Autologous, Gene-Modified Hematopoietic Stem and Progenitor Cells Repopulate the Central Nervous System with Distinct Clonal Variants

Myeloid-differentiated hematopoietic stem cells (HSCs) have contributed to a number of novel treatment approaches for lysosomal storage diseases of the central nervous system (CNS), and may also be applied to patients infected with HIV. We quantified hematopoietic stem and progenitor cell (HSPC) trafficking to 20 tissues including lymph nodes, spleen, liver, gastrointestinal tract, CNS, and reproductive tissues. We observed efficient marking of multiple macrophage subsets, including CNS-associated myeloid cells, suggesting that HSPC-derived macrophages are a viable approach to target gene-modified cells to tissues. Gene-marked cells in the CNS were unique from gene-marked cells at any other physiological sites including peripheral blood. This novel finding suggests that these cells were derived from HSPCs, migrated to the brain, were compartmentalized, established myeloid progeny, and could be targeted for lifelong delivery of therapeutic molecules. Our findings have highly relevant implications for the development of novel therapies for genetic and infectious diseases of the CNS. Peterson, Adair, and colleagues investigated the trafficking and distribution of autologous hematopoietic stem cells and their progeny to an extensive array of tissues. Gene-marked macrophages were prominent, especially in lymphoid organs. Intriguingly, gene-marked myeloid cells in the CNS were unique from those at other sites. This observation holds great promise to therapeutically deliver disease-relevant transgenes to specific tissue sites.