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Cited by 1,962Hemoglobinopathies and Related DisordersCRISPR and Genetic EngineeringVirus-based gene therapy research

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

Open access
Frangoul, Haydar, Altshuler, David, Cappellini, M. Domenica, Chen, Yi-Shan, Domm, Jennifer, Eustace, Brenda K., Foell, Juergen, de la Fuente, Josu +18 more·2021·New England Journal of Medicine
DOI 10.1056/nejmoa2031054
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Abstract

Summ a r yTransfusion-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.govnumbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.)T ransfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are the most common monogenic diseases worldwide, with an annual diagnosis in approximately 60,000 patients with TDT and 300,000 patients with SCD.[1][2][3] Both diseases are caused by mutations in the hemoglobin β subunit gene (HBB).Mutations in HBB that cause TDT 4 result in reduced (β + ) or absent (β 0 ) β-globin synthesis and an imbalance between the α-like and β-like globin (e.g., β, γ, and δ) chains of hemoglobin, which causes ineffective erythropoiesis.5,6 Sickle hemoglobin is the result of a point mutation in HBB that replaces glutamic acid with valine at amino acid position 6.Polymerization of deoxygenated sickle hemoglobin causes erythrocyte deformation, hemolysis, anemia, painful vaso-occlusive episodes, irreversible end-organ damage, and a reduced life expectancy.5 Treatment options primarily consist of transfusion and iron chelation in patients with TDT 7 and pain management, transfusion, and hydroxyurea in those with SCD. 8 Recently approved therapies, including luspatercept 9 and crizanlizumab, 10 have reduced transfusion requirements in patients with TDT and the incidence of vaso-occlusive episodes in those with SCD, respectively, but neither treatment addresses the underlying cause of the disease nor fully ameliorates disease manifestations.Allogeneic bone marrow transplantation can cure both TDT and CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

Integrity signals

Registry

Crossref · 10.1056/nejmoa2031054

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

21 of 28 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured

  • Premisecitation
    § Brief Report

    Genomewide association studies found SNPs associated with higher fetal hemoglobin in adults.

    “Genomewide association studies have identified single-nucleotide polymorphisms (SNPs) associated with increased expression of fetal hemoglobin in adults.26”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] 26. Bauer DE, Kamran SC, Lessard S, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemo- globin level. Science 2013; 342: 253-7. source
  • Premisecitation
    § Brief Report

    Co-inheritance of hereditary persistence of fetal hemoglobin results in little or no disease in TDT or SCD.

    “Patients with TDT or SCD who co-inherit hereditary persistence of fetal hemoglobin, in which fetal expression continues into adulthood, have little or no disease.25”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] 25. Steinberg MH. Fetal hemoglobin in sickle cell anemia. Blood 2020; 136: 2392- 400. source

      The “F-cells: heterogeneity of HbF concentrations” section reports that people with HbS-HPFH usually have no symptoms or hemolytic anemia, supporting the SCD part of the claim. It does not establish the same outcome for patients with transfusion-dependent thalassemia (TDT), so the claim extends beyond the source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Abstract

    Crizanlizumab reduced vaso-occlusive episodes in SCD.

    “Recently approved therapies, including luspatercept 9 and crizanlizumab, 10 have reduced transfusion requirements in patients with TDT and the incidence of vaso-occlusive episodes in those with SCD, respectively, but neither treatment addresses the underlying cause of the disease nor fully ameliorates disease manifestations.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] 10. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 2017; 376: 429-39. source
  • Premisecitation
    § Brief Report

    Some SNPs in the BCL11A locus on chromosome 2 are linked to less severe TDT and SCD.

    “Some of these SNPs are located in the BCL11A locus on chromosome 2 and are associated with a lower severity of both TDT and SCD.27”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] 27. Uda M, Galanello R, Sanna S, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phe- notype of β-thalassemia. Proc Natl Acad Sci U S A 2008; 105: 1620-5. source

      The Results (page unavailable) place rs11886868 in BCL11A on chromosome 2 and find its C allele more frequent in milder, largely non-transfusion-dependent thalassemia intermedia than in transfusion-dependent thalassemia major. For SCD, the Discussion (page unavailable) reports an association with HbF levels, but says that using the variant to predict disease severity requires future study. The paper therefore does not establish lower severity within TDT or SCD. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Abstract

    BCL11A acts as a repressor of γ-globin and fetal hemoglobin in erythroid cells.

