Treatment of Individuals with Severe Sickle Cell Disease with OTQ923, an Autologous, Ex Vivo , CRISPR/Cas9-Edited, CD34+ Hematopoietic Stem and Progenitor Cell Product, Leads to Durable Engraftment and Fetal Hemoglobin Induction

作者：Akshay Sharma, Jaap Jan Boelens, Maria Cancio, Jane Hankins, Prafulla A Bhad, Andrew Lewandowski, Xiaojun Zhao, Shripad Chitnis, Radhika Peddinti, Zheng Yan, Neena Kapoor, Fabio Ciceri, Jianping Yuan, Vionnie W. Yu, Susan C. Stevenson, Serena De Vita, James L. LaBelle · 发表于：Blood · 年份：2022 · DOI：10.1182/blood-2022-166254 · 被引用次数：5 · 研究领域：Hemoglobinopathies and Related Disorders、Prenatal Screening and Diagnostics、Blood groups and transfusion

Introduction: Increased levels of fetal hemoglobin (HbF; encoded by γ-globin [HBG1/HBG2]) are protective against complications of sickle cell disease (SCD). BCL11A is a transcription factor that binds to HBG1/HBG2 promoters and produces a γ-to-β globin (fetal-to-adult hemoglobin) switch. Inhibiting BCL11A binding to its target can reverse the switch and induce HbF expression in adult red blood cells (RBCs). OTQ923 is an autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product with a targeted disruption of the HBG1/HBG2 promoters on chromosome 11. Targeting this region in preclinical models led to HbF induction, phenotypically recapitulating hereditary persistence of fetal hemoglobin (a naturally occurring condition whose co-inheritance ameliorates SCD severity). This approach is more targeted than complete elimination of BCL11A expression in erythrocyte precursors for treating hemoglobinopathies. Additionally, unlike lentiviral vector gene addition, induction of endogenous γ-globin transcription could concur with reduction of βS-globin expression to avoid α- and β-like globin chain imbalance. Methods: Subjects with severe SCD, defined by a history of stroke, recurrent vaso-occlusive events (VOE), acute chest syndrome (ACS), chronic transfusions, recurrent priapism or red cell alloimmunization, were eligible to participate in the adult cohort (≥18-≤40 years old) of this clinical trial (NCT04443907). OTQ923 was manufactured from cryopreserved, peripheral blood derived CD...