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
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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
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Greco, F., Cosentino, M., & Marino, F. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1356578 · Cited by 18
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Self-citationScreening and treatment of thalassemia
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Genome editing for primary immunodeficiencies: A therapeutic perspective on Wiskott-Aldrich syndrome
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“The most exemplificative application of this approach is the use of gene editing to disrupt the erythroid enhancer for the BCL11A transcription factor, a repressor of foetal haemoglobin expression, which yielded promising results in two clinical trials to treat Sickle Cell Disease and b-thalassemia (NCT03655678 and NC…”
MethodGamage, U., Warnakulasuriya, K., Hansika, S., & Silva, G. N. (2023) · Thalassemia Reports · doi:10.3390/thalassrep13010006 · Cited by 17
“Recently, preliminary results of a CRISPR-phase-1 clinical trial have uplifted the hope for a possible breakthrough one-time curative option for β-thalassemia [64].”
BackgroundCRISPR gene therapy shows promise against blood diseases
Ledford, H. K. (2020) · Nature · doi:10.1038/d41586-020-03476-x · Cited by 16
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The Fetal-to-Adult Hemoglobin Switch — Mechanism and Therapy
Orkin, S. H. (2025) · New England Journal of Medicine · doi:10.1056/nejmra2405260 · Cited by 18
Advances in RNA therapeutics: Classes, innovations and clinical applications
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Modern Strategies of Drug Therapy: Multi-Target Drug Delivery, Bioimaging, Diagnostics
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Current state of gene therapy in sickle cell disease
Tang, M. S., & Shan, H. (2024) · Vox Sanguinis · doi:10.1111/vox.13612 · Cited by 15
“Off-target editing is also a concern with CRISPR-Cas9-based gene therapy, although the limited published data so far have not reported this phenomenon [17, 20].”
BackgroundMethodInfluentialCrispr-Cas based biosensing: A fast-expanding molecular diagnostic tool
Singh, S., Thakran, R., Kaushal, A., Saini, R. V., Saini, A. K., & Datta, S. (2024) · Microchemical Journal · doi:10.1016/j.microc.2024.110421 · Cited by 14
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Molecular Manipulations and Intestinal Stem Cell-Derived Organoids in Inflammatory Bowel Disease
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A CRISPR view of hematopoietic stem cells: Moving innovative bioengineering into the clinic
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Targeting the Hematopoietic Stem Cell Niche in β-Thalassemia and Sickle Cell Disease
Aprile, A., Sighinolfi, S., Raggi, L., & Ferrari, G. (2022) · Pharmaceuticals · doi:10.3390/ph15050592 · Cited by 16
“Ongoing clinical trials in TDT and SCD patients are testing the safety and efficacy of HSPCs edited with CRISPR-Cas9 (CTX001 drug product) [13] or with ZFNs (ST-400 drug product).”
MethodEffective therapies for sickle cell disease: are we there yet?
Crossley, M., Christakopoulos, G. E., & Weiss, M. J. (2022) · Trends in Genetics · doi:10.1016/j.tig.2022.07.003 · Cited by 18
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Development of curative therapies for sickle cell disease
Tanhehco, Y. C., Nathu, G., & Vasović, L. V. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.1055540 · Cited by 15
“Other gene therapy approaches being studied include upregulating the expression of HbF with CRISPR Cas-9 disruption of the BCL11a gene (34), CRISPR-Cas-12 mutation of the HGB 1 and 2 enhancer sites (35, 36), and RNAi-induced suppression of BCL11a mRNA transcription through a short hairpin RNA expressed through a lenti…”
BackgroundGene therapy for hemophilia, a clinical viewpoint
Chou, S., Hsu, Y., & Lin, S. (2023) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2023.05.008 · Cited by 15
Joore, I. P., Shehata, S., Muffels, I. J. J., Castro-Alpízar, J., Jiménez-Curiel, E., Nagyova, E., Levy, N., Tang, Z., Smit, K., Vermeij, W. P., et al. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003207 · Cited by 20
“To prepare for future in vivo mitochondrial gene editing, we examined delivery strategies for gene editors that are currently evolving into curative gene correction therapies for nuclear genetic disorders [30–33].”
