Project description
A new tool for cancer-selective gene editing
The CRISPR-Cas9 system represents a prominent genome-editing technology frequently applied in gene therapy contexts. A significant challenge, however, persists in achieving selective targeting of malignant cells while preserving the integrity of healthy tissues. Distinct patterns of DNA methylation are observed between cancerous and healthy cells, presenting a promising basis for targeted therapeutic interventions. Within this framework, the ERC-funded DeLIVER project investigates a specially engineered Cas9 variant termed ThermoCas9. This variant possesses the unique capacity to differentiate between methylated and unmethylated DNA sequences. ThermoCas9 has been designed to disrupt demethylated genes in liver cancer cells while preserving the surrounding healthy tissue. The project will validate this editing strategy, paving the way for a next-generation precision cancer therapy.
Objective
CRISPR-Cas technology has revolutionized genome editing, and Cas9-based systems have already enabled successful ex vivo and in vivo gene therapies. We have discovered and engineered a unique Cas9 variant, ThermoCas9, that combines attractive features – compact size, high stability, and exceptional specificity – with an unprecedented property: strict sensitivity to CpG methylation within its PAM recognition site.
This property creates therapeutic opportunities that are not achievable with canonical Cas9 enzymes. In hepatocellular carcinoma (HCC), essential genes often become demethylated and transcriptionally active, while the same genes remain methylated and silenced in healthy hepatocytes. By exploiting this difference, ThermoCas9 can selectively disrupt essential genes only in the tumor context, eliminating cancer cells while sparing healthy tissue.
We have recently demonstrated methylation-dependent discrimination in biochemical assays and in human cell lines (HEK293, HCT116) (manuscript under review). The DeLIVER project will now provide the first proof-of-concept for a therapeutic application. Specifically, we will test whether demethylated target genes in Huh7 liver cancer cells can be efficiently disrupted via ThermoCas9-mediated InDel formation, leading to selective killing of diseased cells while leaving healthy control cells (iPSC-derived hepatocytes) unaffected.
The primary outcome will be in vitro validation of this cancer-selective editing strategy, followed by testing in Huh7-derived xenograft models. In parallel, we will develop a business and IP strategy to enable future commercialization. Our long-term vision is to pioneer a next-generation therapeutic strategy by delivering ThermoCas9 as an mRNA/sgRNA payload via lipid nanoparticles – harnessing tumor-specific methylation signatures to achieve safe, selective, and highly effective treatment of cancer.
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 human-validated.
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 human-validated.
- medical and health sciences medical biotechnology genetic engineering gene therapy
- social sciences sociology social issues social inequalities
- medical and health sciences clinical medicine oncology
- engineering and technology nanotechnology nano-materials
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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)
MAIN PROGRAMME
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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-POC - HORIZON ERC Proof of Concept 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-2025-POC
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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.
6708 PB Wageningen
Netherlands
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