Objective
Objectives:
Fanconi anaemia, xeroderma pigmentosum and ataxia telangectasia are all representatives of a group of human genetic disorders characterized by hypersensitivity to DNA-damaging agents and increased propensity to development of malignancy. Haematopoietic failure and proneness to AML are the prime lifethreatening symptoms in Fanconi patients.
The only efficient treatment to Fanconi Anaemia (FA) to date is bone marrow transplantation (BMT). Gene Therapy represents an alternative of major interest since in addition to innocuousness, this approach addresses a majority of FA-patients. Addition of a functional FA-gene to haematopoietic stem cells should lead to major improvement of patients' condition. The purpose of this research programme is to provide demonstration of efficient recovery of haematologic anomalies.
Knowledge derived from this study making use of a novel vector addressing a disorder of the haematopoietic stem cell with a newly cloned gene, will impact on transfer and expression of a variety of genes into the haematopoietic tissue as well as in a broad range of target cells. This will facilitate the development of gene therapy in a wide variety of disorders.
Brief description:
The normal FAA gene will be transferred into haematopoietic stem cells of FA-A patients. In vivo selective growth advantage of successfully transduced cells is expected. This is likely to help genetically engineered haematopoietic progenitors settle and reconstitute host without prior myeloablation. The retrovirus vector is a novel Friend virus-derived backbone, which harbours high titers and has been optimized for translation/expression features. It is efficient at transducing CD34+ progenitors with marker genes. Pre-clinical studies are designed in such a way that demonstration of phenotypic correction of FA-A patients cells can be established. These include in vivo studies in NOD/SCID mice reconstituted with retrovirally transduced early haematopoietic progenitors of human origin. A conditional FAA-null mouse will be generated. In case a phenotype can be evidenced in the bone-marrow, correction of putative mutant features will be examined following transfer of the normal human cDNA. Various sources of human haematopoietic progenitors will be tested. This includes cytokine mobilized peripheral blood progenitors (PBSC's), umbilical cord blood and bone-marrow cells. Access to true haematopoietic stem cells for the purpose of in vitro genetic manipulation might prove difficult, like in FAC patients. Potential benefit of in vivo infusion of bone-marrow will be examined taking advantage of a novel device and production of virus particles resistant to complement-induced lysis. Achievement of a series of successive milestones is thus mandatory to provide adequate ground for the initiation of a pilot clinical trial in 10 FA-A patients in compliance with established regulation.
Keywords:
Somatic Gene Therapy, Fanconi Anaemia, FM-gene cloning, Retrovirus-mediated gene transfer, novel Friend-virus vector, Haematopoietic stem cells, NOD/SCID-mice, Ex vivo and In vivo delivery, Early steps in the manufacture of clinical grade product.
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 microbiology virology
- medical and health sciences medical biotechnology cells technologies stem cells
- medical and health sciences clinical medicine transplantation
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Coordinator
75475 Paris
France
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