The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index; 21 of the 28 sources its claims cite were checked for support.
CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
Open accessAbstract
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
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
21 of 28 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Genomewide association studies have identified single-nucleotide polymorphisms (SNPs) associated with increased expression of fetal hemoglobin in adults.26”
What the sources say
- Supportedcites [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
The paper states that GWAS identified variants at BCL11A associated with fetal hemoglobin (HbF) level. It also reports a common variant associated with elevated HbF, supporting the citing sentence’s summary (Abstract; page not provided). (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
What the sources say
- Partly supportedcites [25] 25. Steinberg MH. Fetal hemoglobin in sickle cell anemia. Blood 2020; 136: 2392- 400. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
What the sources say
- Supportedcites [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
The Discussion reports a significantly lower frequency of sickle cell–related pain crises with crizanlizumab than with placebo in patients with SCD. This supports the attributed reduction in vaso-occlusive episodes; the cited paper reports the benefit for high-dose crizanlizumab. (LLM, conf=0.93)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells.”
What the sources say
- Supportedcites [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
The Genetic evidence connecting BCL11A and HbF regulation section identifies BCL11A as a transcriptional repressor and reports that its knockdown in human erythroid precursors leads to fetal hemoglobin expression. It also describes BCL11A's repression of γ-globin; the claim does not imply that BCL11A binds the γ-globin genes directly. (LLM, conf=0.94)
- Supportedcites [23] 23. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3(1): a011643. source
In “Early Molecular Studies Lead to Therapeutic Approaches for HbF Induction,” the paper reports that BCL11A knockdown robustly induces γ-globin in primary adult erythroid progenitors. The same section describes BCL11A as a transcriptional regulator that functions to silence HbF. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Elevated levels of fetal hemoglobin (consisting of two alpha and two gamma chains) are associated with improved morbidity and mortality in patients with TDT and SCD.[20][21][22]”
What the sources say
- Partly supportedcites [20] 20. Musallam KM, Sankaran VG, Cappel- lini MD, Duca L, Nathan DG, Taher AT. Fetal hemoglobin levels and morbidity in untransfused patients with β-thalassemia intermedia. Blood 2012; 119: 364-7. sourceExperimental — accuracy not yet measured
The Introduction reports that HbF modifies morbidity and mortality in adults with sickle cell disease. The Abstract and Results and discussion find lower morbidity with higher HbF in untransfused patients with β-thalassemia intermedia, not transfusion-dependent thalassemia (TDT); the study does not establish a mortality association in TDT. Passage-level page numbers are unavailable in our copy. (LLM, conf=0.88)
- Partly supportedcites [21] 21. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life expec- tancy and risk factors for early death. N Engl J Med 1994; 330: 1639-44. sourceExperimental — accuracy not yet measured
The Risk Factors for Early Death section (p. 4) links higher fetal hemoglobin to lower mortality in patients with sickle cell anemia, and the Discussion (p. 6) reports improved life expectancy. The paper does not establish that association for transfusion-dependent thalassemia (TDT), or link fetal hemoglobin levels to improved morbidity. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [22] 22. Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates mor- bidity in sickle cell anemia? Blood 1984; 63: 921-6. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“As a product that is enriched with CD34+ cells, CTX001 may have contributed to the delay in lymphocyte recovery, similar to what has been observed after T-cell-depleted transplantation.33,34”
What the sources say
- Supportedcites [33] 33. Bomberger C, Singh-Jairam M, Rodey G, et al. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic pro- genitors. Blood 1998; 91: 2588-600. source
The paper’s Discussion (page unavailable) reports delayed quantitative lymphocyte recovery after transplantation with FACS-sorted CD34+ cells compared with conventional PBSC autografts. It also says sorting substantially depleted T cells, supporting the citing sentence’s qualified analogy to T-cell-depleted transplantation. The paper does not study CTX001, and the citing sentence does not claim that it does. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [34] 34. Nachbaur D, Kropshofer G, Heitger A, et al. Phenotypic and functional lympho- cyte recovery after CD34+-enriched versus non-T cell-depleted autologous peripheral blood stem cell transplantation. J Hema- tother Stem Cell Res 2000; 9: 727-36. source
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Levels of fetal hemoglobin increased rapidly from 0.3 g per deciliter at baseline to 8.4 g per deciliter at month 3, 12.4 g per deciliter at month 12, and 13.1 g per deciliter at month 18 (Fig. 2A).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After the administration of CTX001, high levels of edited alleles in bone marrow CD34+ cells and nucleated peripheral-blood cells were maintained (Table 1).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After the administration of CTX001 and over time, high levels of edited alleles in bone marrow CD34+ cells and nucleated peripheral-blood cells were maintained (Table 1).”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- Probably not a substantial claim. 8
- It may state two separate claims as one. 18
- The quote only partly states this claim. 2
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
What the sources say
- Supportedcites [28] 28. Bak RO, Dever DP, Porteus MH. CRISPR/Cas9 genome editing in human hematopoietic stem cells. Nat Protoc 2018; 13: 358-76. sourceExperimental — accuracy not yet measured
The Introduction explains that an sgRNA guides Cas9 to a chosen DNA sequence, where a locus-specific break can be made. It also explains that repair of such breaks can produce insertions or deletions at the break site. Together, these passages support programmable targeting of indels, though indels are a possible repair outcome rather than a guaranteed one. (LLM, conf=0.92)
- Supportedcites [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. sourceExperimental — accuracy not yet measured
The paper’s introductory passage (indexed as Abstract; page unavailable) explains that guide RNA directs Cas9 to a chosen genomic DNA sequence and that repair of the resulting break can create insertions or deletions at that site. Its reported experiments also measure targeted indels at specific loci. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
What the sources say
- Not matchedcites [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.
