AI Article Synopsis
- Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are serious genetic disorders that require ongoing medical treatment and can be life-threatening.
- Researchers utilized CRISPR-Cas9 technology to modify CD34+ stem cells from healthy donors, targeting a specific enhancer to increase fetal hemoglobin production by altering BCL11A, a gene that suppresses it.
- Two patients, one with TDT and the other with SCD, received these edited cells after a preparative procedure and showed significant improvements after a year, including high fetal hemoglobin levels, independence from blood transfusions, and reduced complications from SCD.
Article Abstract
Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).
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| http://dx.doi.org/10.1056/NEJMoa2031054 | DOI Listing |
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