Gene therapy for patients with Fanconi anemia. The overall goal of this project is to develop gene therapy for patients with Fanconi Anemia (FA). FA is an autosomal recessive syndrome which is characterized by congenital abnormalities, predisposition to malignancy and bone marrow failure. Current treatment options for patients with FA include supportive care, growth factor treatment with G-CSF, and hematopoietic stem cell transplantation for patients with HLA-matched siblings; transplantation from unrelated donors has been less successful in a number of different protocols are currently being studied. Gene therapy has also been described, however, gene transfer efficiency has been low and the detection of genetically modified cells in patients has only been transient.. Thus, this project will incorporate a number of recently developed technologies to improve CD34+ peripheral blood stem cell (PBSC) mobilization and transduction. Specifically we propose to 1) study mobilization with a combination of G-CSF and SCF to improve CD34+ mobilization in patients with FA, 2) evaluate hematopoietic stem ell gene transfer efficiency using fibronectin assisted transduction in patients with FA, 3) develop improved retroviral packaging cells and vectors for gene transfer into hematopoietic repopulating cells, 4) evaluate novel transduction conditions, vectors and multiple infusions of transduced CD34+ cells in future gene therapy protocols for patients with FA. Other advances from other projects of this RFA and from ongoing stem cell transduction studies in our baboon model will be incorporated into future gene therapy protocols for patients with FA.
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