    “BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [1] 1. Bauer DE, Orkin SH. Hemoglobin switching's surprise: the versatile tran- scription factor BCL11A is a master re- pressor of fetal hemoglobin. Curr Opin Genet Dev 2015; 33: 62-70. source
    • cites [23] 23. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3(1): a011643. source
  • Classified as probably not a substantial claim. 8
  • May combine two claims. 18
  • The quote only partly states this claim. 2

  • Classified as probably not a substantial claim.

    Premisecitation
    § Brief Report

    CRISPR-Cas9 enables programmable targeting of indels at a chosen genomic site.

    “The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease system, a bacterial immune system that can cleave bacteriophage or plasmid DNA, enables programmable targeting of insertions or deletions (indels) at a specific genomic DNA site.28,29”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [28] 28. Bak RO, Dever DP, Porteus MH. CRISPR/Cas9 genome editing in human hematopoietic stem cells. Nat Protoc 2018; 13: 358-76. source
      Experimental — accuracy not yet measured
    • cites [29] 29. Hendel A, Bak RO, Clark JT, et al. Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human pri- mary cells. Nat Biotechnol 2015; 33: 985-9. source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Brief Report

    Betibeglogene autotemcel is approved in the EU for TDT with non-β0 mutations and no matched sibling donor, and is under study in β0/β0 TDT and SCD.

    “Betibeglogene autotemcel, a lentiviral vector-based gene-addition product, is approved in the European Union for the treatment of patients with TDT who have non-β 0 mutations and who do not have a matched sibling donor 14 and is being studied in patients with β 0 /β 0 TDT genotypes and in those with SCD.15,16”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [14] 14. European Medicines Agency. Zynteglo: summary of product characteristics (https:// www . ema . europa . eu/ en/ documents/ product -information/ zynteglo -epar -product -information_en . pdf).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15] 15. Thompson AA, Walters MC, Kwiat- kowski J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med 2018; 378: 1479-93. source
    • cites [16] 16. Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med 2017; 376: 848-55. source

      The Discussion reports ongoing studies of the BB305 vector in patients with sickle cell disease and β-thalassemia. It also identifies four recipients as having transfusion-dependent β-thalassemia, but does not specify a β0/β0 genotype. The EU approval statement is attached to a different citation in the citing sentence and is not judged here. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Brief Report

    Erythroid-specific BCL11A knockdown via lentiviral shRNA reactivates γ-globin and is in early clinical development.

    “an erythroid-specific knockdown of BCL11A delivered by a lentiviral-encoded, microRNA-adapted short hairpin RNA molecule has been shown to reactivate the γ-globin gene and is in early clinical development.[17][18][19]”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [17] 17. Brendel C, Guda S, Renella R, et al. Lineage-specific BCL11A knockdown cir- cumvents toxicities and reverses sickle phenotype. J Clin Invest 2016; 126: 3868- 78. source

      The Results (pp. 4, 6) describe a lentiviral, erythroid-specific BCL11A shRNA-miR vector that induces γ-globin. But the paper calls its findings preclinical (Discussion, p. 8) and says they form the basis for a clinical trial application (p. 1); it does not establish that this approach was already in clinical development. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] 18. Brendel C, Negre O, Rothe M, et al. Preclinical evaluation of a novel lentiviral vector driving lineage-specific BCL11A knockdown for sickle cell gene therapy. Mol Ther Methods Clin Dev 2020; 17: 589- 600. source
    • cites [19] 19. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med 2021;384:205-15. source

  • May combine two claims.

    Premisecitation
    § Abstract

    Neither luspatercept nor crizanlizumab addresses the underlying cause or fully ameliorates disease.

    “Recently approved therapies, including luspatercept 9 and crizanlizumab, 10 have reduced transfusion requirements in patients with TDT and the incidence of vaso-occlusive episodes in those with SCD, respectively, but neither treatment addresses the underlying cause of the disease nor fully ameliorates disease manifestations.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [9] 9. Cappellini MD, Viprakasit V, Taher AT, et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med 2020; 382: 1219-31. source
    • cites [10] 10. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 2017; 376: 429-39. source

  • May combine two claims.

