Targeting gene-modified hematopoietic cells to the central nervous system:Use of green fluorescent protein uncovers microglial engraftment

Gene therapy in the central nervous system (CNS) is hindered by the presenc e of the blood-brain barrier, which restricts access of serum constituents and peripheral cells to the brain parenchyma. Expression of exogenously adm inistered genes in the CNS has been achieved in vivo using highly invasive routes, or ex vivo relying on the direct implantation of genetically modifi ed cells into the brain. Here we provide evidence for a novel, noninvasive approach for targeting potential therapeutic factors to the CNS. Geneticall y-modified hematopoietic cells enter the CNS and differentiate into microgl ia after bone-marrow transplantation. Up to a quarter of the regional micro glial population is donor-derived by four months after transplantation. Mic roglial engraftment is enhanced by neuropathology, and gene-modified myeloi d cells are specifically attracted to the sites of neuronal damage. Thus, m icroglia may serve as vehicles for gene delivery to the nervous system.