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
Cites
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Self-citationChemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells
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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
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Self-citationGene Therapy in Patients with Transfusion-Dependent β-Thalassemia
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An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level
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Items 201–300 of 1,950
A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin
Shen, F., Zheng, G., Setegne, M. T., Tenglin, K., Izadi, M., Xie, H. T. H., Zhai, L., Orkin, S. H., & Dassama, L. M. K. (2022) · ACS Central Science · doi:10.1021/acscentsci.2c00998 · Cited by 49
“Genetic approaches, notably clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 (25, 26) editing and RNA interference (27) have been used to downregulate BCL11A in patients and validate the clinical utility of disabling BCL11A.”
MethodO’Geen, H., Beitnere, U., Garcia, M. S., Adhikari, A., Cameron, D. L., Fenton, T. A., Copping, N. A., Deng, P., Lock, S., Halmai, J. A. N. M., et al. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.01.013 · Cited by 51
Progress and Perspective of CRISPR‐Cas9 Technology in Translational Medicine
Zheng, R., Zhang, L., Parvin, R., Su, L., Chi, J., Shi, K., Ye, F., & Huang, X. (2023) · Advanced Science · doi:10.1002/advs.202300195 · Cited by 56
Toward Gene Transfer Nanoparticles as Therapeutics
Kavanagh, E. W., & Green, J. J. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202102145 · Cited by 47
Modern therapeutic approaches to liver-related disorders
Gardin, A., Remih, K., Gonzales, E. M., Andersson, E. R., & Strnad, P. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2021.12.015 · Cited by 51
Genome editing in large animal models
Maynard, L. H., Humbert, O., Peterson, C. W., & Kiem, H. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.09.026 · Cited by 50
Hokland, P., Daar, S., Khair, W., Sheth, S., Taher, A. T., Torti, L., Hantaweepant, C., & Rund, D. G. (2023) · British Journal of Haematology · doi:10.1111/bjh.18671 · Cited by 49
Self-citationSubica, A. M. (2023) · American Journal of Public Health · doi:10.2105/ajph.2023.307315 · Cited by 55
Palanki, R., Riley, J. S., Bose, S. K., Luks, V. L., Dave, A., Kus, N. J., White, B. M., Ricciardi, A. S., Swingle, K. L., Xue, L., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2400783121 · Cited by 50
“…regularly interspaced short palindromic repeat (CRISPR) - based gene editing technology and ex vivo gene delivery to HSCs have enabled United States Food and Drug Administration (FDA) approval of autologous HSC - based gene therapies for the treatment of sickle cell disease and β thalassemia (6).”
BackgroundGene Editing of Hematopoietic Stem Cells: Hopes and Hurdles Toward Clinical Translation
Ferrari, S., Vavassori, V., Canarutto, D., Jacob, A., Castiello, M. C., Omer, A., & Genovese, P. (2021) · Frontiers in Genome Editing · doi:10.3389/fgeed.2021.618378 · Cited by 52
“, 2021), as well as by CRISPR-mediated knockout (Frangoul et al., 2021).”
BackgroundInfluentialStimulus-Responsive Smart Nanoparticles-Based CRISPR-Cas Delivery for Therapeutic Genome Editing
Naeem, M., Hoque, M. Z., Ovais, M., Basheer, C., & Ahmad, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011300 · Cited by 51
“Severe sickle cell disease BCL11A gene I/II [21] β-thalassemia HBB I [22] Advanced esophageal cancer PD-1 II [23] Gastrointestinal epithelial cancer CISH II [24] Hematological malignancies CCR5 Not available [25] Solid tumors PD-1 and TCR Receptors I [26] Leber congenital amaurosis (LCA) Photoreceptors gene I [27] Her…”
BackgroundGene Therapy for Hemoglobinopathies
Leonard, A. K., Tisdale, J. F., & Bonner, M. A. (2022) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.03.008 · Cited by 49
Rewriting regulatory DNA to dissect and reprogram gene expression
Martyn, G. E., Montgomery, M. T., Jones, H., Guo, K., Doughty, B. R., Linder, J., Bisht, D., Xia, F., Cai, X. S., Chen, Z., et al. (2023) · Cell · doi:10.1016/j.cell.2025.03.034 · Cited by 59
Stem cell therapy: a revolutionary cure or a pandora's box
Marei, H. E. S. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04334-1 · Cited by 56
“Patients have reported long-lasting increases in fetal hemoglobin levels in clinical trials employing CRISPR-edited hematopoietic stem cells for sickle cell disease and beta-thalassemia [30].”
