Project description
Ex vivo gene therapy for GM1-gangliosidosis
GM1-gangliosidosis is an inherited disorder caused by mutations in the GLB1 gene that encodes the lysosomal hydrolase β-galactosidase. Patients accumulate undegraded metabolites in lysosomes which triggers cell damage, affecting mainly the central nervous system. The EU-funded GT-GM1 project proposes to develop a gene therapy approach for delivering the GLB1 gene alone or in association with a neuroprotective factor. Scientists will employ a mouse model of the disease and lentiviral vectors for the ex vivo delivery of the gene to hematopoietic stem/progenitor cells. Genetically modified cells will be re-infused intravenously and into the brain ventricles of animals for a therapeutic effect.
Objective
"GM-gangliosidosis (OMIM #230500) is a rare, autosomal recessive, neurodegenerative Lysosomal Storage Disorder. It is caused by mutations in the GLB1 gene, encoding the lysosomal hydrolase β-galactosidase. Infantile GM1-gangliosidosis is characterized by neurodevelopmental delay, hypotonia, dysphagia, seizures and death by 3 years of life. Due to the rapid progression and severe nature of this disease, which involves storage of undegraded metabolites and secondary mechanisms of cell damage, correction requires a rapid and robust enzyme delivery to the whole central nervous system (CNS), possibly associated to reduction of local inflammation. Here we propose an ex vivo gene therapy (GT) strategy aimed at preventing or ameliorating the symptoms of the disease in the murine model. Multiple copies of GLB1, alone or in association with a neuroprotective factor, will be delivered ex vivo to hematopoietic stem/progenitor cells by lentiviral gene transfer to determine a sustained and robust expression of the therapeutic enzyme in the CNS of transplanted mice. Genetically modified HSPCs will be administered by a novel approach combining the conventional intravenous route with direct administration into the brain lateral ventricles, to anticipate the myeloid reconstitution in the brain and possibly the therapeutic effect. Our working hypothesis is that this optimized GT strategy could successfully control disease manifestations in the animal model. Moreover, a deep genome-wide genomics analysis will be performed on individual brain cells to elucidate the molecular mechanisms at the basis of the disease and mediating the therapeutic effect. The study will generate a proof of concept for a future clinical development of an efficacious ex vivo GT for infantile GM1-gangliosidosis and will inspire the development of therapies for other LSDs.
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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 neurobiology
- medical and health sciences medical biotechnology genetic engineering gene therapy
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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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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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
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.
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.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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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) H2020-MSCA-IF-2018
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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.
35122 PADOVA
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.