- Supportedcites [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
The β0/β0 TDT study clause is supported: the Methods describe two phase 1–2 studies of LentiGlobin BB305, and the patient-characteristics table includes participants with β0/β0 genotypes. The separate EU-approval clause is attached to citation 14, not to the citation for this study. (LLM, conf=0.91)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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]”
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
The Discussion states that erythroid-specific BCL11A knockdown using a lentiviral shRNAmiR reactivates γ-globin. It also identifies an ongoing pilot and feasibility clinical trial using this approach (NCT03282656). (LLM, conf=0.94)
- Supportedcites [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
The Methods describe an open-label pilot study using a lentiviral vector encoding a microRNA-embedded shRNA for erythroid-specific BCL11A knockdown. The Discussion says this approach allows transcription of the endogenous γ-globin gene, supporting both the reactivation and early clinical-development parts of the claim. (LLM, conf=0.94)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
For crizanlizumab, the Discussion reports a 45.3% lower annual pain-crisis rate than placebo, not elimination of crises. It also reports no significant change in markers of hemolysis, while the paper describes crizanlizumab as a P-selectin inhibitor. Together, these passages support that it does not address the underlying cause or fully ameliorate sickle cell disease; this citation does not establish the claim about luspatercept. (LLM, conf=0.87)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
What the sources say
- Partly supportedcites [23] 23. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3(1): a011643. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [24] 24. Canver MC, Orkin SH. Customizing the genome as therapy for the β-hemo- globinopathies. Blood 2016; 127: 2536- 45. sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
What the sources say
- Supportedcites [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
In “Effects of common genetic variation on BCL11A,” the review places HbF-associated variants in an erythroid enhancer and reports that rs1427407 is associated with reduced BCL11A expression in human erythroid precursors. “Genetic evidence connecting BCL11A and HbF regulation” describes BCL11A as an HbF repressor and reports that reducing it permits HbF expression. Together, these passages support the claimed direction of effect. (LLM, conf=0.90)
- Partly supportedcites [23] 23. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3(1): a011643. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The patient received her last transfusion of packed red cells 30 days after the CTX001 infusion (Fig. 2C).”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“F-cell expression increased from 10.1% at baseline to 99.7% at month 6 and was maintained through month 18 (Fig. 2B).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CTX001 drug product had an allelic editing frequency of 68.9%.”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Four other enrolled patients with SCD withdrew from the study before being treated with CTX001 (Table S16).”
Strength:plain· not yet calibratedn = 4Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Without CTX001, the patients' pre-enrollment disease severity would have continued, making pre-enrollment rates a valid comparator.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The generalizability of these early results with respect to other patients with TDT and SCD remains to be determined.”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“CRISPR/Cas-9 for targeted sickle cell disease (SCD) therapy and β-thalassemia have been also applied in clinical trials.23”
From Mechanism and Applications of CRISPR/Cas-9-Mediated Genome Editing (2021) · cites this paper as [23]
Citations
Cites
Mortality in sickle cell disease. Life expectancy and risk factors for early death
Platt, O. S., Brambilla, D. J., Rosse, W. F., Milner, P. F., Castro, O., Steinberg, M. H., & Klug, P. P. (1994) · New England Journal of Medicine · doi:10.1056/nejm199406093302303 · Cited by 3,320
Self-citationPiel, F. B., Steinberg, M. H., & Rees, D. C. (2017) · New England Journal of Medicine · doi:10.1056/nejmra1510865 · Cited by 1,488
Self-citationChemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells
Hendel, A., Bak, R. O., Clark, J. T., Kennedy, A. B., Ryan, D. E., Roy, S., Steinfeld, I., Lunstad, B. D., Kaiser, R. J., Wilkens, A. B., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3290 · Cited by 1,090
Crizanlizumab for the prevention of pain crises in sickle cell disease.
