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Haematopoiesis is the process of blood cell development from stem cells that reside in the bone marrow. Hematopoietic stem cells (HSC) are the paradigm of a cell that has both self-renewal and differentiation capacity. Defects in the differentiated progeny of HSC can manifest with different disease phenotypes; defects in haemoglobin synthesis results in thalassemias while defects in neutrophil and lymphocyte development results in immunodeficiencies. Since most of these genetic defects can be cured by transplantation of normal HSC from suitable donors, the transfer of gene-corrected HSC could provide an alternative option for those patients who do not have an HLA-matched donor. In our lab we are developing HSC gene transfer technology with viral vectors derived from lenti and foamy viruses (FV). Specifically, we have focused on the FV vectors and have developed therapeutic vectors for two single-gene disorders, beta-thalassemia and chronic granulomatous disease. Our experimental procedures include both in vitro and in vivo assays with transplantation of gene corrected HSC into ablated mouse models.

Similar to the process of normal haematopoiesis, the malignant haematopoiesis of leukaemia is also characterized by the presence of stem cells (LSC) with self-renewal potential. These stem LSC have some unique properties such as the potential to establish leukaemia in the NOD/SCID mouse model that accepts human grafts. Using this model and the RNAi technology that permits targeted gene silencing, we have explored the activity of the wnt signalling path in LSC. In addition, we are currently pursuing a similar question in a preleukemic condition known as Myelodysplastic syndrome (MDS). Finally, we have explored the stem cell phenotype of neuroblastoma, a paediatric solid tumour that will occasionally colonize the bone marrow. Apart from stem cell characterization in different disorders, we are developing FV vectors with endogenous bidirectional promoters and FV vectors with shRNA suitable for targeted gene knock-down. These tools could prove valuable for interventions requiring coordinated transgene expression or elimination of a specific transcript from a cell of interest.

At the clinical level, we have performed genetic association studies of granuloma-forming lesions (such as Hodgkin’s, sarcoidosis and tuberculosis) with SNP of the innate immunity genes MyD88 and TLR9; we have explored this mechanism since it has been established that both genes are required for proper phagosome maturation.