    Premisecitation
    § Brief Report

    Infants with TDT or SCD are usually asymptomatic while fetal hemoglobin is high and become symptomatic in the first year as fetal hemoglobin falls.

    “Neonates and infants with TDT or SCD are typically asymptomatic while their fetal hemoglobin levels remain high and become symptomatic during the first year of life when the synthesis of fetal hemoglobin declines 23,24 (Fig. 1A).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [23] 23. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3(1): a011643. source

      In “THE FETAL-TO-ADULT GLOBIN SWITCH” (page not provided), the paper says infants with β-thalassemia begin to show symptoms as HbF declines in the months after birth. It also links elevated HbF to an asymptomatic period in SCD, but says symptoms appear after infancy rather than during the first year; it discusses β-thalassemia generally, not TDT specifically. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [24] 24. Canver MC, Orkin SH. Customizing the genome as therapy for the β-hemo- globinopathies. Blood 2016; 127: 2536- 45. source

      The Introduction (page not provided) says fetal hemoglobin is silenced in the months after birth and protects against disease severity in β-globin disorders, including SCD and β-thalassemia. It does not say that infants with TDT or SCD are typically asymptomatic while HbF is high or that they become symptomatic during the first year as it falls. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Brief Report

    The fetal hemoglobin-associated SNPs lie in an erythroid-specific enhancer, lower BCL11A expression, and raise fetal hemoglobin.

    “the SNPs that are associated with fetal hemoglobin are in an erythroid-specific enhancer, downregulate BCL11A expression, and increase the expression of fetal hemoglobin.1,23”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [1] 1. Bauer DE, Orkin SH. Hemoglobin switching's surprise: the versatile tran- scription factor BCL11A is a master re- pressor of fetal hemoglobin. Curr Opin Genet Dev 2015; 33: 62-70. source
    • cites [23] 23. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3(1): a011643. source

      The section on early molecular studies reports that variants within BCL11A are associated with HbF levels and that experimentally knocking down BCL11A induces γ-globin expression. It does not say those SNPs lie in an erythroid-specific enhancer or establish that the SNPs themselves lower BCL11A expression and thereby raise HbF. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Figure 1 (facing page). CTX001 Molecular Approach and Preclinical Studies.

    Patient 1 had 32 adverse events, mostly grade 1 or 2; two serious events, pneumonia with neutropenia and VOD-SOS, began on day 13 and resolved.

    “During the 21.5 months after receiving CTX001, Patient 1 had 32 adverse events, most of which were considered to be grade 1 or 2 in severity (Table S6).Study investigators classified 2 adverse events as serious: pneumonia in the presence of neutropenia and veno-occlusive liver disease with sinusoidal obstruction syndrome (VOD-SOS), both of which began on study day 13.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Figure 1 (facing page). CTX001 Molecular Approach and Preclinical Studies.

    Patient 1's last packed red cell transfusion occurred 30 days after CTX001 infusion.

    “The patient received her last transfusion of packed red cells 30 days after the CTX001 infusion (Fig. 2C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Figure 1 (facing page). CTX001 Molecular Approach and Preclinical Studies.

    Patient 1's F-cell expression rose from 10.1% at baseline to 99.7% at month 6 and remained at that level through month 18.

    “F-cell expression increased from 10.1% at baseline to 99.7% at month 6 and was maintained through month 18 (Fig. 2B).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § Patient 1

    Patient 1 had β0/β+ (IVS-I-110) TDT and had received 34 units of packed red cells per year before enrollment.

    “Patient 1 was a 19-year-old female with the β 0 /β + (IVS-I-110) genotype of TDT.Before enrollment, she had received 34 units of packed red cells per year, annualized over a 2-year period.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Preclinical Studies of BCL11A Editing

    In immunocompromised mice, control and edited cells engrafted equivalently, and edits remained stable at 16 weeks with preserved diversity.

    “In immunocompromised mice, there was equivalent engraftment for control and single-guide RNA-edited cells, and the persistence and pattern of edits were stable at 16 weeks, with maintenance of the diversity of edits (Tables S2 and S3 and Fig. S1 in the Supplementary Appendix).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § Patient 2

    Patient 2 had βS/βS SCD with a single α-globin deletion and averaged seven severe VOCs per year before enrollment.

