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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Items 101–200 of 1,950
Allen, D. G., Rosenberg, M., & Hendel, A. (2021) · Frontiers in Genome Editing · doi:10.3389/fgeed.2020.617910 · Cited by 89
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MethodCRISPR–Cas9 Gene Editing: Curing Genetic Diseases by Inherited Epigenetic Modifications
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Targeted nonviral delivery of genome editors in vivo
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“The first CRISPR–Cas medicines leverage error-prone NHEJ and MMEJ disruption of target genes rather than HDR 2,3 .”
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Interpreting non-coding disease-associated human variants using single-cell epigenomics
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Molecular Basis and Genetic Modifiers of Thalassemia
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Thalassemia: Pathophysiology, Diagnosis, and Advances in Treatment
Sadiq, I. Z., Abubakar, F. S., Usman, H. S., Abdullahi, A. D., Ibrahim, B., Katsayal, B. S., Ibrahim, M., & Hassan, H. A. (2024) · Thalassemia Reports · doi:10.3390/thalassrep14040010 · Cited by 99
“Recent developments in gene-editing technologies, such as CRISPR-Cas9, have revolutionized the potential for curative treatments in thalassemia patients [150].”
Thalassemia, a human blood disorder
Shafique, F., Ali, S., Almansouri, T., van Eeden, F. J. M., Shafi, N., Khalid, M., Khawaja, S., Andleeb, S., & Hassan, M. U. (2021) · Brazilian Journal of Biology · doi:10.1590/1519-6984.246062 · Cited by 74
Applications of CRISPR-Cas9 as an Advanced Genome Editing System in Life Sciences
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“A recent trial of two patients (19 year-old with transfusion dependent thalassemia and 33 year-old with HbSS and a single α-globin deletion) showed that infusion of autologous CRISPR-Cas9–edited CD34+ hematopoietic stem and progenitor cells resulted in an early, significant, and sustained increase in total Hb and HbF…”
BackgroundGenetic engineering meets hematopoietic stem cell biology for next-generation gene therapy
Ferrari, S., Valeri, E., Conti, A., Scala, S., Aprile, A., Micco, R. D., Kajaste‐Rudnitski, A., Montini, E., Ferrari, G., Aiuti, A., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.04.014 · Cited by 75
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“…are developing and testing a variety of ex vivo delivery meth-ods, including viral vectors (e.g., lentiviruses [78] and adeno-associated viruses [79]), non-viral vectors (e.g., nanoparticles [80] and liposomes [81]), and physical methods (e.g., electroporation [82] and microinjection [83]).”
BackgroundEditing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation
Rao, S., Yao, Y., & Bauer, D. E. (2021) · Genome Medicine · doi:10.1186/s13073-021-00857-3 · Cited by 72
“Disruption of GATA1 binding sequences within the erythroid-specific enhancer of BCL11A in hematopoietic stem and progenitor cells (HSPCs) by either CRISPR/Cas9 or base editors significantly reduced BCL11A expression in erythroid-lineage cells, restored γ-globin synthesis, and reactivated production of fetal hemoglobin…”
BackgroundImmunological barriers to haematopoietic stem cell gene therapy
Charlesworth, C. T., Hsu, I., Wilkinson, A. C., & Nakauchi, H. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00698-0 · Cited by 71
Gene editing therapeutics based on mRNA delivery
Popovitz, J., Sharma, R. K., Hoshyar, R., Kim, B. S., Murthy, N., & Lee, K. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115026 · Cited by 73
Raguram, A., An, M., Chen, P., & Liu, D. R. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02467-x · Cited by 82
“…of the BCL11A erythroid-specific enhancer in HSPCs leads to the induction of fetal hemoglobin expression in erythrocytes, which is sufficient to rescue disease phenotypes associated with these blood disorders and is the first US Food and Drug Administration-approved gene editing drug 56,61,62 .”
Harnessing lipid nanoparticles for efficient CRISPR delivery
Yan, J., Kang, D. D., & Dong, Y. (2021) · Biomaterials Science · doi:10.1039/d1bm00537e · Cited by 69
Gene editing and its applications in biomedicine
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“All patients receiving the treatment are able to produce sufficient fetal hemoglobin, which helps them become independent of transfusions (Frangoul et al., 2021).”