Ataga, K. I., Kutlar, A., Kanter, J., Liles, D., Cancado, R., Friedrisch, J., Guthrie, T. H., Knight-Madden, J., Alvarez, O. A., Gordeuk, V. R., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1611770 · Cited by 914
BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis
Canver, M. C., Smith, E. C., Sher, F., Pinello, L., Sanjana, N. E., Shalem, O., Chen, D. D., Schupp, P. G., Vinjamur, D. S., Garcia, S. P., et al. (2015) · Nature · doi:10.1038/nature15521 · Cited by 886
Cao, A., & Galanello, R. (2010) · Genetics in Medicine · doi:10.1097/gim.0b013e3181cd68ed · Cited by 722
Gene therapy in a patient with sickle cell disease
Ribeil, J.-A., Hacein-Bey-Abina, S., Payen, E., Magnani, A., Semeraro, M., Magrin, E., Caccavelli, L., Neven, B., Bourget, P., El Nemer, W., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1609677 · Cited by 696
Self-citationGene Therapy in Patients with Transfusion-Dependent β-Thalassemia
Thompson, A. A., Walters, M. C., Kwiatkowski, J., Rasko, J. E. J., Ribeil, J.-A., Hongeng, S., Magrin, E., Schiller, G. J., Payen, E., Semeraro, M., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1705342 · Cited by 684
Self-citationUda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V. G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711566105 · Cited by 672
An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level
Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., Shao, Z., Canver, M. C., Smith, E. C., Pinello, L., et al. (2013) · Science · doi:10.1126/science.1242088 · Cited by 653
Flagged first, then by citations
Cited by
Sorted by citations
Items 301–400 of 1,950
Strategies for precise gene edits in mammalian cells
Fichter, K. M., Setayesh, T., & Malik, P. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.04.012 · Cited by 34
Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection
Xue, Y., Wang, C., Li, H., Du, S., Zhong, Y., Zhang, Y., Wang, S., Guo, K., Hou, X., Kang, D. D., et al. (2025) · Advanced Materials · doi:10.1002/adma.202417097 · Cited by 34
Sickle cell disease in children: an update of the evidence in low- and middle-income settings
Odame, I. (2022) · Archives of Disease in Childhood · doi:10.1136/archdischild-2021-323633 · Cited by 36
Single-cell chromatin accessibility and transcriptome atlas of mouse embryos
Jiang, S., Huang, Z., Li, Y., Yu, C., Yu, H., Ke, Y., Jiang, L., & Liu, J. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112210 · Cited by 34
Metabolic regulation of erythrocyte development and disorders
Lyu, J., Ni, M., Weiss, M. J., & Xu, J. (2024) · Experimental Hematology · doi:10.1016/j.exphem.2024.104153 · Cited by 36
Raigani, M., Eftekhari, Z., Adeli, A., & Kazemi‐Lomedasht, F. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102666 · Cited by 36
“103,104 Genetic blood disorders encompass a range of inherited conditions caused by mutations affecting blood cells, such as red blood cells, platelets, and white blood cells.”
InfluentialSickle cell disease is a global prototype for integrative research and healthcare
Royal, C. D. M., Babyak, M. A., Shah, N., Srivatsa, S., Stewart, K. A., Tanabe, P. J., Wonkam, A., & Asnani, M. (2021) · Advanced Genetics · doi:10.1002/ggn2.10037 · Cited by 31
“From evolution to genome editing, SCD is preeminent in research on both the origins and eradication of human disease.(11,14,53) Whether”
BackgroundDiverse Approaches to Gene Therapy of Sickle Cell Disease
White, S. L., Hart, K. L., & Kohn, D. B. (2022) · Annual Review of Medicine · doi:10.1146/annurev-med-042921-021707 · Cited by 33
Therapeutic gene editing of T cells to correct CTLA-4 insufficiency
Fox, T. A., Houghton, B. C., Petersone, L., Waters, E., Edner, N. M., McKenna, A. J., Preham, O., Hinze, C., Williams, C., Albuquerque, A. S., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abn5811 · Cited by 35
Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway
Dreismann, A. K., Hallam, T. M., Tam, L. C. S., Nguyen, C. V., Hughes, J. P., Ellis, S., & Harris, C. L. (2022) · Immunological Reviews · doi:10.1111/imr.13149 · Cited by 36
Genome Editing for Cystic Fibrosis
Wang, G. (2023) · Cells · doi:10.3390/cells12121555 · Cited by 40
“Excitingly, the first such trial for sickle cell disease and β-thalassemia achieved a sustained cure for these two deadly transfusion-dependent blood diseases [14], greatly inspiring basic researchers and clinical practitioners to pursue similar treatments for other genetic diseases, including cystic fibrosis (CF).”
BackgroundBerta, T., Strong, J. A., Zhang, J., & Ji, R. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2247563 · Cited by 38
“It allows for precise gene editing and regulation, and has already been used experimentally in clinic for blood diseases and certain forms of hereditary blindness [187– 189].”
Exosomes for CRISPR-Cas9 Delivery: The Cutting Edge in Genome Editing
Aslan, C., Zolbanin, N. M., Faraji, F., & Jafari, R. (2023) · Molecular Biotechnology · doi:10.1007/s12033-023-00932-7 · Cited by 35
“…potential to be used in the treatment of monogenic diseases such as sickle cell disease, β-thalassemia, and hemophilia, as well as infectious diseases such as acquired immunodeficiency syndrome (AIDS) and cancer caused by human immuno-deficiency virus (HIV) and human papillomavirus (HPV) [11, 12].”
