Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease

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Abstract

Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF.

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

Haydar Frangoul, David Altshuler, M Cappellini … (2020)

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 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. (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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BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis

Matthew Canver, Elenoe Smith, Falak Sher … (2015)

Summary Enhancers, critical determinants of cellular identity, are commonly identified by correlative chromatin marks and gain-of-function potential, though only loss-of-function studies can demonstrate their requirement in the native genomic context. Previously we identified an erythroid enhancer of BCL11A, subject to common genetic variation associated with fetal hemoglobin (HbF) level, whose mouse ortholog is necessary for erythroid BCL11A expression. Here we develop pooled CRISPR-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse enhancers. This approach reveals critical minimal features and discrete vulnerabilities of these enhancers. Despite conserved function of the composite enhancers, their architecture diverges. The crucial human sequences appear primate-specific. Through editing of primary human progenitors and mouse transgenesis, we validate the BCL11A erythroid enhancer as a target for HbF reinduction. The detailed enhancer map will inform therapeutic genome editing. The screening approach described here is generally applicable to functional interrogation of noncoding genomic elements.

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Mortality in sickle cell disease. Life expectancy and risk factors for early death.

Orah Platt, Donald Brambilla, Wendell F. Rosse … (1994)

Information on life expectancy and risk factors for early death among patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, and the sickle cell-beta-thalassemias) is needed to counsel patients, target therapy, and design clinical trials. We followed 3764 patients who ranged from birth to 66 years of age at enrollment to determine the life expectancy and calculate the median age at death. In addition, we investigated the circumstances of death for all 209 adult patients who died during the study, and used proportional-hazards regression analysis to identify risk factors for early death among 964 adults with sickle cell anemia who were followed for at least two years. Among children and adults with sickle cell anemia (homozygous for sickle hemoglobin), the median age at death was 42 years for males and 48 years for females. Among those with sickle cell-hemoglobin C disease, the median age at death was 60 years for males and 68 years for females. Among adults with sickle cell disease, 18 percent of the deaths occurred in patients with overt organ failure, predominantly renal. Thirty-three percent were clinically free of organ failure but died during an acute sickle crisis (78 percent had pain, the chest syndrome, or both; 22 percent had stroke). Modeling revealed that in patients with sickle cell anemia, the acute chest syndrome, renal failure, seizures, a base-line white-cell count above 15,000 cells per cubic millimeter, and a low level of fetal hemoglobin were associated with an increased risk of early death. Fifty percent of patients with sickle cell anemia survived beyond the fifth decade. A large proportion of those who died had no overt chronic organ failure but died during an acute episode of pain, chest syndrome, or stroke. Early mortality was highest among patients whose disease was symptomatic. A high level of fetal hemoglobin predicted improved survival and is probably a reliable childhood forecaster of adult life expectancy.

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David A. Williams: (View ORCID Profile)

Journal

Title: New England Journal of Medicine

Abbreviated Title: N Engl J Med

Publisher: Massachusetts Medical Society

ISSN (Print): 0028-4793

ISSN (Electronic): 1533-4406

Publication date (Electronic): December 05 2020

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[1 ]From the Dana–Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School (E.B.E., L.E.L., A.B., C.B., M.F.C., B.M., K.B., S.-Y.P., W.B.L., C.D., M.M.H., D.A.W.), the Harvard Stem Cell Institute, Harvard Medical School (A.B., C.B.), the Gene Therapy Program, Dana–Farber/Boston Children’s Cancer and Blood Disorders Center (A.B., M.F.C., B.M., E.M., A.F., S.-Y.P., C.D., D.A.W.), the Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School (M. Achebe), the Connell...

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DOI: 10.1056/NEJMoa2029392

PMC ID: 7962145

PubMed ID: 33283990

SO-VID: 27d38a70-6345-454b-abeb-a7524b7b6fad

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http://www.nejmgroup.org/legal/terms-of-use.htm

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Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease

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Abstract

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Most cited references 42

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

BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis

Mortality in sickle cell disease. Life expectancy and risk factors for early death.

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