Genome editing approaches to β-hemoglobinopathies

Abstract

β-hemoglobinopathies are the most common monogenic disorders worldwide and are caused by mutations in the β-globin locus altering the production of adult hemoglobin (HbA). Transplantation of autologous hematopoietic stem cells (HSCs) corrected by lentiviral vector-mediated addition of a functional β-like globin raised new hopes to treat sickle cell disease and β-thalassemia patients; however, the low expression of the therapeutic gene per vector copy is often not sufficient to fully correct the patients with a severe clinical phenotype. Recent advances in the genome editing field brought new possibilities to cure β-hemoglobinopathies by allowing the direct modification of specific endogenous loci. Double-strand breaks (DSBs)-inducing nucleases (i.e., ZFNs, TALENs and CRISPR-Cas9) or DSB-free tools (i.e., base and prime editing) have been used to directly correct the disease-causing mutations, restoring HbA expression, or to reactivate the expression of the fetal hemoglobin (HbF), which is known to alleviate clinical symptoms of β-hemoglobinopathy patients. Here, we describe the different genome editing tools, their application to develop therapeutic approaches to β-hemoglobinopathies and ongoing clinical trials using genome editing strategies.

Trial registration: ClinicalTrials.gov NCT04205435 NCT04211480 NCT03432364 NCT03653247 NCT03655678 NCT03745287.

Keywords: BCL11A enhancer; Fetal hemoglobin; Genome editing; HBG promoters; Sickle cell disease; β-Globin-gene correction; β-Thalassemia.