Emerging Gene Therapeutics for Epidermolysis Bullosa under Development
Bischof, J., Hierl, M., & Koller, U. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042243 · Cited by 36
Zhang, K., Wan, P., Wang, L., Wang, Z., Tan, F., Li, J., Ma, X., Cen, J., Yuan, X., Liu, Y., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.04.022 · Cited by 36
Zhu, C., Mu, J., & Liang, L. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02969-5 · Cited by 36
Targeted Delivery of mRNA with Polymer–Lipid Nanoparticles for In Vivo Base Editing
Chen, Q., Chang, Y., He, X., Ding, Y., Wang, R., Luo, R., Yuan, J., Chen, J., Zhong, G., Yang, H. Y., et al. (2025) · ACS Nano · doi:10.1021/acsnano.4c14041 · Cited by 34
The impact of rare diseases on the quality of life in paediatric patients: current status
Dumbuya, J. S., Zeng, C., Deng, L., Li, Y., Chen, X., Ahmad, B., & Lü, J. (2025) · Frontiers in Public Health · doi:10.3389/fpubh.2025.1531583 · Cited by 45
Harnessing artificial intelligence to advance CRISPR-based genome editing technologies
Thomson, T., Li, G. L., Strilchuk, A. W., Cui, H., Wang, B., & Li, B. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-025-00907-1 · Cited by 34
CRISPR genome surgery in a novel humanized model for autosomal dominant retinitis pigmentosa
Wu, W.-H., Tsai, Y.-T., Huang, I.-W., Cheng, C.-H., Hsu, C., Cui, X., Ryu, J., Quinn, P. M. J., Caruso, S. M., Lin, C., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.02.010 · Cited by 35
Pre-clinical non-viral vectors exploited for in vivo CRISPR/Cas9 gene editing: an overview
Rouatbi, N., McGlynn, T., & Al‐Jamal, K. T. (2022) · Biomaterials Science · doi:10.1039/d1bm01452h · Cited by 33
Regenerative medicine: postnatal approaches
Tam, P. K. H., Wong, K. K. Y., Atala, A., Giobbe, G. G., Booth, C., Gruber, P. J., Mononen, M., Rafii, S., Rando, T. A., Vacanti, J. P., et al. (2022) · The Lancet Child & Adolescent Health · doi:10.1016/s2352-4642(22)00193-6 · Cited by 33
CRISPR applications in cancer diagnosis and treatment
Wang, M., Chen, M., Wu, X., Huang, X., & Yu, B. (2023) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-023-00483-4 · Cited by 36
“Over the years, researchers have made various modifications to improve its specificity and efficiency, leading to promising preliminary results in ongoing clinical trials [22].”
BackgroundAffordable Pricing of CRISPR Treatments is a Pressing Ethical Imperative
Rueda, J., Beriaín, Í. D. M., & Montoliu, L. (2024) · The CRISPR Journal · doi:10.1089/crispr.2024.0042 · Cited by 32
Packaged delivery of CRISPR–Cas9 ribonucleoproteins accelerates genome editing
Karp, H., Zoltek, M., Wasko, K. M., Vazquez, A. L., Brim, J. I., Ngo, W., Schepartz, A., & Doudna, J. A. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf105 · Cited by 37
“RNP electroporation is the most common strategy, currently used in several CRISPR genome editing therapies for blood disorders [ 16 , 17 ].”
Advancements in CRISPR/Cas systems for disease treatment
Xu, Y., Le, H., Wu, Q., Wang, N., & Gong, C. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.05.007 · Cited by 35
Genome Editing for β-Hemoglobinopathies: Advances and Challenges
Frati, G., & Miccio, A. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10030482 · Cited by 31
“However, while many therapeutic targets have been identified and, for some strategies, early clinical data are very encouraging [83,91,92], the genome editing technologies still face some challenges.”
