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

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.

Adeno-associated virus as a delivery vector for gene therapy of human diseases

“…Non-oncologic hematologic conditions can be classified into cellular or acellular diseases, meaning that genetic mutations affect cellular function (e.g., sickle cell disease) 282 or components of blood (e.g., hemophilia), 283 respectively. The distinction is crucial for gene therapy as it determines the target cell/organ.…”

Current and Future Therapeutics for Treating Patients with Sickle Cell Disease

“…BEAM-101 utilizes CRISPR-based adenine base editors to induce point mutations in the HBG1/2 promoter, resulting in increased HbF production. In preclinical mouse models, greater than 90% of edited HSCs were stably edited and resulted in over 65% HbF expression [74]. In 2022, the BEACON study began, evaluating the safety and efficacy of BEAM-101 in patients with SCD.…”

CRISPR technology in human diseases

“… 156 , 237 , 238 , 239 , 240 Reversing BCL11A inhibition of γ‐globin expression and reactivating HbF via gene editing represents a promising strategy for SCD therapy (Figure 4B ). 241 , 242 After editing the GATA binding protein 1 (GATA1) binding site in the BCL11A enhancer +58 using the Cas9 RNP complex to reduce BCL11A expression and increase fetal γ‐globin, the HbF level in patients with SCD increased from 13.9 to 47.5%, indicating that the gene editing resulted in long‐lasting HbF induction, and CIRCLE‐seq (Circularization for In vitro Reporting of CLeavage Effects by Sequencing) did not detect off‐target activity. 243 In addition, a Cas9:sgRNA RNP complex was constructed to target the BCL11A binding motif in the γ‐globin gene promoter in HSPCs, abolishing the BCL11A binding site and increasing the HbF level to a therapeutic level, which is a highly specific and safe treatment strategy for SCD.…”