Important Advance for Two Different Blood Disorders: A Complete Functional Cure with Genetic Scissors

A CRISPR/Cas9-based experimental treatment for transfusion-dependent beta-thalassemia and sickle cell disease may provide lasting disease control for nearly all patients.

After infusion of the drug called Exagamglogene autotemcel (exa-cell), 95% of patients with beta-thalassemia no longer needed red blood cell transfusions, and none of the patients with sickle cell disease experienced severe vaso-occlusive crises.

A New Approach to Beta-Thalassemia and Sickle Cell Disease

The study’s first author, Dr. Franco Locatelli, clinical head of the Department of Pediatric Hematology and Oncology at Bambino Gesu Children’s Hospital in Rome, Italy, and Professor of Pediatrics at Sapienza University, said, “These results show that exa-cell has the potential to be the first CRISPR/Cas9-based therapy to provide a functional cure for beta-thalassemia and severe sickle cell disease.”

• Related topic: 2020 Nobel Prize in Chemistry – Genetic Scissors CRISPR-Cas9

Locatelli presented the latest developments on 12 June at the 2022 Annual Meeting of the European Hematology Association in Vienna.

Transfusion-dependent beta-thalassemia and sickle cell disease share a distinct mutation in the gene encoding the hemoglobin beta subunit. This mutation reduces or eliminates production of the hemoglobin beta chain or causes abnormal hemoglobin polymerization with deoxygenation.

Luspatercept and crizanlizumab are among recently approved treatments that can improve disease symptoms but are not curative. Allogeneic bone marrow transplantation is a curative option, but compatible donors are limited.

Exa-cell therapy approaches beta-thalassemia and sickle cell disease from another angle – it targets mechanisms that increase fetal hemoglobin production, which is associated with improvement in both diseases. More specifically, exa-cell uses CRISPR/Cas9 to edit single-nucleotide polymorphisms at the BCL11A locus in autologous hematopoietic stem and progenitor cells, which may increase fetal hemoglobin expression and reduce disease severity.

Earlier data from the CLIMB THAL-11 and CLIMB SCD-121 trials showed that a single dose of exa-cell, code-named CTX001, could increase fetal and total hemoglobin sufficiently to eliminate red blood cell transfusions and vaso-occlusive crises. The current research reported efficacy and safety data from the first 75 patients in these important ongoing trials.

A total of 44 people with beta-thalassemia and 31 with sickle cell disease received a single infusion of exa-cell. After this CRISPR/Cas9 treatment, patients underwent myeloablation (a reduction in the number of defense cells) with bisülfan.

Overall, among patients with beta-thalassemia, 95% (42 out of 44) no longer needed red blood cell transfusions over the following years. The requirements of the other two patients were reduced by up to 89%.

Among patients with sickle cell disease, none of the 31 patients experienced a severe vaso-occlusive crisis.

Clinically meaningful increases in fetal and total hemoglobin levels were observed in both disease groups, and the increases persisted throughout follow-up.

Does the Treatment Have Side Effects?

Side effects were consistent with those observed with bisulfan-induced myeloablation and autologous stem cell transplantation. Two patients with beta-thalassemia experienced serious side effects considered related to exa-cell. 

However, these serious side effects fully resolved, and the patients achieved neutrophil engraftment on day 56. All other patients achieved neutrophil engraftment on day 43 after exa-cell infusion.

No deaths, interruptions, or second cancers were reported.

These findings point to a new treatment option that is effective and potentially safer than conventional bone marrow transplantation.