Role of Iron in the Molecular Pathogenesis of Diseases and Therapeutic Opportunities
Abbasi, U., Abbina, S., Gill, A., Takuechi, L. E., & Kizhakkedathu, J. N. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00122 · Cited by 48
Engineered Cas12i2 is a versatile high-efficiency platform for therapeutic genome editing
McGaw, C., Garrity, A. J., Munoz, G., Haswell, J. R., Sengupta, S., Keston-Smith, E., Hunnewell, P., Ornstein, A., Bose, M., Wessells, Q. N., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30465-7 · Cited by 43
Evolution of Gene Therapy, Historical Perspective
Malech, H. L., Garabedian, E., & Hsieh, M. M. (2022) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.05.001 · Cited by 51
Volodina, O., & Smirnikhina, S. (2024) · Molecular Biotechnology · doi:10.1007/s12033-024-01070-4 · Cited by 52
“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 elimination of vaso-occlusive episodes for patient with SCD [44].”
Nabar, N., Dacoba, T. G., Covarrubias, G., Romero-Cruz, D., & Hammond, P. T. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2307809121 · Cited by 54
CRISPRthripsis: The Risk of CRISPR/Cas9-induced Chromothripsis in Gene Therapy
Amendola, M., Brusson, M., & Miccio, A. (2022) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szac064 · Cited by 46
TAPE-seq is a cell-based method for predicting genome-wide off-target effects of prime editor
Kwon, J., Kim, M., Bae, S.-M., Jo, A., Kim, Y.-H., & Lee, J. K. (2022) · Nature Communications · doi:10.1038/s41467-022-35743-y · Cited by 45
Ravichandran, M., & Maddalo, D. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1273994 · Cited by 47
“At present, CRISPR-based gene knockout and base editor-mediated silencing of the BCL11A enhancer are actively being tested as a precision genome-editing therapy in the clinic (Khosravi et al., 2019; Frangoul et al., 2020).”
MethodRecent Therapeutic Gene Editing Applications to Genetic Disorders
Deneault, É. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46050255 · Cited by 54
“Casgevy™ was developed from CTX001, an investigational, autologous ex vivo CRISPR-Cas9 gene editing therapy, in which hematopoietic stem cells (HSCs) from patients with TDT or severe SCD were edited to produce high levels of fetal hemoglobin (HbF) in red blood cells [66].”
MethodEfficient Peptide-Mediated In Vitro Delivery of Cas9 RNP
Gustafsson, O., Rädler, J., Roudi, S., Lehto, T., Hällbrink, M., Lehto, T., Gupta, D., Andaloussi, S. E., & Nordin, J. Z. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13060878 · Cited by 44
“Several clinical studies are being performed or have been completed utilizing CRISPR/Cas9 to cure genetic disorders [6].”
BackgroundTherapy Development by Genome Editing of Hematopoietic Stem Cells
Koniali, L., Lederer, C. W., & Kleanthous, M. (2021) · Cells · doi:10.3390/cells10061492 · Cited by 50
“Over the last decade, a plethora of preclinical studies have provided proof of concept for the therapeutic potential of gene-edited autologous HSCs, vindicated by recent results from clinical trials of gene editing treatment for hemoglobinopathies [31].”
BackgroundApplications of CRISPR as a potential therapeutic
Luthra, R., Kaur, S. P., & Bhandari, K. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119908 · Cited by 48
Engineering of efficiency-enhanced Cas9 and base editors with improved gene therapy efficacies
Yin, S., Zhang, M., Liu, Y., Sun, X., Guan, Y., Chen, X., Yang, L., Huo, Y., Yang, J., Zhang, X., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.11.014 · Cited by 47
CRISPR-Cas System: The Current and Emerging Translational Landscape
Bhokisham, N., Laudermilch, E., Traeger, L. L., Bonilla, T. D., Ruíz-Estévez, M., & Becker, J. R. (2023) · Cells · doi:10.3390/cells12081103 · Cited by 46
“7% editing efficiency (patient two received two lots of exa-cel for sickle cell disease) [92].”