Genetic therapies and potential therapeutic applications of CRISPR activators in the eye
Ng, B., Kaukonen, M. K., McClements, M. E., Shamsnajafabadi, H., MacLaren, R. E., & Cehajic‐Kapetanovic, J. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101289 · Cited by 13
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“Ongoing clinical trials are investigating the therapeutic potential of CRISPR/Cas in treating hematological disorders, such as beta-thalassemia [138] and sickle cell disease [139], by editing hematopoietic stem cells to correct the underlying genetic defects.”
CRISPR delivery systems for organ-specific targeting: Advances and challenges
Du, J., Wu, Q., Liu, C., Wang, N., & Gong, C. (2025) · Precision medicine and engineering. · doi:10.1016/j.preme.2025.100048 · Cited by 20
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Clinical application of base editing for treating β-thalassaemia
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A short, idiosyncratic history of genome editing
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Selecting β-thalassemia Patients for Gene Therapy: A Decision-making Algorithm
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Fetal hemoglobin in β hemoglobinopathies: Is enough too much?
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Self-citationXue, Y., & Shang, L. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.939295 · Cited by 13
Modifications in Biomacromolecules
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Finotti, A., & Gambari, R. (2023) · Frontiers in Genome Editing · doi:10.3389/fgeed.2023.1204536 · Cited by 13
“Interestingly, after 1 year follow-up, the β-thalassemia patient exhibited pancellular increases in HbF production and transfusion independence, while in the SCD patient elimination of vasoocclusive episodes was found (Frangoul et al., 2021).”
BackgroundInfluentialMurugesan, R., Karuppusamy, K. V., Marepally, S. K., & Thangavel, S. (2023) · Frontiers in Genome Editing · doi:10.3389/fgeed.2023.1148693 · Cited by 15
“Numerous electroporation devices, including the Lonza 4DNucleofector, the MaxCyte electroporation system, the Neon electroporation system, and the Harvard Apparatus/BTX ECM600 Electro Cell Manipulator/apparatus, are currently being used for HSPC gene editing (Vakulskas et al., 2018; Métais et al., 2019; Frangoul et al…”
Context base editing for splice correction of IVSI-110 β-thalassemia
Naiisseh, B., Papasavva, P. L., Papaioannou, N. Y., Tomazou, M., Koniali, L., Felekis, X., Constantinou, C. G., Sitarou, M., Christou, S., Kleanthous, M., et al. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102183 · Cited by 13
Base Editors-Mediated Gene Therapy in Hematopoietic Stem Cells for Hematologic Diseases
Zhang, C., Xu, J., Wu, Y., Xu, C., & Xu, P. (2024) · Stem Cell Reviews and Reports · doi:10.1007/s12015-024-10715-5 · Cited by 16
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Kunz, J. B., & Tagliaferri, L. (2024) · Transfusion Medicine and Hemotherapy · doi:10.1159/000540149 · Cited by 14
Recent progress in gene therapy for familial hypercholesterolemia treatment
Luo, Y., Hou, Y., Zhao, W., & Yang, B. (2024) · iScience · doi:10.1016/j.isci.2024.110641 · Cited by 13
Treating Sickle Cell Disease: Gene Therapy Approaches
Cavazzana, M., Corsia, A., Brusson, M., Miccio, A., & Semeraro, M. (2024) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-022124-022000 · Cited by 15
Tissue-specific modulation of CRISPR activity by miRNA-sensing guide RNAs
Garcia-Guerra, A., Sathyaprakash, C., de Jong, O. G., Lim, W. F., Vader, P., Andaloussi, S. E., Bath, J., Reiné, J., Aoki, Y., Turberfield, A. J., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf016 · Cited by 15
Multiplex base editing to protect from CD33 directed drugs for immune and gene therapy
Borot, F., Humbert, O., Ehmsen, J. T., Fields, E., Kohli, S., Radtke, S., Swing, K., Pande, D., Enstrom, M., Laszlo, G. S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59713-2 · Cited by 17
Fabozzi, F., Strocchio, L., Mastronuzzi, A., et al. (2021) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2021.101278 · Cited by 13
The EHA Research Roadmap: Hematopoietic Stem Cell Gene Therapy
Naldini, L., Cicalese, M. P., Bernardo, M. E., Gentner, B., Gabaldo, M., Ferrari, G., & Aiuti, A. (2022) · HemaSphere · doi:10.1097/hs9.0000000000000671 · Cited by 16
Pharmacologic induction of PGC ‐1α stimulates fetal haemoglobin gene expression
Sun, Y., Habara, A. H., Le, C. Q., Nguyen, N., Chen, R., Murphy, G. J., Chui, D. H. K., Steinberg, M. H., & Cui, S. (2022) · British Journal of Haematology · doi:10.1111/bjh.18042 · Cited by 14
Self-citationInhibition of nonhomologous end joining‐mediated DNA repair enhances anti‐HBV CRISPR therapy
Murai, K., Kodama, T., Hikita, H., Shimoda, A., Fukuoka, M., Fukutomi, K., Shigeno, S., Shiode, Y., Motooka, D., Higuchi, Y., et al. (2022) · Hepatology Communications · doi:10.1002/hep4.2014 · Cited by 14
“Gene therapy using CRISPR/Cas9 for the treatment of βthalassemia is already in clinical trials.[13] In HBV, it has been reported that the CRISPR/Cas9 system is capable of directly targeting cccDNA and exerting antiviral effects in HBV- susceptible cells[14– 16] and humanized liver chimeric mice.”
