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Optimisation of retroviral vectors for gene transfer to human pluripotenthematopoietic cells and application to chronic granulomatous disease


Research objectives and content
Somatic gene therapy constitute an alternative strategy to Bone Marrow Transplantation in order to cure primary immunodeficiencies, such as Chronic Granulomatous Disease. The optimal target cell population for such a strategy is the pluripotent hematopoietic stem cell, which is defined by the capacity for extensive self-renewal, retention of multilineage differentiation potential and long term reconstitution of entire haematopoietic system. Nevertheless successes in mouse model, retroviral-mediated gene transfer into a significant proportion of human hematopoietic repopulating cells using vectors based on the Moloney murine leukemia remains inefficient.
To overcome some of these problems, different pseudotyped retroviral vectors, such as the feline endogenous virus | or the gibbon ape leukemia virus, will be tested to transduce human stem cell from cord blood and bone marrow | cells. The ability to efficiently transduce these cells will be tested using an in vivo functional assay for primitive . human hematopoietic cells based on their ability to repopulate bone marrow of immunodeficient nonobese . diabetic/severe combined immunodeficient mice..
Because defect genes, such as P47phox, implicated in Chronic Granulomatous Disease are expressed in myeloid . cells, the second objective is to achieve optimal expression of the transgene in the mature myeloid cells. We will test optimised retroviral regulatory sequences to achieve this goal. Training content (objective, benefit and expected impact)
The participation of the proposed project would allow me to expand my knowledge on gene therapy, haematology I and in vivo mouse model. Because a number of gene therapy programmeare under-development in Europe, this ( research experience at the Institute of Child Health which presents biology and medical interface, will constitute a significant advantage for the future.
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