Promising CRISPR gene editing results in β-thalassaemia and sickle cell disease

CTX00, a first-in-human, CRISPR-Cas9-modified autologous product of CD34-positive haematopoietic stem and progenitor cells (HSPCs), resulted in increased foetal haemoglobin (HbF) and total Hb in the first 7 infused patients with transfusion-dependent β-thalassaemia and sickle cell disease. All participants demonstrated haematopoietic engraftment with a post-infusion safety profile generally consistent with myeloablation [1].

BCL11A is a key transcription factor suppressing the production of HbF in red blood cells (RBCs), leading to the production of adult Hb (HbA). In diseases with haemoglobin production defects, such as β-thalassaemia or sickle cell disease, HbF upregulation could ameliorate anaemia and reduce transfusion requirements, such as in β-thalassaemia, or reduce clinical complications, including vaso-occlusive crises, in sickle cell disease [1]. To induce potentially curative levels of HbF in erythrocytes, Dr Haydar Frangoul (Sarah Cannon Research Institute, USA) and colleagues used the ex vivo CRISPR-Cas9-based gene-editing platform to edit the erythroid enhancer region of BCL11A in HSPCs, producing CTX001.

CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) are multicentre, first-in-human studies of CTX001 for transfusion-dependent β-thalassaemia and sickle cell disease, respectively. Dr Frangoul presented available safety and efficacy results from all patients with ≥3 months of follow-up from both studies. All patients demonstrated increases in total Hb and HbF over time. Patients with transfusion-dependent β-thalassaemia ceased receiving packed RBC transfusions soon after CTX001 infusion, with the last packed RBC transfusion occurring between 0.9 and 1.9 months after CTX001 infusion.

The first patient with transfusion-dependent β-thalassaemia who received CTX001 has remained transfusion-free for over 15 months. Patients with sickle cell disease have had no vaso-occlusive crises since CTX001 infusion. The first sickle cell disease patient who received CTX001 has remained free of vaso-occlusive crises for over 1 year. In all 7 patients, the safety profile after CTX001 infusion was generally consistent with busulfan myeloablation.

According to Dr Frangoul, this early data suggests that CTX001 could be a functional treatment of transfusion-dependent β-thalassaemia and sickle cell disease.

1. Frangoul H, et al. Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β-Thalassemia and Sickle Cell Disease: Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-CAS9–Modified CD34+ Hematopoietic Stem and Progenitor Cells. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 4.

Posted on 18 February 202117 May 2024