BackgroundBiophysical and rheological biomarkers of red blood cell physiology and pathophysiology
Gurkan, U. A. (2021) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000639 · Cited by 31
Using CRISPR to understand and manipulate gene regulation
Akıncı, E., Hamilton, M. C., Khowpinitchai, B., & Sherwood, R. I. (2021) · Development · doi:10.1242/dev.182667 · Cited by 36
The Off-Targets of Clustered Regularly Interspaced Short Palindromic Repeats Gene Editing
Vicente, M. M., Chaves‐Ferreira, M., Jorge, J. M. P., Proença, J. T., & Barreto, V. M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.718466 · Cited by 31
Evolutionary Biology and Gene Editing of Cat Allergen, Fel d 1
Brackett, N. F., Davis, B. W., Adli, M., Pomés, A., & Chapman, M. D. (2022) · The CRISPR Journal · doi:10.1089/crispr.2021.0101 · Cited by 31
Overview of advances in CRISPR/deadCas9 technology and its applications in human diseases
Kanafi, M. M., & Tavallaei, M. (2022) · Gene · doi:10.1016/j.gene.2022.146518 · Cited by 37
Review: Precision Medicine Approaches for Genetic Cardiomyopathy: Targeting Phospholamban R14del
Deiman, F. E., Bömer, N., van der Meer, P., & Beverborg, N. G. (2022) · Current Heart Failure Reports · doi:10.1007/s11897-022-00558-x · Cited by 31
Xu, C., Jiang, S., Ma, X., Jiang, Z., Pan, Y., Li, X., Zhang, L., Zhou, H., Chen, S., Xing, X., et al. (2022) · Archives of Toxicology · doi:10.1007/s00204-022-03404-0 · Cited by 31
Direct correction of haemoglobin E β-thalassaemia using base editors
Badat, M., Ejaz, A., Peng, H., Rice, S., Zhang, W., Hentges, L. D., Fisher, C. A., Denny, N., Schweßinger, R., Yasara, N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37604-8 · Cited by 30
New Approaches for Targeting PCSK9: Small-Interfering Ribonucleic Acid and Genome Editing
Oostveen, R. F., Khera, A. V., Kathiresan, S., Stroes, E. S. G., Fitzgerald, K., Harms, M. J., Oakes, B. L., & Kastelein, J. J. P. (2023) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.122.317963 · Cited by 31
Reichenbach, P., Attianese, G. M. P. G., Ouchen, K., Cribioli, E., Triboulet, M. M., Ash, S., Saillard, M., de Silly, R. V., Coukos, G., & Irving, M. B. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-023-01013-5 · Cited by 32
RNA Nanomedicine: Delivery Strategies and Applications
Byun, J., Wu, Y., Park, J.-W., Kim, J. S., Li, Q., Choi, J., Shin, N., Lan, M., Cai, Y., Lee, J., et al. (2023) · The AAPS Journal · doi:10.1208/s12248-023-00860-z · Cited by 32
CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia
Zeng, S., Lei, S.-Y., Qu, C., Wang, Y., Teng, S., & Huang, P. C. (2023) · Human Genetics · doi:10.1007/s00439-023-02610-9 · Cited by 31
“The allelic editing frequency was 68.9% in one 19-year-old β 0 / β + patient, and after 4 months of treatment, the patient’s HbF level increased to 12.1 g/dL and sustained at a normal level through month 18 (the cut-off date of the study) (Frangoul et al. 2021).”
BackgroundInfluentialBaik, R., Cromer, M. K., Glenn, S. E., Vakulskas, C. A., Chmielewski, K. O., Dudek, A. M., Feist, W. N., Klermund, J., Shipp, S., Cathomen, T., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-43413-w · Cited by 31
Breaking genetic shackles: The advance of base editing in genetic disorder treatment
Xu, F., Zheng, C., Xu, W., Zhang, S., Liu, S., Chen, X., & Yao, K. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1364135 · Cited by 32
“Furthermore, electroporation-based CRISPR therapies for β - thalassemia and sickle cell disease (SCD) have progressed to clinical trials (Frangoul et al., 2021).”
BackgroundStructural variants in the 3D genome as drivers of disease
Sreenivasan, V. K. A., Yumiceba, V., & Spielmann, M. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-025-00862-x · Cited by 45
“For instance, fetal γ-globin expression can be sustained through two approaches: non-coding disruption of the γ-globin repressor enhancer 203,204 , which is now an FDA-approved gene therapy, and enhancer hijacking following boundary disruption 205,206 , which serves as another promising therapeutic…”
New Insights into the Therapeutic Applications of CRISPR/Cas9 Genome Editing in Breast Cancer
Ahmed, M., Daoud, G. H., Mohamed, A., & Harati, R. (2021) · Genes · doi:10.3390/genes12050723 · Cited by 31
“Two patients—one with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD)—received autologous CRISPR/Cas9 edited CD4+ cells; a year later, both patients showed great results with an increase in fetal hemoglobin pancellularly distributed and transfusion independence [172].”
BackgroundPraljak, N., Iram, S., Goreke, U., Singh, G., Hill, A., Gurkan, U. A., & Hinczewski, M. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008946 · Cited by 34
Recent advances of the biological and biomedical applications of CRISPR/Cas systems
Wang, Y., Chun, H., & Zhao, W. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07519-6 · Cited by 29
The potential of gene editing for Huntington’s disease
Duan, W., Urani, E., & Mattson, M. P. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.02.005 · Cited by 31
Base Editing and Prime Editing: Potential Therapeutic Options for Rare and Common Diseases
Testa, L. C., & Musunuru, K. (2023) · BioDrugs · doi:10.1007/s40259-023-00610-9 · Cited by 34
“They electroporated mRNA encoding the IBE with the shifted editing window (termed IBE12) and sgRNA into SCD patient-derived fibroblasts and observed up to 50% editing 48 h post-electroporation.”