    “Patient 2 was a 33-year-old female with SCD (βS/ βS and a single α-globin deletion).In the 2 years before enrollment, she had averaged seven severe vaso-occlusive episodes per year.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Patient 2

    Patient 2's fetal hemoglobin rose from 9.1% at baseline to 37.2% at month 3 and 43.2% at month 15; sickle hemoglobin was 74.1% at baseline, 32.6% at month 3, and 52.3% at month 15.

    “At baseline, the fetal hemoglobin level was 9.1% and the sickle hemoglobin level was 74.1%.At month 3, the fetal hemoglobin level rose to 37.2% and the sickle hemoglobin level was 32.6%.At month 15, the fetal hemoglobin level rose to 43.2% and the sickle hemoglobin increased to 52.3% (Fig. 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Preclinical Studies of BCL11A Editing

    Preclinical editing of CD34+ HSPCs from 10 healthy donors achieved mean allelic editing of 80±6%, maintained across subpopulations including long-term HSCs.

    “High frequencies of allelic editing (mean [±SD], 80±6%) were observed and maintained across all subpopulations of CD34+ cells, including long-term hematopoietic stem cells.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data
    § Figure 1 (facing page). CTX001 Molecular Approach and Preclinical Studies.

    Patient 1's CTX001 drug product had an allelic editing frequency of 68.9%.

    “The CTX001 drug product had an allelic editing frequency of 68.9%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Discussion

    Four other enrolled SCD patients withdrew before CTX001 treatment.

    “Four other enrolled patients with SCD withdrew from the study before being treated with CTX001 (Table S16).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Patient 2

    Patient 2 had 114 adverse events; three serious events, sepsis with neutropenia, cholelithiasis, and abdominal pain, all resolved.

    “Patient 2 had 114 adverse events during the 16.6 months after receipt of the CTX001 infusion (Table S11).Study investigators classified 3 adverse events as serious: sepsis in the presence of neutropenia (on day 16), cholelithiasis (on day 49), and abdominal pain (on day 56).All 3 adverse events resolved with treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Patient 2

    Patient 2 had no vaso-occlusive episodes during the 16.6 months after CTX001, and last transfusion was 19 days after infusion.

    “Patient 2 had no vaso-occlusive episodes during the 16.6 months after the infusion of CTX001, and the last transfusion of packed red cells was 19 days after infusion (Fig. 2F).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Without CTX001, the patients' pre-enrollment disease severity would have continued, making pre-enrollment rates a valid comparator.

  • May combine two claims.

    Findingown data
    § Patient 2

    Patient 2's F-cell expression was 99.9% at month 5 and nearly 100% through month 15.

    “F-cell expression was 99.9% at month 5 and was maintained at nearly 100% through month 15, her most recent study visit (Fig. 2E).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationown data
    § Patient 2

    Patient 2 had intermittent nonserious lymphopenia, probably due to delayed T-cell recovery after CTX001, which resolved by day 351.

    “Study investigators observed intermittent, nonserious lymphopenia, which they considered to be probably due to a delay in T-cell recovery after the infusion of CTX001 and which had resolved by study day 351.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data
    § Discussion

    The study did not perform similar on-target/off-target analyses or clonal diversity characterization on clinical samples.

    “An additional limitation of our study is that although we performed comprehensive preclinical on-target and off-target analyses and assays of erythrocyte differentiation, we have not performed similar analyses on clinical samples nor characterized their clonal diversity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § Study Oversight

    Study protocols were designed by sponsors with oversight by steering committees and an independent data monitoring committee.

    “The study sponsors (CRISPR Therapeutics and Vertex Pharmaceuticals) designed the study protocols, with oversight provided by the study steering committees and an independent data monitoring committee.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    Initial results show intended BCL11A editing in long-term HSCs, durable engraftment, high fetal hemoglobin, and elimination of VOCs or transfusion need.

