CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

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 <i>BCL11A</i> 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 <i>BCL11A</i> 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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Affiliated Institutions

• Sarah Cannon US
• University of Milan IT
• University of Tübingen DE
• Université Paris Cité FR
• Assistance Publique – Hôpitaux de Paris FR
• University of Regensburg DE
• University of Illinois Chicago US
• BC Children's Hospital CA
• University of Toronto CA
• University School US
• University Children's Hospital Tübingen DE
• University of British Columbia CA
• University of Pennsylvania US
• Boston University US
• SickKids Foundation CA
• St. Jude Children's Research Hospital US
• Hospital for Sick Children CA
• Children's Hospital of Philadelphia US
• Bambino Gesù Children's Hospital IT
• Vertex Pharmaceuticals (United States) US
• Children’s Hospital at TriStar Centennial US
• St. Mary’s Hospital ZA
• Mylan (Switzerland) CH
• Sapienza University of Rome IT
• Temple Street Children's University Hospital IE
• Columbia University US
• Hôpital Necker-Enfants Malades FR
• Cornell University US
• CRISPR Therapeutics (Switzerland) CH
• National and Kapodistrian University of Athens GR
• Imperial College Healthcare NHS Trust GB

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