Backgroundi-CRISPR: a personalized cancer therapy strategy through cutting cancer-specific mutations
Jiang, J., Chen, Y., Zhang, L., Jin, Q., Wang, L., Xu, S., Chen, K., Li, L., Zeng, T., Fan, X., et al. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01612-x · Cited by 14
Self-citationKassim, A. A., & Leonard, A. K. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11164775 · Cited by 13
“9) g/dL with 96% F+ cells reported in four patients [48,90].”
BackgroundCigan, A. M., & Knap, P. W. (2022) · CABI Agriculture and Bioscience · doi:10.1186/s43170-022-00107-5 · Cited by 15
Genome editing technology and applications with the type I CRISPR system
Yoshimi, K., & Mashimo, T. (2022) · Gene and Genome Editing · doi:10.1016/j.ggedit.2022.100013 · Cited by 18
Sickle Cell Disease Pathophysiology and Related Molecular and Biophysical Biomarkers
Saah, E. N., Fadaei, P., Gurkan, U. A., & Sheehan, V. (2022) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.06.005 · Cited by 14
Avram-Shperling, A., Kopel, E., Twersky, I., Gabay, O., Ben-David, A., Karako‐Lampert, S., Rosenthal, J. J. C., Levanon, E. Y., Eisenberg, E., & Ben‐Aroya, S. (2023) · PLoS Genetics · doi:10.1371/journal.pgen.1010661 · Cited by 14
“This approach offers a solution to chronic conditions by introducing a life-long permanent genetic modification [14–16].”
An integrated therapeutic approach to sickle cell disease management beyond infancy
Ribeil, J., Pollock, G., Frangoul, H., & Steinberg, M. H. (2023) · American Journal of Hematology · doi:10.1002/ajh.26956 · Cited by 13
“CTX001 gene editing were showed promising results with over 99% pancellular HbF expression.(9)”
BackgroundSelf-citationAlaburde, S., Ivaška, J., Kaspute, G., & Ivaškienė, T. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1623689 · Cited by 12
Removal of promoter CpG methylation by epigenome editing reverses HBG silencing
Bell, H. W., Feng, R., Shah, M., Yao, Y., Douglas, J., Doerfler, P. A., Mayuranathan, T., O'Dea, M. F., Li, Y., Wang, Y., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62177-z · Cited by 18
“Disruption of UHRF1 in CD34 + HSPCs followed by in vitro differentiation raised HBG and HbF in erythroid progeny to nearly the same levels as disruption of the BCL11A erythroid enhancer according to a clinically approved strategy 15 (Fig.”
CRISPR and gene editing for kidney diseases: where are we?
D’Ambrosio, V., Chen, H., Vo, N., Siew, K., Evans, R. D. R., Freedman, B., & Pesce, F. (2025) · Clinical Kidney Journal · doi:10.1093/ckj/sfaf246 · Cited by 14
Regenerative medicine: current research and perspective in pediatric surgery
Deguchi, K., Zambaiti, E., & Coppi, P. D. (2023) · Pediatric Surgery International · doi:10.1007/s00383-023-05438-6 · Cited by 12
“Furthermore, these stem cells can be genetically modified or corrected using gene editing technologies (such as the CRISPER-Cas system) [7].”