BackgroundInfluentialde Souza, D. C., Hebert, N., Esrick, E. B., Ciuculescu, M. F., Archer, N. M., Armant, M. A., Audureau, É., Brendel, C., Caprio, G. D., Galactéros, F., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40923-5 · Cited by 32
Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia
Liu, Y., & Karlsson, S. (2023) · Leukemia · doi:10.1038/s41375-023-02082-w · Cited by 39
Frati, G., Brusson, M., Sartre, G., Mlayah, B., Félix, T., Chalumeau, A., Antoniou, P., Hardouin, G., Concordet, J., Romano, O., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.07.015 · Cited by 32
Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank
Gaynor, S. M., Joseph, T., Bai, X., Zou, Y., Boutkov, B., Maxwell, E. K., Delaneau, O., Hofmeister, R. J., Krasheninina, O. A., Balasubramanian, S., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01930-4 · Cited by 32
“hypercholesterolemia [4], and CRISPR editing of BCL11A for the treatment of sickle cell disease [5, 6].”
Wu, Y., Chen, J., & Jong, Y. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-025-01123-z · Cited by 32
Tang, S., Chen, X., Tong, X., & Zhu, L. (2025) · International Journal of Medical Sciences · doi:10.7150/ijms.112724 · Cited by 31
“Around 80% of the alleles at this locus were successfully modified, with no indications of off-target editing [182].”
Genetic therapies for the first molecular disease
Doerfler, P. A., Sharma, A., Porter, J. S., Zheng, Y., Tisdale, J. F., & Weiss, M. J. (2021) · Journal of Clinical Investigation · doi:10.1172/jci146394 · Cited by 30
Self-citationGene therapy for sickle cell disease: where we are now?
Kanter, J., & Falcon, C. (2021) · Hematology · doi:10.1182/hematology.2021000250 · Cited by 30
Regulatory Considerations for Clinical Trial Applications with CRISPR-Based Medicinal Products
Anliker, B., Childs, L. H., Rau, J., Renner, M., Schüle, S., Schuessler‐Lenz, M., & Sebe, A. (2022) · The CRISPR Journal · doi:10.1089/crispr.2021.0148 · Cited by 33
Chaiyadet, S., Tangkawattana, S., Smout, M. J., Ittiprasert, W., Mann, V. H., Deenonpoe, R., Arunsan, P., Loukas, A. C., Brindley, P. J., & Laha, T. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010839 · Cited by 30
“Nonetheless, somatic genome editing is increasingly expedient in the clinic including for the treatment of hemoglobinopathies [58] and the identification of targets for disease intervention in translational medicine [59].”
BackgroundReddy, J. V., Raudenbush, K., Papoutsakis, E. T., & Ierapetritou, M. (2023) · Biotechnology Advances · doi:10.1016/j.biotechadv.2023.108179 · Cited by 32
GATA 2 Deficiency: Focus on Immune System Impairment
Fabozzi, F., Mastronuzzi, A., Ceglie, G., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.865773 · Cited by 28
Specificity of CRISPR-Cas9 Editing in Exagamglogene Autotemcel
Yen, A., Zappala, Z., Fine, R. S., Majarian, T. D., Sripakdeevong, P., & Altshuler, D. (2024) · New England Journal of Medicine · doi:10.1056/nejmc2313119 · Cited by 30
Self-citationHe, L., Li, Z., Su, D., Du, H., Zhang, K., Zhang, W., Wang, S., Xie, F., Qiu, Y., Ma, S., et al. (2024) · Advanced Science · doi:10.1002/advs.202403858 · Cited by 31
Gene therapy in pediatrics – Clinical studies and approved drugs (as of 2023)
Gol, T. M., Zahedipour, F., Trosien, P., Ureña-Bailén, G., Kim, M., Antony, J. S., & Mezger, M. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122685 · Cited by 30
Advanced material technologies for space and terrestrial medicine
Chua, C. Y. X., Jiménez, M., Mozneb, M., Traverso, G., Lugo, R., Sharma, A., Svendsen, C. N., Wagner, W. R., Langer, R., & Grattoni, A. (2024) · Nature Reviews Materials · doi:10.1038/s41578-024-00691-0 · Cited by 30
Self-citationPrecisely Targeted Nanoparticles for CRISPR-Cas9 Delivery in Clinical Applications
Liu, X., Gao, M., & Bao, J. (2025) · Nanomaterials · doi:10.3390/nano15070540 · Cited by 31
“For example, CRISPR-Cas9-mediated knock-out of heat shock protein 90 (Hsp90) effectively reduces the thermal resistance of cancer cells, resulting in a mild NIR-light-triggered PTT [85,140].”
New Frontiers: Precise Editing of Allergen Genes Using CRISPR
Brackett, N. F., Pomés, A., & Chapman, M. D. (2022) · Frontiers in Allergy · doi:10.3389/falgy.2021.821107 · Cited by 29
“Preliminary data from two patients showed that the percentage of circulating erythrocytes expressing fetal hemoglobin increased from ∼4 to >98% within 15 months of treatment (42).”
BackgroundAdvantages and Limitations of Gene Therapy and Gene Editing for Friedreich’s Ataxia
Sivakumar, A., & Cherqui, S. (2022) · Frontiers in Genome Editing · doi:10.3389/fgeed.2022.903139 · Cited by 32
“…adrenoleukodystrophy, and mucopolysaccharidosis type I (Gentner et al., 2021; Mamcarz et al., 2019; De Ravin et al., 2016; Kohn et al., 2021; Magnani et al., 2022; Ma et al., 2021; Ferrua and Aiuti, 2017; Morris et al., 2017; Biffi et al., 2013; Eichler et al., 2017b; Fumagalli et al., 2022).”
Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3
Cupo, R. R., Rizo, A. N., Braun, G. A., Tse, E., Chuang, E., Gupta, K., Southworth, D. R., & Shorter, J. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111408 · Cited by 25
Discovering DNA Methylation, the History and Future of the Writing on DNA
Tompkins, J. D. (2022) · Journal of the History of Biology · doi:10.1007/s10739-022-09691-8 · Cited by 29
Injectable and Photocurable Gene Scaffold Facilitates Efficient Repair of Spinal Cord Injury
Gao, Y., Wang, K., Wu, S., Wu, J., Zhang, J., Li, J., Lei, S., Duan, X., & Men, K. (2024) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.3c14902 · Cited by 33
Current and Future Therapeutics for Treating Patients with Sickle Cell Disease
Barak, M., Hu, C., Matthews, A. K., & Fortenberry, Y. M. (2024) · Cells · doi:10.3390/cells13100848 · Cited by 32
Bzhilyanskaya, V., Ma, L., Liu, S., Fox, L. R., Whittaker, M. N., Meis, R. J., Choi, U., Lawson, A., Ma, M., Theobald, N., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adj6779 · Cited by 27
Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells
Zeng, J., Nguyen, M. A., Liu, P., da Silva, L. F., Levesque, S., Lin, L. Y., Justus, D. G., Petri, K., Clement, K., Porter, S. N., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.11.001 · Cited by 34
“An independent analysis using GUIDE-seq, an empiric cell-based assay, and in silico homology analysis, discovered no off-targets for sg1617 editing in CD34+ HSPCs at 223 candidate sites, detected to a threshold of 0.2% allele frequency 6 .”
InfluentialGenome editing using CRISPR/Cas9 to treat hereditary hematological disorders
Chen, Y., Wen, R., Yang, Z., & Chen, Z. (2021) · Gene Therapy · doi:10.1038/s41434-021-00247-9 · Cited by 29
Self-citationGenome editing approaches to β-hemoglobinopathies
Brusson, M., & Miccio, A. (2021) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2021.01.025 · Cited by 29
Genomics in medicine: A new era in medicine
Pattan, V., Kashyap, R., Bansal, V., Candula, N., Koritala, T., & Surani, S. (2021) · World Journal of Methodology · doi:10.5662/wjm.v11.i5.231 · Cited by 31
Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy
Rosanwo, T. O., & Bauer, D. E. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.10.002 · Cited by 30
Liu, B., Brendel, C., Vinjamur, D. S., Zhou, Y., Harris, C. E., McGuinness, M. K., Manis, J. P., Bauer, D. E., Xu, H., & Williams, D. A. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.05.002 · Cited by 29
A Novel Anti-Cancer Therapy: CRISPR/Cas9 Gene Editing
Chen, X., Guo, R., Zhao, C., Xu, J., Song, H., Yu, H., Pilarsky, C. P., Nainu, F., Li, J., Zhou, X., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.939090 · Cited by 29
“Meanwhile, long-term safety monitoring is needed to confirm the effects and unknown adverse reactions (Frangoul et al., 2021; Gillmore et al., 2021).”
BackgroundEvolution of nanobodies specific for BCL11A
Yin, M., Izadi, M., Tenglin, K., Viennet, T., Zhai, L., Zheng, G., Arthanari, H., Dassama, L. M. K., & Orkin, S. H. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2218959120 · Cited by 28
Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies
Paschoudi, K., Yannaki, E., & Psatha, N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119527 · Cited by 30
“parallel, two-phase 1/2 clinical trials, funded by VERTEX-Therapeutics in collaboration with CRISPR-Therapeutics, based on CRISPR-Cas9 disruption of BCL11A erythroid enhancer in CD34+cells derived from transfusion-dependent thalassemic (TDT) patients [NCT03655678; CTX001-111] and SCD-patients [NCT03745287; CTX001-121]…”
MethodHeritable polygenic editing: the next frontier in genomic medicine?
Visscher, P. M., Gyngell, C., Yengo, L., & Savulescu, J. (2025) · Nature · doi:10.1038/s41586-024-08300-4 · Cited by 33
Zou, W., Huo, B., Tu, Y., Zhu, Y., Hu, Y., Li, Q., Yu, X., Liu, B., Tang, W., Tan, S., et al. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.04.031 · Cited by 27
Peeling back the layers of immunogenicity in Cas9-based genomic medicine
Stigzelius, V., Cavallo, A. L., Chandode, R. K., & Nitsch, R. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.06.045 · Cited by 30
CRISPR-based therapeutic genome editing for inherited blood disorders
Levesque, S., & Bauer, D. E. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01236-y · Cited by 31
“16) via nuclease-driven indels or base editing has been shown to restore HbF expression and ameliorate disease phenotypes 12,18–20, 146– 148”
InfluentialThe transformative potential of HSC gene therapy as a genetic medicine
Sagoo, P., & Gaspar, H. B. (2021) · Gene Therapy · doi:10.1038/s41434-021-00261-x · Cited by 27
“Although a detailed review of this method is outside the scope of this article, promising early clinical data with gene-editing in the treatment of sickle-cell anemia and β-thalassemia have recently been published [25, 26].”