BackgroundApplications of Artificial Intelligence in Thalassemia: A Comprehensive Review
Ferih, K., Elsayed, B., Elshoeibi, A. M., Elsabagh, A. A., Elhadary, M. R., Soliman, A. T., Abdalgayoom, M., & Yassin, M. A. (2023) · Diagnostics · doi:10.3390/diagnostics13091551 · Cited by 49
“Thalassemia is predominant in the Mediterranean, African, and Southeast Asian populations [5,6].”
BackgroundLiposome-Based Carriers for CRISPR Genome Editing
Yin, X., Harmancey, R., McPherson, D. D., Kim, H., & Huang, S. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612844 · Cited by 44
Vishy, C. E., Thomas, C. J., Vincent, T., Crawford, D. K., Goddeeris, M. M., & Freedman, B. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.03.005 · Cited by 47
Exploiting Single-Cell Tools in Gene and Cell Therapy
Bode, D., Cull, A. H., Rubio-Lara, J. A., & Kent, D. G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.702636 · Cited by 44
Cromer, M. K., Majeti, K. R., Rettig, G. R., Murugan, K., Kurgan, G. L., Bode, N. M., Hampton, J. P., Vakulskas, C. A., Behlke, M. A., & Porteus, M. H. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.02.011 · Cited by 42
Massively targeted evaluation of therapeutic CRISPR off-targets in cells
Pan, X., Qu, K., Yuan, H., Xiang, X., Anthon, C., Pashkova, L., Liang, X., Han, P., Corsi, G. I., Xu, F., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31543-6 · Cited by 42
Genetic Variation and Sickle Cell Disease Severity
Kirkham, J. K., Estepp, J. H., Weiss, M. J., & Rashkin, S. R. (2023) · JAMA Network Open · doi:10.1001/jamanetworkopen.2023.37484 · Cited by 48
El-Kharrag, R., Berckmueller, K., Madhu, R., Cui, M., Campoy, G., Mack, H. M., Wolf, C. B., Perez, A. M., Humbert, O., Kiem, H., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.02.026 · Cited by 42
Nanoscale delivery platforms for RNA therapeutics: Challenges and the current state of the art
Rhym, L. H., & Anderson, D. G. (2022) · Med · doi:10.1016/j.medj.2022.02.001 · Cited by 45
Development of CRISPR/Cas Delivery Systems for In Vivo Precision Genome Editing
Chen, Y., & Yuan, P. (2023) · Accounts of Chemical Research · doi:10.1021/acs.accounts.3c00279 · Cited by 48
Self-citationThe state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap
Jonker, A. H., Tãtaru, E.-A., Graeßner, H., Dimmock, D., Jaffé, A., Baynam, G. S., Davies, J. O. J., Mitkus, S., Iliach, O., Horgan, R., et al. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01059-3 · Cited by 48
“Examples where gene therapy was developed for very small groups of people with rare diseases include spastic paraplegia 50 (SPG50) and Tay–Sachs disease 41,42 , as well as a private effort to develop a very specific vector-based treatment for Duchenne muscular dystrophy.”
Genomic enhancers in cardiac development and disease
Anene-Nzelu, C. G., Lee, C. J. M., Tan, W. L. W., Dashi, A., & Foo, R. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00597-2 · Cited by 39
Mehta, S., Buyanbat, A., Yan, K., Karayel, Ö., Goldman, S. R., Seruggia, D., Zhang, K., Fujiwara, Y., Donovan, K. A., Zhu, Q., et al. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.06.007 · Cited by 42
Gene therapy for primary mitochondrial diseases: experimental advances and clinical challenges
Falabella, M., Minczuk, M. A., Hanna, M. G., Viscomi, C. F., & Pitceathly, R. D. S. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00715-9 · Cited by 42
Carvill, G. L., Matheny, T., Hesselberth, J. R., & Demarest, S. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01137-z · Cited by 39
“The first successful use of gene editing in humans was ex vivo in sickle cell anemia and in vivo for retinal dystrophy [57, 58].”
