Implications of hematopoietic stem cells heterogeneity for gene therapies

Abstract

Hematopoietic stem cell transplantation (HSCT) is the therapeutic concept to cure the blood/immune system of patients suffering from malignancies, immunodeficiencies, red blood cell disorders, and inherited bone marrow failure syndromes. Yet, allogeneic HSCT bear considerable risks for the patient such as non-engraftment, or graft-versus host disease. Transplanting gene modified autologous HSCs is a promising approach not only for inherited blood/immune cell diseases, but also for the acquired immunodeficiency syndrome. However, there is emerging evidence for substantial heterogeneity of HSCs in situ as well as ex vivo that is also observed after HSCT. Thus, HSC gene modification concepts are suggested to consider that different blood disorders affect specific hematopoietic cell types. We will discuss the relevance of HSC heterogeneity for the development and manufacture of gene therapies and in exemplary diseases with a specific emphasis on the key target HSC types myeloid-biased, lymphoid-biased, and balanced HSCs.

Keywords: Gene therapy; Hematopoietic stem cells; Heterogeneity; Lineage; Subpopulation.

Fig. 1. HSC subsets and gene therapies in clinical trials.

SCD sickle cell disease; G6PDD glucose-6-phosphate dehydrogenase deficiency; PKD pyruvate kinase deficiency; SCID severe combined immunodeficiency X-CGD X-linked chronic granulomatous disease; LAD-1 leukocyte adhesion deficiency-1. Arrows indicate reversible phenotype shift from dormant HSCs to activated HSCs.

Fig. 2. Drivers of HSPC heterogeneity at distinct stages of HSC-based gene therapies.

HSPC heterogeneity is relevant, likely to variable degrees, in all phases of HSC-based gene therapies: in the BM niche in vivo before HSPC collection: disease-specific effects on HSPC subsets that interact with the nice; during HSPC mobilization (*does only pertain to PBSC collection, but not to BM collection): preferred mobilization of HS(P)C subsets; ex vivo during HSC selection/enrichment and manufacture of the gene therapeutic: interactions with immune cells and cytokines possibly impact HS(P)C subsets and manufacture protocols select for HSC subsets with variable transduction and survival rates; in situ again: interactions of modified HS(P)C subsets with the niche that has been altered by the conditioning regime could affect engraftment and long-term reconstitution.