Kulcsár, P. I., Tálas, A., Ligeti, Z., Tóth, E., Rakvács, Z., Bartos, Z., Krausz, S. L., Welker, Á., Végi, V. L., Huszár, K., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41393-5 · Cited by 14
Yu, X., Huo, G., Yu, J., Li, H., & Li, J. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.127025 · Cited by 13
Vashishta, L., Bapat, P., Bhattacharya, Y., et al. (2023) · Journal of Biosciences · doi:10.1007/s12038-023-00363-1 · Cited by 12
Self-citationChatterjee, S., Bhattacharya, M., Lee, S., & Chakraborty, C. (2023) · Current Research in Biotechnology · doi:10.1016/j.crbiot.2023.100150 · Cited by 12
Cavazza, A., Hendel, A., Bak, R. O., Rı́o, P., Güell, M., Lainšček, D., Arechavala‐Gomeza, V., Peng, L., Hapil, F. Z., Harvey, J. P., et al. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.102066 · Cited by 12
de Assis, A. J. B., Santana, B. L. D. O., Gualberto, A. C. M., & Pittella-Silva, F. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1322937 · Cited by 16
Genetic Tools for Cell Lineage Tracing and Profiling Developmental Trajectories in the Skin
Nathans, J. F., Ayers, J., Shendure, J., & Simpson, C. L. (2024) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2024.02.006 · Cited by 12
β-Thalassemia gene editing therapy: Advancements and difficulties
Hu, J., Zhong, Y., Xu, P., Xin, L., Zhu, X., Jiang, X., Gao, W., Yang, B., & Chen, Y. (2024) · Medicine · doi:10.1097/md.0000000000038036 · Cited by 19
“[25] CTX001 has entered phase III clinical trials (Table 1).”
BackgroundSelf-citationOliTag-seq enhances in cellulo detection of CRISPR-Cas9 off-targets
Yang, Z.-X., Deng, D.-H., Gao, Z.-Y., Zhang, Z.-K., Fu, Y.-W., Wen, W., Zhang, F., Li, X., Li, H., Zhang, J., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06360-w · Cited by 17
Luna, S. E., Camarena, J., Hampton, J. P., Majeti, K. R., Charlesworth, C. T., Soupène, E., Selvaraj, S., Jia, K., Sheehan, V., Cromer, M. K., et al. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01222-6 · Cited by 17
“…we could use CRISPR to introduce this natural EPOR variant ( tEPOR ) to increase erythropoietic output from edited HSPCs. Previous work has highlighted the challenge of achieving long-term correction of disease following delivery of gene therapy or genome-editing correction strategies 2,36,37 .”
Gene therapy and gene editing strategies in inherited blood disorders
Song, X., Liu, J., Chen, T., Zheng, T., Wang, X., & Guo, X. (2024) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2024.07.004 · Cited by 13
Navigating the CRISPR/Cas Landscape for Enhanced Diagnosis and Treatment of Wilson’s Disease
Choi, W., Cha, S., & Kim, K. (2024) · Cells · doi:10.3390/cells13141214 · Cited by 15
“For example, the successful CRISPR-Cas9 targeted gene editing of CD34+ hematopoietic stem and progenitor cells has shown potential as a treatment for transfusion-dependent β -thalassemia and sickle cell disease (SCD) [263].”
BackgroundGenome Editing Dilemma: Navigating Dual-Use Potential and Charting the Path Forward
Badea, A. R., & Feeney, O. (2024) · Journal of Bioethical Inquiry · doi:10.1007/s11673-024-10358-8 · Cited by 12
NF-κB-activated oncogene inhibition strategy for cancer gene therapy
Dai, W., Wu, J. Y., Shui, Y., Wu, Q., Wang, J., & Xia, X. (2024) · Cancer Gene Therapy · doi:10.1038/s41417-024-00828-x · Cited by 11
Genome Editing Therapy for the Blood: Ex Vivo Success and In Vivo Prospects
George, C. A., Sahu, S. U., de Oñate, L., Souza, B. S. D. F., & Wilson, R. C. (2024) · The CRISPR Journal · doi:10.1089/crispr.2024.0036 · Cited by 15
Levis, H., Lewis, C. J., Fainor, M., Lawal, A., Stockham, E., Weston, J. D., Farhang, N., Gullbrand, S. E., & Bowles, R. D. (2024) · Acta Biomaterialia · doi:10.1016/j.actbio.2024.11.007 · Cited by 12
Yang, H. M., Zheng, G., Li, G. Y., Alshaye, A., & Orkin, S. H. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.108077 · Cited by 12
“Moreover, erythroid-speci fi c downregulation of BCL11A via CRISPR/ Cas9 editing forms the basis of approved therapy for sickle cell disease and b -thalassemia (12, 13).”