BackgroundMethodGene Therapy and Gene Editing for β-Thalassemia
Christakopoulos, G. E., Telange, R., Yen, J. S., & Weiss, M. J. (2023) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.12.012 · Cited by 43
Palacios, A. M., Korus, P., Wilkens, B. G. C., Heshmatpour, N., & Patnaik, S. R. (2024) · Frontiers in Genome Editing · doi:10.3389/fgeed.2024.1342193 · Cited by 49
“This has been proven to show signi fi cant therapeutic implications for diseases caused by a single gene mutation or aberrant gene regulation, such as inherited blood disorders or genetic blindness (Maeder et al., 2019; Brusson and Miccio, 2021; Frangoul et al., 2021).”
BackgroundEnhancing pediatric access to cell and gene therapies
Mackall, C. L., Bollard, C. M., Goodman, N., Carr, C., Gardner, R., Rouce, R. H., Sotillo, E., Stoner, R., Urnov, F. D., Wayne, A. S., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03035-1 · Cited by 43
“New approaches for targeted genome editing using the CRISPR platform continue to emerge 15–17 , and next-generation immune cell therapies for infectious disease, autoimmunity and potentially tissue regeneration, are poised to broaden the array of pediatric diseases amenable to treatment with this…”
Lee, B., Lozano, R. J., & Dunbar, C. E. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.09.001 · Cited by 39
Sun, N., Zhao, D., Li, S., Zhang, Z., Bi, C., & Zhang, X. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.03.023 · Cited by 40
The Bibliometric Landscape of Gene Editing Innovation and Regulation in the Worldwide
Wei, X., Pu, A., Liu, Q., Hou, Q., Zhang, Y., An, X., Long, Y., Jiang, Y., Dong, Z., Wu, S., et al. (2022) · Cells · doi:10.3390/cells11172682 · Cited by 39
“The base editor and prime editor appeared in 2016 and 2019, respectively, and can be used to new CRISPR Human obesity (mouse model) FTO [30] Resistance to Clostridium septicum alpha-toxin or 6-thioguanine (mouseEScells) Whole genome [40] Functional genomics in human cells Anthrax and diphtheria toxin host genes [41] H…”
Translating musculoskeletal bioengineering into tissue regeneration therapies
Khodabukus, A., Guyer, T., Moore, A. C., Stevens, M. M., Guldberg, R. E., & Bursac, N. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abn9074 · Cited by 40
Sickle Cell Disease: From Genetics to Curative Approaches
Hardouin, G., Magrin, E., Corsia, A., Cavazzana, M., Miccio, A., & Semeraro, M. (2023) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-120122-081037 · Cited by 40
CRISPR Therapy of Sickle Cell Disease: The Dawning of the Gene Editing Era
Adashi, E. Y., Gruppuso, P. A., & Cohen, I. G. (2024) · The American Journal of Medicine · doi:10.1016/j.amjmed.2023.12.018 · Cited by 39
Autologous gene therapy for hemoglobinopathies: From bench to patient’s bedside
Locatelli, F., Cavazzana, M., Frangoul, H., de la Fuente, J., Algeri, M., & Meisel, R. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.005 · Cited by 43
Self-citationPathogenesis and Function of Interleukin-35 in Rheumatoid Arthritis
Xin, P. L., Jie, L. F., Cheng, Q., Bin, D. Y., & Dan, C. W. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.655114 · Cited by 43
“For example, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer, γ-globin expression and fetal hemoglobin in erythroid cells is promoted in Transfusion-dependent β-thalassemia and sickle cell disease (Frangoul et al., 2021), and it is reported that CRISPR gene editing is used for cancer immunotherapy by…”
BackgroundCD7-deleted hematopoietic stem cells can restore immunity after CAR T cell therapy
Kim, M. Y., Cooper, M. L., Jacobs, M. T., Ritchey, J., Hollaway, J., Fehniger, T. A., & DiPersio, J. F. (2021) · JCI Insight · doi:10.1172/jci.insight.149819 · Cited by 40
“HSCs has only recently entered human clinical trials (24, 25), and we still await the long-term effects of”
Paving the way towards precise and safe CRISPR genome editing
