Clustered regularly interspaced short palindromic repeats- (CRISPR) Cas9-based gene editing may help to reduce the disease burden for patients with transfusion-dependent β-thalassemia (TDT) or sickle cell disease (SCD), according to a brief report published in The New England Journal of Medicine.

Patients with TDT or SCD, monogenic diseases together diagnosed in more than 350,000 people per year, live with a host of clinical issues and have a reduced life expectancy. Mutations in the hemoglobin β subunit gene (HBB) cause both illnesses.

While transfusion and iron chelation may be effective in patients with TDT, and transfusion, hydroxyurea, and pain management may benefit patients with SCD, neither these, nor novel treatments, treat the underlying cause of disease.

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For these patient populations, elevated levels of fetal hemoglobin are linked to improved morbidity and mortality. A team of investigators hypothesized that genetically modifying the production of fetal hemoglobin would help to address the disease itself, rather than the effects thereof, in patients with SCD and TDT. Using CRISPR-Cas9, the researchers aimed to modify 80% of alleles at the BCL11A locus to induce fetal hemoglobin production in 2 patients. The treatment, CTX001, involved injection of autologous CRISPR-Cas9-edited CD34+ hematopoietic stem and progenitor cells, which were modified to reactivate fetal hemoglobin production (CLIMB THAL-111, Clinical Identifier: NCT03655678; CLIMB SCD-121, Clinical Identifier: NCT03745287).

One patient with TDT (aged 19 years) and 1 patient with SCD (aged 33 years) were included in the studies. Both patients were women.  

More than 12 months after treatment initiation, high (at least 60%) allelic editing levels in both bone marrow and blood were noted; the patients were also transfusion-independent and showed increases in fetal hemoglobin levels. The elimination of vaso-occlusive levels was also noted in the patient with SCD.

At 21.5 months following CTX001 treatment, the patient with TDT had 32 adverse events (AEs), 2 of which were serious, including pneumonia in the presence of neutropenia and veno-occlusive liver disease with sinusoidal obstruction syndrome. At 16.6 months following treatment, the patient with SCD had 114 AEs, 3 of which were considered serious, including sepsis in the presence of neutropenia, cholelithiasis, and abdominal pain.

“Initial results from the follow-up of the first two patients who were treated with CTX001 have shown the intended CRISPR-Cas9 editing of BCL11A in long-term hematopoietic stem cells, with durable engraftment, high levels of fetal hemoglobin expression, and the elimination of vaso-occlusive episodes or need for transfusion,” the authors wrote. “The generalizability of these early results with respect to other patients with TDT and SCD remains to be determined.”

Disclosures: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. Published online December 5, 2020. doi:10.1056/NEJMoa2031054