Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives

Abstract

Here I review the scientific background, current stage of development and future perspectives that I foresee in the field of genetic manipulation of hematopoietic stem cells with a special emphasis on clinical applications.

Keywords: gene editing; gene therapy; hematopoietic stem cells; lentiviral vectors; transplantation.

Figure 1. HSC gene therapy

A schematic representation of HSC GT showing the crucial steps of the process and its potential clinical applications: (1) HSPC are harvested from the mobilized peripheral blood or bone marrow of a patient and (2) cultured ex vivo in suitable conditions allowing maintenance or expansion of the rare cells with long‐term repopulating potential, while they are subjected to gene transfer or gene editing. The patient is then administered a conditioning regimen which depletes endogenous HSPC from the bone marrow and makes space for her/is ex vivo engineered cells, which are then infused back (autologous cell therapy). The gene‐modified cells engraft in the bone marrow, where they self‐renew potentially for the lifetime of the individual while giving rise to differentiating progeny along all hematopoietic lineages. The mature gene corrected cells repopulate vascular and extravascular compartments with functional cells that can reverse pre‐existing pathologies affecting the lymphoid system, such as primary immunodeficiencies, the erythroid lineages, such as thalassemia and sickle cell disease, scavenger cells of myeloid lineage found throughout peripheral organs and, in part, the central nervous system and suffering from storage disease due to a lysosomal enzyme deficiency. As we are becoming confident with the safety and efficacy of genetic engineering of hematopoiesis, new applications are also explored which, rather than replacing inherited defective genes, are instructing new functions to selected lineages to better fight cancer or chronic infections.