Śledziński, P., Dabrowska, M., Nowaczyk, M., & Olejniczak, M. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107737 · Cited by 43
Gene therapy for chronic pain: emerging opportunities in target-rich peripheral nociceptors
Ovsepian, S. V., & Waxman, S. G. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00673-7 · Cited by 44
Mahato, R. K., Bhattacharya, S., Khullar, N., Sidhu, I. S., Reddy, P. H., Bhatti, G. K., & Bhatti, J. S. (2023) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2023.12.003 · Cited by 40
Novel drugs approved by the EMA, the FDA, and the MHRA in 2023: A year in review
Papapetropoulos, A., Topouzis, S., Alexander, S. P. H., Cortese-Krott, M. M., Kendall, D. A., Martemyanov, K. A., Mauro, C., Nagercoil, N., Panettieri, R. A., Patel, H. H., et al. (2024) · British Journal of Pharmacology · doi:10.1111/bph.16337 · Cited by 39
The Current Role of Hydroxyurea in the Treatment of Sickle Cell Anemia
Rubio, M. L., & Marina, M. A. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13216404 · Cited by 44
“Gene therapy offers a promising yet experimental approach to the treatment of SCD. Advanced techniques such as CRISPR-Cas9 and lentiviral gene editing aim to correct the underlying genetic mutation responsible for SCD or induce the production of HbF by disrupting the BCL11A gene [68,69].”
BackgroundAl-Ouqaili, M. T. S., Ahmad, A., Jwair, N. A., & Al-Marzooq, F. I. (2025) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1588446 · Cited by 47
Megabase-scale human genome rearrangement with programmable bridge recombinases
Perry, N. T., Bartie, L. J., Katrekar, D., Gonzalez, G. A., Durrant, M. G., Pai, J. J., Fanton, A., Martins, J. Q., Hiraizumi, M., Ricci-Tam, C., et al. (2025) · Science · doi:10.1126/science.adz0276 · Cited by 42
Yogasundaram, H., Alhumaid, W., Dzwiniel, T., Christian, S., & Oudit, G. Y. (2021) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2021.01.016 · Cited by 43
Hematopoietic Stem Cell-Targeted Gene-Addition and Gene-Editing Strategies for β-hemoglobinopathies
Drysdale, C. M., Nassehi, T., Gamer, J., Yapundich, M., Tisdale, J. F., & Uchida, N. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.01.001 · Cited by 39
Human cell based directed evolution of adenine base editors with improved efficiency
Fu, J., Li, Q., Liu, X., Tu, T., Lv, X., Yin, X., Lv, J., Song, Z., Qu, J., Zhang, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26211-0 · Cited by 35
Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing
Anurogo, D., Budi, N. Y. P., Ngo, M.-H. T., Huang, Y., & Pawitan, J. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126275 · Cited by 43
Novel Therapeutic Advances in β-Thalassemia
Makis, A. C., Voskaridou, E., Papassotiriou, I., & Hatzimichael, E. C. (2021) · Biology · doi:10.3390/biology10060546 · Cited by 39
“The safety report after CTX001 treatment was similar to that with busulfan myeloablation [33,34].”
ResultEx vivo expansion of hematopoietic stem cells: Finally transitioning from the lab to the clinic
Zimran, E., Papa, L., & Hoffman, R. (2021) · Blood Reviews · doi:10.1016/j.blre.2021.100853 · Cited by 39
Advances in CRISPR Delivery Methods: Perspectives and Challenges
Demirci, S., Essawi, K., Germino-Watnick, P., Liu, X., Hakami, W., & Tisdale, J. F. (2022) · The CRISPR Journal · doi:10.1089/crispr.2022.0051 · Cited by 37
CRISPR/Cas9-based gene-editing technology for sickle cell disease
Ma, L., Yang, S., Peng, Q., Zhang, J., & Zhang, J. (2023) · Gene · doi:10.1016/j.gene.2023.147480 · Cited by 45
Sickle cell disease classification using deep learning
Jennifer, S. S., Shamim, M. H., Reza, A. W., & Siddique, N. H. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e22203 · Cited by 43
“Sickle cell disease (SCD) is a genetic disorder, brought on by a beta-globin gene mutation [1], leading to abnormal haemoglobin formation [2].”