MethodZuccato, C., Cosenza, L. C., Zurlo, M., Lampronti, I., Borgatti, M., Scapoli, C., Gambari, R., & Finotti, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413433 · Cited by 26
CRISPR-Cas technology a new era in genomic engineering
Parsaeimehr, A., Ebirim, R. I., & Ozbay, G. (2022) · Biotechnology Reports · doi:10.1016/j.btre.2022.e00731 · Cited by 27
Biology in balance: human diploid genome integrity, gene dosage, and genomic medicine
Lupski, J. (2022) · Trends in Genetics · doi:10.1016/j.tig.2022.03.001 · Cited by 22
The landscape of CRISPR/Cas9 for inborn errors of metabolism
Leal, A. F., Nidhi, F., Benincore-Flórez, E., Herreño-Pachón, A. M., Echeverri-Peña, O. Y., Alméciga-Díaz, C. J., & Tomatsu, S. (2022) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2022.106968 · Cited by 27
Fraser, S. M., Pabst, L. M., & Smith, F. S. (2023) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001145 · Cited by 26
Xie, R., Wang, Y., & Gong, S. (2021) · Biomaterials Science · doi:10.1039/d1bm00558h · Cited by 26
Gondek, L. P., Sheehan, V., & Fitzhugh, C. D. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11113160 · Cited by 27
Transformer-based anti-noise models for CRISPR-Cas9 off-target activities prediction
Guan, Z., & Jiang, Z. (2023) · Briefings in Bioinformatics · doi:10.1093/bib/bbad127 · Cited by 27
Li, C. L., Georgakopoulou, A., Paschoudi, K., Anderson, A. K., Huang, L., Gil, S., Giannaki, M., Vlachaki, E., Newby, G. A., Liu, D. R., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.10.018 · Cited by 28
Biosafety considerations triggered by genome-editing technologies
Li, X., Gao, Y., Zhang, Z., Deng, W., Cao, W., Wei, X. C., Gao, Z., Yao, L., Wang, S., Xie, Y., et al. (2025) · Biosafety and Health · doi:10.1016/j.bsheal.2025.05.003 · Cited by 32
Kovalev, M. A., Mamaeva, N. Y., Kristovskiy, N. V., Feskin, P. G., Vinnikov, R. S., Oleinikov, P. D., Sosnovtseva, A. O., Yakovlev, V. A., Glukhov, G. S., & Shaytan, A. К. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136371 · Cited by 29
Integrated epigenetic and genetic programming of primary human T cells
Goudy, L., Ha, A. S., Borah, A. A., Umhoefer, J. M., Chow, L., Tran, C., Winters, A., Talbot, A., Hernandez, R., Li, Z., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02856-w · Cited by 38
“These studies can also provide important information for mapping and dissecting the functions of noncoding elements in the genome, which can lead to novel therapeutic strategies as with the context-specific enhancer targeted in therapies for sickle cell disease and β -thalassemia recently approved by the US Food and D…”
Epigenetic editing: from concept to clinic
Heller, E. A., Bintu, L., & Rots, M. G. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01323-0 · Cited by 37
Maganti, H. B., Bailey, A. J.-M., Kirkham, A. M., Shorr, R., Pineault, N., & Allan, D. (2021) · Stem Cells Translational Medicine · doi:10.1002/sctm.20-0520 · Cited by 24
“Moreover, the data from the NHP models have been consistent with the early human SCD clinical trial (NCT03655678 and NCT03745287) data that report the persistence (1 year post transplantation) of CRISPR-Cas9 gene edited hematopoietic cells within the peripheral blood and BM of SCD patients at high levels.(41) Hemoglob…”
ResultResearch in Sickle Cell Disease: From Bedside to Bench to Bedside
Cisneros, G. S., & Thein, S. L. (2021) · HemaSphere · doi:10.1097/hs9.0000000000000584 · Cited by 25
Metadata
- 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
- Frangoul, Haydar
- Altshuler, David
- Cappellini, M. Domenica
- Chen, Yi-Shan
- Grupp, Stephan
- Handgretinger, Rupert
- Ho, Tony W.
- Kattamis, Antonis
- Lekstrom-Himes, Julie
- Li, Amanda M.
- Locatelli, Franco
- Mapara, Markus Y.
- Rondelli, Damiano
- Sharma, Akshay
- Sheth, Sujit
- Soni, Sandeep
- Steinberg, Martin H.
- Wall, Donna
- Corbacioglu, Selim
- 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
- 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
- FWCI
- 116.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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 (clinical) › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-27, under version 3 of the claim definition (prompt extract-v3).
A second model labelled each claim on 2026-09-27 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
