, which often requires integration of large therapeutic DNA cargo at precise genomic locations. Advanced DNA editors with programmable specificities, such as the CRISPR technology, are limited by the nuclease-based mechanism and poor efficiency of large DNA insertions. Increased efficiency, specificity and precision of large edits are required to address a broad therapeutic space.
Tyrosine recombinases (YRs) efficiently rearrange large DNA segments without the pitfalls of nuclease-based editors, but with an important caveat – rational reprogramming of their specificities for binding non-native DNA targets is an unsolved problem. EditYR ambitiously aims to develop a rationally programmable tyrosine recombinase platform for efficient integration of large DNA cargo into precise genomic locations. EditYR will expand recombinase engineering capabilities by exploiting the recent advances in large scale DNA synthesis and sequencing coupled with bioinformatics and innovative protein design. Objective 1 will engineer tyrosine recombinase DNA specificities and extract a comprehensive DNA recognition code. Objective 2 will modify their oligomerization properties to enable binding non-palindromic targets, allowing targeting any desired nucleotide sequence. Objective 3 will investigate requirements for irreversible recombination to maximize integration efficiencies and unlock the full therapeutic potential of these enzymes. Finally, Objective 4 will validate engineered enzymes by identification of targetable sequences in therapeutically relevant genomic regions and integration of therapeutic DNA cargo in various human cell types for different disease cases.EditYR will establish tyrosine recombinases as advanced tools for genome editing, creating a DNA editing technology that will elevate the capabilities of gene therapies to unprecedented levels
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.
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.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics genomes
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-STG
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1000 Ljubljana
Slovenia
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