BackgroundMeaker, G. A., & Wilkinson, A. C. (2023) · Experimental Hematology · doi:10.1016/j.exphem.2023.12.001 · Cited by 38
Building CRISPR Gene Therapies for the Central Nervous System
Salomonsson, S. E., & Clelland, C. D. (2024) · JAMA Neurology · doi:10.1001/jamaneurol.2023.4983 · Cited by 42
Im, S. H., Jang, M., Park, J., & Chung, H. J. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02427-2 · Cited by 43
Alariqi, M., Ramadan, M., Yu, L., Hui, F., Hussain, A., Zhou, X., Yu, Y., Zhang, X., & Jin, S. (2025) · Advanced Science · doi:10.1002/advs.202416331 · Cited by 42
Genome Editing, A Superior Therapy for Inherited Retinal Diseases
Yan, A. L., Du, S. W., & Palczewski, K. (2022) · Vision Research · doi:10.1016/j.visres.2023.108192 · Cited by 37
CRISPR/Cas9-based application for cancer therapy: Challenges and solutions for non-viral delivery
Lin, Y., Feng, K.-K., Lu, J.-Y., Le, J., Li, W.-L., Zhang, B., Li, C., Song, X.-H., Tong, L.-W., & Shao, J. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.08.028 · Cited by 38
El-Beshlawy, A. M., Dewedar, H., Hindawi, S., Alkindi, S. S. A., Tantawy, A. A. G., Yassin, M. A., & Taher, A. T. (2023) · Blood Reviews · doi:10.1016/j.blre.2023.101138 · Cited by 44
Revolutionising healing: Gene Editing's breakthrough against sickle cell disease
Dimitrievska, M., Bansal, D., Vitale, M., Strouboulis, J., Miccio, A., Nicolaides, K. H., Hoss, S. E., Shangaris, P., & Jackow, J. (2024) · Blood Reviews · doi:10.1016/j.blre.2024.101185 · Cited by 41
Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs
Baylot, V., Le, T. K., Taïeb, D., Rocchi, P., & Colleaux, L. (2024) · Communications Biology · doi:10.1038/s42003-024-06121-9 · Cited by 44
Mahat, D. B., Kumra, H., Castro, S. A., Metcalf, E., Nguyen, K. B., Morisue, R., Ho, W. W., Chen, I. X., Sullivan, B., Yim, L., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.06.005 · Cited by 44
CRISPR/Cas-Dependent and Nuclease-Free In Vivo Therapeutic Gene Editing
Dasgupta, I., Flotte, T. R., & Keeler, A. M. (2021) · Human Gene Therapy · doi:10.1089/hum.2021.013 · Cited by 38
Leibovitch, J. N., Tambe, A., Cimpeanu, E., Poplawska, M., Jafri, F. M., Dutta, D., & Lim, S. H. (2022) · Blood Reviews · doi:10.1016/j.blre.2021.100925 · Cited by 40
Zhou, T., Zhu, X., Ye, Z., Wang, Y., Yao, C., Xu, N., Zhou, M., Ma, J., Qin, Y., Shen, Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29514-y · Cited by 36
Zuccato, C., Cosenza, L. C., Zurlo, M., Gasparello, J., Papi, C., D’Aversa, E., Breveglieri, G., Lampronti, I., Finotti, A., Borgatti, M., et al. (2022) · Therapeutic Advances in Hematology · doi:10.1177/20406207221100648 · Cited by 36
“12 25 In this context, clinical trials are under-way, such as NCT03655678 (A safety and efficacy study evaluating CTX001 in subjects with TDT), based on the use of autologous CRISPR-Cas9-modified CD34 + human hematopoietic stem and progenitor cells with CTX001.”
MethodCurrent advances of CRISPR-Cas technology in cell therapy
Qiu, H.-Y., Ji, R.-J., & Zhang, Y. (2022) · Cell Insight · doi:10.1016/j.cellin.2022.100067 · Cited by 38
“To reactivate HBG expression, strategies such as knockout negative regulators or disrupting the binding sites on HBG promoter have been shown to alleviate repression and restore γ-globin expression (Frangoul et al., 2021; Newby et al., 2021; Park et al., 2019; Traxler et al., 2016; Wu et al., 2019; Zeng et al., 2020).”
