Hematopoietic Stem Cell-Targeted Gene Therapy Using Lentiviral Vectors

Abstract

Gene therapy targeting hematopoietic stem cells (HSCs) is a promising treatment for a variety of genetic disorders, including immunodeficiency, hemoglobinopathies, congenital cytopenia, and metabolic diseases. HSCs can reconstitute peripheral blood throughout life due to their capacity for self-renewal and their hematopoietic multipotency. This makes it possible to cure genetic diseases for an entire lifetime by replacing or repairing pathogenic mutations/deletions in HSCs. Autologous HSC-targeted gene therapies entailing lentiviral gene addition as well as gene editing are currently under development. These can be widely applied to most patients, as there is no requirement for a suitable donor. Current gene addition/editing therapies are based on harvesting the patient's CD34⁺ HSCs, performing gene modification ex vivo, and then transplanting the modified HSCs back into the patient. The efficacy of ex vivo lentiviral HSC gene therapy has been proved in recent trials; however, the ex vivo process requires a GMP-level cell processing center and is expensive, which limits its global application. It is therefore crucial to develop in vivo HSC gene therapies, in which a therapeutic gene or gene editing tools can be delivered directly into bone marrow HSCs via systemic administration without ex vivo culture. This manuscript presents an overview of the current HSC-targeted gene therapies using lentiviral vectors.