Dilivery of Genes to Hematopoietic Stem Cells

Bone marrow hematopoiesis is maintained by hematopoietic stem cells (HSC) (1 ). Because of their unique features to self-renew and differentiate along all lineages of hematopoietic cells, even a single HSC can completely reconstitute bone marrow hematopoiesis of irradiated recipients (2 ). Therefore, HSCs are considered to be the ideal target cell population in gene-therapy fields for genetic disorders that are susceptible to bone marrow transplantation (3 ). However, because most HSCs are quiescent, it is difficult to transduce them using retroviral vectors (4 ). Furthermore, retroviral vectors, especially Moloney murine leukemia virus (MMLV)-based retroviral vectors that have been commonly used in gene-therapy clinical trials, are very susceptible to de novo methylation in immature cells such as embryonic stem (ES) cells, embryonal carcinoma cells (EC), and HSCs, resulting in shut off/silencing of the transgene expression in vivo (5 ). This is another obstacle for successful gene delivery into HSCs.