    “Initial results from the follow-up of the first two patients who were treated with CTX001 have shown the intended CRISPR-Cas9 editing of BCL11A in long-term hematopoietic stem cells, with durable engraftment, high levels of fetal hemoglobin expression, and the elimination of vaso-occlusive episodes or need for transfusion.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The clinical improvements after CTX001 are attributable to the gene editing rather than to other aspects of treatment or disease fluctuation.
    • Rests on an assumption: Long-term maintenance of edited alleles in peripheral blood reflects editing of long-term hematopoietic stem cells.

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Discussion

    Generalizability of these early results to other TDT and SCD patients remains undetermined.

    “The generalizability of these early results with respect to other patients with TDT and SCD remains to be determined.”
    Quote in the paperSubstantial claim
24 of 24

  • The paper relies on this without support.

    Erythrocytes with high fetal hemoglobin have a survival advantage.

    “consistent with an expected survival advantage of erythrocytes with a high level of fetal hemoglobin.”

  • The paper relies on this without support.

    Without CTX001, the patients' pre-enrollment disease severity would have continued, making pre-enrollment rates a valid comparator.

    “Before enrollment, she had received 34 units of packed red cells per year, annualized over a 2-year period.”
    “In the 2 years before enrollment, she had averaged seven severe vaso-occlusive episodes per year.”

  • The paper relies on this without support.

    The clinical improvements after CTX001 are attributable to the gene editing rather than to other aspects of treatment or disease fluctuation.

    “The clinical course of both patients supports our conclusion that CTX001 mimics the phenotype of hereditary persistence of fetal hemoglobin levels.”

  • The paper relies on this without support.

    Long-term maintenance of edited alleles in peripheral blood reflects editing of long-term hematopoietic stem cells.

    “Initial results from the follow-up of the first two patients who were treated with CTX001 have shown the intended CRISPR-Cas9 editing of BCL11A in long-term hematopoietic stem cells, with durable engraftment, high levels of fetal hemoglobin expression, and the elimination of vaso-occlusive episodes or need for transfusion.”
4 of 4

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Authors
Frangoul, H., Altshuler, D., Cappellini, M. D., Chen, Y.-S., Domm, J., Eustace, B. K., Foell, J., de la Fuente, J., Grupp, S., Handgretinger, R., Ho, T. W., Kattamis, A., Kernytsky, A., Lekstrom-Himes, J., Li, A. M., Locatelli, F., Mapara, M. Y., de Montalembert, M., Rondelli, D., Sharma, A., Sheth, S., Soni, S., Steinberg, M. H., Wall, D., Yen, A., & Corbacioglu, S.
Affiliations
  • Boston University (US)
  • From the Sarah Cannon Center for Blood Cancer at the Children’s Hospital at TriStar Centennial, Nashville (H.F., J.D.), and St. Jude Children’s Research Hospital, Memphis (A.S.) — both in Tennessee; Vertex Pharmaceuticals (D.A., B.K.E., J.L.-H., A.Y.) and Boston University School of Medicine (M.H.S.), Boston, and CRISPR Therapeutics, Cambridge (Y.-S.C., T.W.H., A. Kernytsky, S. Soni) — both in Massachusetts; the University of Milan, Milan (M.D.C.), and Ospedale Pediatrico Bambino Gesù Rome, Sapienza...
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2021-01-21
Volume
384
Issue
3
Pages
252-260
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2031054
OpenAlex
W3112179900
Semantic Scholar
07c69f7ddd34ca8c80618e16981e2fbdb0de6529
Cited by
1,962
References
35
Citations by year
2026: 330 · 2025: 342 · 2024: 392 · 2023: 333 · 2022: 323 · 2021: 232 · 2020: 9 · 2019: 1
FWCI
116.33
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
Funders
  • CRISPR Therapeutics AG
  • Vertex Pharmaceuticals Incorporated
Topics
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
sickle cell disease, beta-thalassemia, CRISPR/Cas9 genome editing, fetal hemoglobin, hematopoietic stem cell transplantation, autologous hematopoietic stem cells, electroporation, transfusion independence, vaso-occlusive crisis
MeSH terms
Gene Editing, Adult, Anemia, Sickle Cell, Female, Fetal Hemoglobin, Humans, Repressor Proteins, Genetic Therapy, beta-Thalassemia, Young Adult, CRISPR-Cas Systems

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