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

被引：1211

作者：

Frangoul, H. ^{[1
]}

Altshuler, D. ^{[3
]}

Cappellini, M. D. ^{[6
]}

Chen, Y-S ^{[5
]}

Domm, J. ^{[1
]}

Eustace, B. K. ^{[3
]}

Foell, J. ^{[8
]}

de la Fuente, J. ^{[10
]}

Grupp, S. ^{[11
]}

Handgretinger, R. ^{[9
]}

Ho, T. W. ^{[5
]}

Kattamis, A. ^{[12
]}

Kernytsky, A. ^{[5
]}

Lekstrom-Himes, J. ^{[3
]}

Li, A. M. ^{[13
]}

Locatelli, F. ^{[7
]}

Mapara, M. Y. ^{[15
]}

de Montalembert, M. ^{[17
]}

Rondelli, D. ^{[18
]}

Sharma, A. ^{[2
]}

Sheth, S. ^{[16
]}

Soni, S. ^{[5
]}

Steinberg, M. H. ^{[4
]}

Wall, D. ^{[14
]}

Yen, A. ^{[3
]}

Corbacioglu, S. ^{[8
]}

机构：

[1] Childrens Hosp TriStar Centennial, Sarah Cannon Ctr Blood Canc, 330 23rd Ave N,Suite 450, Nashville, TN 37203 USA

[2] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA

[3] Vertex Pharmaceut, Boston, MA USA

[4] Boston Univ, Sch Med, Boston, MA USA

[5] CRISPR Therapeut, Cambridge, MA USA

[6] Univ Milan, Milan, Italy

[7] Sapienza Univ Rome, Osped Pediat Bambino Gesu Rome, Rome, Italy

[8] Univ Regensburg, Regensburg, Germany

[9] Univ Tubingen, Childrens Univ Hosp, Tubingen, Germany

[10] Imperial Coll Healthcare NHS Trust, St Marys Hosp, London, England

[11] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA

[12] Univ Athens, Athens, Greece

[13] Univ British Columbia, BC Childrens Hosp, Vancouver, BC, Canada

[14] Univ Toronto, Hosp Sick Children, Toronto, ON, Canada

[15] Columbia Univ, New York, NY 10027 USA

[16] Cornell Univ, Joan & Sanford I Weill Med Coll, New York, NY 10021 USA

[17] Univ Paris, AP HP, Necker Enfants Malad Hosp, Paris, France

[18] Univ Illinois, Chicago, IL USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2021年 / 384卷 / 03期

关键词：

FETAL-HEMOGLOBIN; RISK-FACTORS; BCL11A; GENOME; TRANSPLANTATION; THERAPY; ASSOCIATION; MORBIDITY; ENHANCER; BLOOD;

D O I：

10.1056/NEJMoa2031054

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Transfusion-dependent beta-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 gamma-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 BCL11A 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 BCL11A 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.

引用

页码：252 / 260

页数：9

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