Clinical genome editing to treat sickle cell disease-A brief update

Parinaz Zarghamian; Julia Klermund; Toni Cathomen

doi:10.3389/fmed.2022.1065377

Clinical genome editing to treat sickle cell disease-A brief update

Front Med (Lausanne). 2023 Jan 9:9:1065377. doi: 10.3389/fmed.2022.1065377. eCollection 2022.

Authors

Parinaz Zarghamian^{1

2

3}, Julia Klermund^{1

2}, Toni Cathomen^{1

2}

Affiliations

¹ Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany.
² Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ Ph.D. Program, Faculty of Biology, University of Freiburg, Freiburg, Germany.

Abstract

Sickle cell disease (SCD) is one of the most common hemoglobinopathies. Due to its high prevalence, with about 20 million affected individuals worldwide, the development of novel effective treatments is highly warranted. While transplantation of allogeneic hematopoietic stem cells (HSC) is the standard curative treatment approach, a variety of gene transfer and genome editing strategies have demonstrated their potential to provide a prospective cure for SCD patients. Several stratagems employing CRISPR-Cas nucleases or base editors aim at reactivation of γ-globin expression to replace the faulty β-globin chain. The fetal hemoglobin (HbF), consisting of two α-globin and two γ-globin chains, can compensate for defective adult hemoglobin (HbA) and reverse the sickling of hemoglobin-S (HbS). Both disruption of cis-regulatory elements that are involved in inhibiting γ-globin expression, such as BCL11A or LRF binding sites in the γ-globin gene promoters (HBG1/2), or the lineage-specific disruption of BCL11A to reduce its expression in human erythroblasts, have been demonstrated to reestablish HbF expression. Alternatively, the point mutation in the HBB gene has been corrected using homology-directed repair (HDR)-based methodologies. In general, genome editing has shown promising results not only in preclinical animal models but also in clinical trials, both in terms of efficacy and safety. This review provides a brief update on the recent clinical advances in the genome editing space to offer cure for SCD patients, discusses open questions with regard to off-target effects induced by the employed genome editors, and gives an outlook of forthcoming developments.

Keywords: CRISPR-Cas; HBB gene; HbF; base editing; clinical trial; gene editing; γ-globin.

Publication types

Review

Grants and funding

This research projects on hemoglobinopathies were supported by the European Commission (HORIZON-RIA EDITSCD grant no. 101057659 to TC) and the German Academic Exchange Service (DAAD fellowship grant no. 91764871 to PZ). We further acknowledge support by the Open Access Publication Fund of the University of Freiburg.