Results for the first 2 patients treated with a gene editing approach for either sickle cell disease (SCD) or b-thalassemia indicate elevated levels of fetal hemoglobin in these patients at a follow-up of over 1 year. The gene editing approach involves clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease technology, and for these patients, it was used to aid in the production of fetal hemoglobin. Results were published in The New England Journal of Medicine.

The patients were participants in the phase 1/2 CLIMB SCD-121 trial ( Identifier: NCT03745287) and the phase 1/2 CLIMB THAL-111 trial ( Identifier: NCT03655678). CLIMB SCD-121 includes patients with SCD, and CLIMB THAL-111 includes patients with transfusion-dependent b-thalassemia (TDT). Multiple outcomes are being assessed in these ongoing studies.

In both trials, CRISPR-Cas9 technology is used to subdue expression of BCL11A transcription factor; BCL11A is a repressor of erythroid-cell fetal hemoglobin. The therapy, called CTX001, is an autologous therapy, with gene editing performed on CD34+ hematopoietic stem and progenitor cells (HSPCs) extracted from the patient. Patients in this report underwent myeloablation with busulfan prior to receiving the therapy.

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In this analysis, CTX001 was initially tested in CD34+ HSPCs from 10 healthy donors. Reportedly, in these healthy donor HSPCs, approximately 80% (SD, 6%) of alleles showed editing at the BCL11A locus.

Results were presented in the report for the first patient in each of the 2 trials after treatment with CTX001. At this follow-up, both patients showed higher levels of fetal hemoglobin and transfusion independence. At 12 months, in peripheral blood cells the rate of allelic editing was slightly over 60% in each patient. In bone marrow it occurred in 80.4% of alleles in the patient with SCD and in 76.1% in the patient with TDT. Vaso-occlusive episodes reportedly ceased for the patient with SCD.

A total of 114 adverse events occurred in the patient with SCD at 16.6 months following infusion, with 3 considered serious. These were sepsis with neutropenia, cholelithiasis, and abdominal pain. For the patient with TDT, there were 32 adverse events reported at 21.5 months following infusion. Of these, 2 were rated as serious, including pneumonia with neutropenia and veno-occlusive liver disease with sinusoidal obstruction syndrome.

The study investigators concluded that the gene editing approach used in these studies has yielded durable engraftment with high levels of fetal hemoglobin in these 2 patients, among related outcomes, although they cautioned that the generalizability of these outcomes to other patients is not yet clear.

Disclosures: Some authors have declared affiliations with or received grant support 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. 2021;384(3):252-260. doi:10.1056/NEJMoa2031054