Transplantation of engineered hematopoietic stem and progenitor cells (HSPCs) showed curative potential in patients affected by neurometabolic diseases treated in early stage. Favoring the engraftment and maturation of the engineered HSPCs in the central nervous system (CNS) could allow enhancing further the therapeutic potential of this approach. To this goal, we propose a gene addition strategy involving CX3CR1, a microglia chemokine receptor regulating microglia ontogeny and function. We showed that Cx3cr1 haplo-insufficient (Cx3cr1-/+) HSPCs are favored in generating microglia-like progeny cells (MLCs) as compared to WT (Cx3cr1+/+) HSPCs upon transplantation in mice. Thus, we designed a CRISPR-based gene addition strategy at the human CX3CR1 locus that resulted in enhanced ability of edited human HSPCs to engraft and repopulate the hematopoietic system and the CNS myeloid compartments of transplant recipients, and in lineage specific, regulated and robust transgene expression in their MLC progeny. This approach, which benefits from the modulation of pathways involved in microglia maturation and migration in haplo-insufficient cells, may thus broaden the application of HSPC gene therapy to a larger spectrum of neurometabolic and neurodegenerative diseases.