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DNA-binding domain Conditioned Precision Genome Editing

Project description

Advancing precision tools for genome editing

Genome editing is opening new possibilities for treating genetic diseases via the correction of harmful mutations in the genome. However, many DNA-editing tools have raised safety concerns as they can cause off-target effects. To address this, the ERC-funded DC-PGE project is pioneering a fresh approach. Instead of relying on conventional enzymes that require host cell repair, researchers propose to engineer enzymes whose activity can be tightly controlled to modify only the intended DNA sequences. The project’s aim is to establish a versatile editing platform that can be adapted to target almost any gene. The approach will be validated for the treatment of severe genetic disorders, and if successful, it could transform genome editing tools.

Objective

Genome editing in human therapies has the potential to revolutionize modern medicine. With numerous clinical trials underway and the recent approval of the first genome editing therapy, the field is rapidly advancing. However, there is a consensus that clinical genome editing tools must be efficient, precise and safe. Current tools predominantly rely on host cell DNA repair pathways to complete the editing process, which poses a risk for unintended editing events. Host cell DNA repair independent, fully programmable editing tools represent a new class of genome editing technologies, significantly expanding the potential for delivering life-saving therapies to patients.
Genome editing tools that fulfil these characteristics are enzymes that recombine DNA. While there has been some success in engineering these enzymes to recognize and act on therapeutically relevant targets, their time-consuming and labour-intensive generation has hindered widespread implementation. DC-PGE aims to address this shortcoming. We have recently demonstrated that recombinase activity can be conditioned by internally fusing a zinc-finger DNA-binding domain into the enzyme's coding sequence, thereby making the enzyme activity contingent on zinc finger DNA binding. This pioneering discovery presents a genuine opportunity to develop next generation and best-in-class genome editing enzymes.
DC-PGE aims to i) build a platform to apply DNA-binding conditioned precision genome editing to DNA-recombining enzymes, ii) develop a pan-recombinase system for immediate targeting of virtually any genomic sequence and iii) apply the technology to correct the genetic cause of MECP2 duplication syndrome at nucleotide precision. DC-PGE will serve as a foundation for advancing innovative treatments and improving patient outcomes. Our unique approach lies in combining different disciplines and cutting-edge technologies with the potential to transform the field of genome editing and elevate it to the next level.

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Keywords

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2024-ADG

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Host institution

TECHNISCHE UNIVERSITAET DRESDEN
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.

€ 2 386 205,00
Address
HELMHOLTZSTRASSE 10
01069 DRESDEN
Germany

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Region
Sachsen Dresden Dresden, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost

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Beneficiaries (1)

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