BackgroundCompact Cas9d and HEARO enzymes for genome editing discovered from uncultivated microbes
Goltsman, D. S. A., Alexander, L. M., Lin, J., Ocampo, R. F., Freeman, B., Lamothe, R. C., Rivas, A. P., Temoche-Diaz, M. M., Chadha, S., Nordenfelt, N. S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-35257-7 · Cited by 37
“For example, a pair of Zn-binding ribbon motifs delineate a Zn-finger (CX(2,4)CX(27,31)CX(2,4)[C/H]) within the HNH domain, likely involved in target recognition and catalysis (Supplementary Figs.”
BackgroundHematopoietic Stem Cell Transplantation in Thalassemia
Algeri, M., Lodi, M., & Locatelli, F. (2023) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.12.009 · Cited by 36
Self-citationLiang, Y., Zhang, J., Xu, C., Wang, J., Han, W., Yang, J., Wu, S., An, J., Liu, J., Zhang, Z., et al. (2023) · ACS Nano · doi:10.1021/acsnano.3c04116 · Cited by 36
Enhancing homology-directed repair efficiency with HDR-boosting modular ssDNA donor
Jin, Y.-Y., Zhang, P., Liu, L., Zhao, X. H., Hu, X., Liu, S.-Z., Li, Z., Liu, Q., Wang, J.-Q., Hao, D., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50788-x · Cited by 36
“We next extended our fi ndings to primary cells by inducing gene editinginhumanperipheralblood(hPB)CD34+cells,animportantcell type for treating blood disorders 29 .”
Gene regulation technologies for gene and cell therapy
Butterfield, G. L., Reisman, S. J., Iglesias, N., & Gersbach, C. A. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.004 · Cited by 43
“166 By targeting the erythroid-specific enhancer of BCL11A , these therapies achieve two crucial outcomes: they increase fetal hemoglobin to physiological levels while simultaneously repressing sickle hemoglobin, and they confer cell type specificity by mediating this switch exclusively in the…”
Yin, H., Zhou, B., Dong, C., Zhang, Y., Yu, J., Pu, Y., Feng, W., Sun, L., Hu, H., Chen, Y., et al. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202107093 · Cited by 36
Self-citationGene Therapies for Monogenic Autism Spectrum Disorders
Weuring, W. J., Geerligs, J., & Koeleman, B. P. C. (2021) · Genes · doi:10.3390/genes12111667 · Cited by 40
“For example, patients with transfusion-dependent β thalassemia (TDT) and sickle-cell disorder (SCD) caused by reduced levels of y-globulin can be treated by using CRISPR-KO targeted to a transcription factor named BCL11A [46].”
Backgroundβ-Thalassemia: evolving treatment options beyond transfusion and iron chelation
Langer, A. L., & Esrick, E. B. (2021) · Hematology · doi:10.1182/hematology.2021000313 · Cited by 39
Lüftinger, R., Zubarovskaya, N., Galimard, J., Cseh, A., Salzer, E., Locatelli, F., Algeri, M., Yeşilipek, A., de la Fuente, J., Isgrò, A., et al. (2022) · Annals of Hematology · doi:10.1007/s00277-021-04732-4 · Cited by 35
Self-citationMerlin, J. P. J., & Abrahamse, H. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117516 · Cited by 35
Gene therapy for genetic diseases: challenges and future directions
Beibei, Q. I. E., Tuo, J., Chen, F., Ding, H., & Lyu, L. (2025) · MedComm · doi:10.1002/mco2.70091 · Cited by 38
Tang, A., Strat, A. N., Rahman, M., Zhang, H., Bao, W., Liu, Y., Shi, D., An, X., Manwani, D. G., Shi, P. A., et al. (2021) · Blood · doi:10.1182/blood.2021012663 · Cited by 33
Sguazzi, G. P., Muto, V., Tartaglia, M., Bertini, E., & Compagnucci, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413674 · Cited by 37
Clinical genome editing to treat sickle cell disease—A brief update
Zarghamian, P., Klermund, J., & Cathomen, T. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2022.1065377 · Cited by 39
“Non-serious lymphopenia was also reported, most likely due to a delay in lymphocyte recovery (41, 42).”
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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