Gene Therapy and Gene Editing for β-Thalassemia

Abstract

After many years of intensive research, emerging data from clinical trials indicate that gene therapy for transfusion-dependent β-thalassemia is now possible. Strategies for therapeutic manipulation of patient hematopoietic stem cells include lentiviral transduction of a functional erythroid-expressed β-globin gene and genome editing to activate fetal hemoglobin production in patient red blood cells. Gene therapy for β-thalassemia and other blood disorders will invariably improve as experience accumulates over time. The best overall approaches are not known and perhaps not yet established. Gene therapy comes at a high cost, and collaboration between multiple stakeholders is required to ensure that these new medicines are administered equitably.

Keywords: Gene editing; Gene therapy; β-thalassemia.

Figure 1.. Gene therapy for transfusion-dependent β-thalassemia.

The multi-step process includes: (I) Informed consent, including patient/family education and written consent; (II) mobilization, apheresis collection and enrichment of patient (autologous) hematopoietic stem cells (HSCs); (III) Ex vivo genetic manipulation of HSCs to restore erythroid expression of β-globin or induce fetal hemoglobin (HbF) expression; (IV) Administration of bone marrow conditioning followed by infusion of the modified HSCs.

Figure 2.. Genetic manipulation of autologous HSCs for TDT gene therapy.

(A) Patient HSCs are transduced with lentiviral vector (LVV) particles encoding a β-like globin gene. (B) Induction of fetal hemoglobin (HbF, α2γ2) by disrupting the +58 erythroid enhancer in intron 2 of the BCL11A by genome editing nuclease mediated non-homologous end joining (NHEJ) or base editing. (C) Alteration of the γ-globin promoter. Bottom shows disruption of BCL11A or ZBTZ7A repressor binding motifs via genome editing nuclease-mediated NHEJ. Top shows installation of new binding motifs for one of several erythroid transcription factors with adenine base editors.