Project description
Nanobodies deliver highly specific kinase inhibitors to prevent arrhythmias
Kinases are ubiquitous and essential enzymes in the body, and the heart is no exception. The delta isoform of Ca2+/Calmodulin-dependent kinase (Camk2d) plays an important role in life-threatening cardiac arrhythmias. Inhibitors have been problematic due to serious side effects, in large part due to the similarity of four isoforms of Camk2. The ERC-funded Nab-Heart project aims to conjugate selected nanobodies to a new Camk2 inhibitory peptide, thereby developing the first selective kinase inhibitor. The team will identify nanobody candidates with the required Camk2d selectivity and affinity, and covalently link Camk2d-inhibitory peptides to them. The therapy will be tested in vivo in mouse and swine models of arrhythmias.
Objective
In cardiac cells, kinase enzymes are key modulators of calcium homeostasis, mitochondrial function, excitation-contraction coupling, and metabolism. Of these, the delta isoform of Ca 2+ /Calmodulin-dependent kinase (Camk2d) is particularly relevant to the induction of life-threatening cardiac arrhythmias.Of the several promising small molecule and peptide Camk2d inhibitors proposed in pre-clinical investigations, none has entered clinical applications. The severity of side effects, a well-known issue for kinase inhibitors, in this case is further amplified by the high homology and the unique Ca 2+ -dependent regulatory physiology among four Camk2 isoforms, plus
the delicate role of the ubiquitously expressed Camk2d in non-cardiac tissues. Since the major obstacle to developing a cardio-specific, Camk2d-specific inhibitor mainly relies on reaching high isoform selectivity, the Nab-Heart project will conjugate selected Nanobodies (Nbs) to a new Camk2 inhibitory peptide to develop the first selective kinase inhibitor. Such a molecule will prevent the development of life-threatening arrhythmias in a variety of cardiac conditions, spanning from inherited arrhythmias such as Long QT Syndrome to
acquired and highly prevalent diseases such as atrial fibrillation and heart failure. The team will identify Nb candidates with the desired Camk2d isoform-selectivity and affinity. Optimized substrate-mimicking Camk2d-inhibitory peptides will be covalently linked to the selected Nbs (Nb-inibs) to ensure delivery of the inhibitory module to the pathologically active Camk2d target with outstanding selectivity and affinity. The strategy will be validated in vivo through cardio-specific AAV9 delivery of the Nb-inib candidates in a mouse model of Catecholaminergic Polymorphic Ventricular Tachycardia and in a Swine model of acquired heart failure, where Camk2d is known to be the trigger of life-threatening arrhythmias.
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 clinical medicine cardiology cardiovascular diseases cardiac arrhythmia
- natural sciences chemical sciences inorganic chemistry alkaline earth metals
- engineering and technology nanotechnology nano-materials
- medical and health sciences basic medicine physiology homeostasis
- 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
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-2024-ADG
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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.
27100 Pavia
Italy
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.