Chu, S. N., Soupène, E., Sharma, D., Sinha, R., McCreary, T., Hernandez, B. N., Shen, H., Wienert, B., Bowman, C., Yin, H., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2024.115141 · Cited by 12
“7 Furthermore, while numerous gene therapy and genome editing strategies have been developed for patients with β -thalassemia, 8–10 there are no such therapies for the most severe forms of α -thalassemia, indicating a major unmet medical need for this patient population.”
Best Practices in Gene Therapy for Sickle Cell Disease and Transfusion-dependent β-Thalassemia
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Self-citationCharacterization of diverse Cas9 orthologs for genome and epigenome editing
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The next innovations in chimeric antigen receptor T cell immunotherapies for cancer
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In vivo delivery systems for CRISPR genome editing: Viral and non-viral carriers
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Heterogeneity of fetal hemoglobin production in adult red blood cells
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A Mutation-Agnostic Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy
Antony, J. S., Daniel-Moreno, A., Lamsfus‐Calle, A., Raju, J., Kaftancioglu, M., Ureña-Bailén, G., Rottenberger, J., Hou, Y., Santhanakumaran, V., Lee, J.-H., et al. (2021) · The CRISPR Journal · doi:10.1089/crispr.2021.0075 · Cited by 12
Self-citationNatural and Experimental Rewiring of Gene Regulatory Regions
Downes, D. J., & Hughes, J. R. (2022) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-112921-010715 · Cited by 12
Fitzhugh, C. D., Volanakis, E. J., Idassi, O. M., Duberman, J. A., DeBaun, M. R., & Friedman, D. L. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11113118 · Cited by 13
Megagiannis, P., Suresh, R., Rouleau, G. A., & Zhou, Y. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114562 · Cited by 12
RNA in Therapeutics: CRISPR in the Clinic
Carroll, D. (2022) · Molecules and Cells · doi:10.14348/molcells.2022.0163 · Cited by 13
“Because this approach relies on inducing expression of fetal hemoglobin, it is applicable to β-thalassemia as well, and very exciting data have been reported for both types of patients (Frangoul et al., 2021).”
CRISPR/Cas9-mediated gene editing. A promising strategy in hematological disorders
Ugalde, L., Fañanas-Baquero, S., Torres-Ruiz, R., Bustamante, O. Q., & Rı́o, P. (2023) · Cytotherapy · doi:10.1016/j.jcyt.2022.11.014 · Cited by 16
Rise of the planet of rare anemias: An update on emerging treatment strategies
Fattizzo, B., & Motta, I. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2022.1097426 · Cited by 12
“A geneediting strategy that aims to reactivate HbF inhibiting BCL11A is CTX001, a CRISPR/Cas9-modified autologous HSCT product currently investigated in both TDT and SCD (17).”
BackgroundMicrobiota–Liver Diseases Interactions
Capparelli, R., Cuomo, P., Gentile, A., & Iannelli, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043883 · Cited by 12
“Remarkable results were also obtained with β-thalassemia, a disease caused by overexpression of the BCLA11A gene [29].”
ResultNucleases in gene-editing technologies: past and prologue
Li, D., Li, L.-Q., & Liu, J. (2023) · National Science Open · doi:10.1360/nso/20220067 · Cited by 12
“…named CTX001), which treats sickle cell disease and β-thalassemia through editing the patient’s own stem cells by CRISPR-Cas9 to produce high level of fetal hemoglobin [175], has been submitted to the U.S. FDA for rolling review and is expected to be the first CRISPR-based gene editing therapy.”
Background
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
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