Project description
Advancing gene therapy for the delivery of large genetic cargos
Gene therapy using adeno-associated viruses (AAV) has shown great promise, with several treatments already available and more in development. However, a major limitation remains: AAV vectors can only carry small genetic payloads, making them unsuitable for treating inherited diseases caused by mutations in large genes. Researchers have explored using inteins (small protein elements that can join protein fragments inside cells) to overcome this barrier. While promising, existing intein-based strategies face challenges, including limited efficiency in certain applications, complex design and unwanted by-products. In this context, the ERC-funded NextGeneTx seeks to optimise AAV-intein technology to create a next-generation AAV platform for treating genetic disorders affecting large genes.
Objective
Despite 6 products on the market and dozens in advanced phases of clinical development, in vivo gene therapy with vectors derived from adeno-associated viruses (AAV) still faces the major challenge of the limited vector cargo capacity (< 5kb). This prevents AAV application for treatment of inherited diseases caused by mutations in large genes. To address this, we have recently developed an AAV-based strategy relying on the use of short protein elements called inteins. These, when fused at the extremities of fragments of a large protein delivered to cells through AAV, can mediate joining of the fragments in a traceless manner, resulting in the reconstitution of the intact target protein. However, despite being extensively utilized as biotechnological tools in vitro, the in vivo application of inteins for therapeutic purposes comes with several limitations. These include: insufficient levels of full-length protein reconstitution for some applications; complex design; and production of undesired, potentially harmful by-products. NextGeneTx aims to expand the potential of AAV-inteins as an innovative in vivo biotechnological tool for therapeutic purposes, by addressing each of these limitations. To achieve this, we will leverage cutting-edge technologies to: i. engineer inteins with improved efficiency and greater design flexibility; ii. modulate intracellular trafficking of intein-containing protein fragments to enhance the efficiency and accuracy of full-length protein reconstitution; iii. develop strategies to reduce the production of unwanted by-products. We will test the therapeutic relevance of evolved AAV-inteins in both gene therapy and genome editing applications, using human retinal organoids and animal models of retinal diseases. The outcomes of NextGeneTx will define a highly adaptable, safe, and effective next-generation AAV-based approach to deliver large genes, thus significantly expanding the patient population that can benefit from in vivo gene therapy.
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.
- medical and health sciences medical biotechnology genetic engineering gene therapy
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine ophthalmology
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics genomes
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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)
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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.
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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 - HORIZON ERC Grants
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Call for proposal
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(opens in new window) ERC-2024-STG
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00185 ROMA
Italy
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