Objective
Treatment options are insufficient for the majority of genetic metabolic diseases. Methylmalonic acidemia (MMA) is one such severe metabolic disease. With current therapeutic strategies, patients still develop metabolic decompensations, brain damage, kidney failure, and have a lifelong risk to acutely become blind. Repair of the genetic cause of disease would revolutionize outcomes for these patients, especially with increasing detection in neonatal screening programs. This makes it possible to correct the cause of disease prior to the onset of irreversible damage. However, efficiency, safety, versatility and delivery of precise gene editing is not yet sufficient for in vivo gene-correction therapies.
The aim of this proposal is to develop an in vivo gene-editing therapy program for patients with metabolic diseases targeting the liver, where most metabolic genes are highly expressed. As a proof-of-principle, I will repair genetic causes of MMA, validate this in personalized cells and mouse models, and lay the groundwork for human trials.
To this end, I will:
(1) Generate a clinically applicable gene-editing technique. I recently demonstrated that the novel gene-editing technique prime editing could accurately correct different mutations in patient-derived organoids. Using an innovative reporter and patient-derived organoids, I will develop prime editing into an efficient and safe strategy that can correct >90% of patient mutations.
(2) Create a system for in vivo delivery of the prime-editing machinery with lipid nanoparticles to target the liver, using patient-derived liver organoids and an existing MMA mouse model.
(3) Develop a roadmap to tailor gene-correction therapies to individual patients, using the reporter with the patient mutation and mutational context, patient-derived organoids, and a mutation-specific animal model for a common MMA mutation.
This foundational work will lay the basis for broad clinical application of precise gene-editing therapies.
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 mutation
- engineering and technology nanotechnology nano-materials
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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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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
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.
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
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2021-STG
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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.
3584 CX Utrecht
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.