Project description
Gene therapy for inherited metabolic liver diseases
Many metabolic disorders result from mutations in single genes that disrupt essential metabolic pathways. The liver is one of the most important organs of metabolism and hepatocytes are thus prime targets for therapeutic intervention. In vivo genetic engineering of hepatocytes holds great promise for treating these conditions, but long-term success depends on understanding liver cell dynamics. The ERC-funded HEPAGENE project aims to investigate postnatal liver maturation by identifying key proliferative cell subsets and mapping hepatocyte heterogeneity. Project results are expected to support the design of safe gene therapies for inherited metabolic diseases in paediatric patients.
Objective
In vivo genetic engineering of hepatocytes may represent a definitive cure for monogenic metabolic diseases. Integration of the therapeutic transgene into the target cell genome is essential for long-term expression after a single dose early in life and can be achieved by semi-randomly integrating lentiviral vectors or site-specific genome editing. Maintenance of the genetic modification upon hepatocytes proliferation in liver growth and turnover requires targeting the cells underlying these processes. Little is known about post-natal liver growth and how different hepatocyte subsets contribute to it. Unexpectedly, we found that most hepatocytes are quiescent during liver growth, and a fraction of them generate most of the adult tissue. The overall goal of HEPAGENE is to dissect hepatocyte heterogeneity in post-natal liver maturation and unravel its implications for in vivo gene engineering, to ultimately design and develop safe, effective, and durable gene therapies to treat diseases of hepatic metabolism in pediatric patients. To achieve this goal, we will: i) characterize molecular programs of proliferating and quiescent hepatocyte subsets; ii) assess their susceptibility to lentiviral gene transfer and nuclease-mediated gene editing, in both normal mice and in a disease model of methylmalonic acidemia, a severe early-onset disease, taken as paradigmatic of inherited metabolic diseases; iii) estimate clonal dynamics of genetically modified hepatocytes in vivo in non-human primates and analyze gene signatures in human liver samples, to establish a correspondence between murine and primate’s hepatocyte subsets. We will exploit state-of-the-art organoid, single-cell and multi-omic analyses including latest-generation spatial transcriptomics. HEPAGENE will lead to improved understanding of liver biology and gene engineering of hepatocytes, paving the way for novel genomic medicine products that offer hope to children affected by otherwise incurable metabolic diseases
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 zoology mammalogy primatology
- 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)
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)
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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 - 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-COG
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20132 Milano
Italy
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