BackgroundMethodSelf-citationThe Potential Revolution of Cancer Treatment with CRISPR Technology
Stefanoudakis, D., Kathuria‐Prakash, N., Sun, A. W., Abel, M. L., Drolen, C. E., Ashbaugh, C. W., Zhang, S., Hui, G., Tabatabaei, Y. A., Zektser, Y., et al. (2023) · Cancers · doi:10.3390/cancers15061813 · Cited by 75
“2019 FDA approved Onasemnogene abeparvovec Zolgensma SMA (Pediatric Patients, < 2 y/o) [45,46]”
BackgroundLipid nanoparticles: The game-changer in CRISPR-Cas9 genome editing
Farsani, A. M., Mokhtari, N., Nooraei, S., Bahrulolum, H., Akbari, A., Farsani, Z. M., Khatami, S., Ebadi, M. S., & Ahmadian, G. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e24606 · Cited by 82
“CRISPR-Cas9 has been applied in clinical studies aimed at treating sickle cell disease (SCD) and thalassemia [35].”
MethodBulcaen, M., Kortleven, P., Liu, R. B., Maule, G., Dreano, E., Kelly, M., Ensinck, M. M., Thierie, S., Smits, M., Ciciani, M., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101544 · Cited by 69
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Opportunities and challenges of protein-based targeted protein degradation
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Advances and applications in single-cell and spatial genomics
Wang, J., Ye, F., Chai, H., Jiang, Y., Wang, T., Ran, X., Xia, Q., Xu, Z., Fu, Y., Zhang, G., et al. (2024) · Science China Life Sciences · doi:10.1007/s11427-024-2770-x · Cited by 70
Translation of New and Emerging Therapies for Genetic Cardiomyopathies
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“One recent and very promising example is for sickle cell disease and b-thalassemia, in which CRISPR-Cas9 gene editing of an erythroid enhancer region resulted in re-expression of fetal hemoglobin and a dramatic clinical response with elimination of vaso-occlusive episodes and need for transfusion (49).”
BackgroundA second space age spanning omics, platforms and medicine across orbits
Mason, C. E., Green, J., Adamopoulos, K. I., Afshin, E. E., Baechle, J. J., Basner, M., Bailey, S. M., Bielski, L., Borg, J., Borg, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07586-8 · Cited by 68
“These advancements, coupled with genomic tools and personalized activation of specific alleles 88 , have the potential to address individual health challenges encountered in space.”
Xu, W., Zhang, S., Qin, H., & Yao, K. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05957-3 · Cited by 74
ON-Target Adverse Events of CRISPR-Cas9 Nuclease: More Chaotic than Expected
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Genetic risk factors have a substantial impact on healthy life years
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Evolution of CRISPR/Cas Systems for Precise Genome Editing
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“Gene-edited HSCs were infused into patient bodies with promising results [50].”
2021 update on clinical trials in β‐thalassemia
Musallam, K. M., Bou‐Fakhredin, R., Cappellini, M. D., & Taher, A. T. (2021) · American Journal of Hematology · doi:10.1002/ajh.26316 · Cited by 66
Self-citationSniper2L is a high-fidelity Cas9 variant with high activity
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Clinical applications of gene therapy for rare diseases: A review
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An Update on the Application of CRISPR Technology in Clinical Practice
Morshedzadeh, F., Ghanei, M., Lotfi, M., Ghasemi, M., Ahmadi, M., Najari-Hanjani, P., Sharif, S., Mozaffari‐Jovin, S., Peymani, M., & Abbaszadegan, M. R. (2023) · Molecular Biotechnology · doi:10.1007/s12033-023-00724-z · Cited by 62
“The results of these trials have been published recently [101].”
Pediatric Drug Development: Reviewing Challenges and Opportunities by Tracking Innovative Therapies
Domingues, C., Jarak, I., Veiga, F., Dourado, M., & Figueiras, A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15102431 · Cited by 69
“…for the treatment of severe monogenic diseases, such as transfusion-dependent β -thalassemia (TDT) and sickle cell disease (SCD), by targeting the BCL11A erythroid-specific enhancer, which is responsible for the repression of γ -globin expression and fetal hemoglobin in erythroid cells [260].”
BackgroundMethodmRNA therapies: Pioneering a new era in rare genetic disease treatment
Shen, G., Liu, J., Yang, H., Xie, N., & Yang, Y. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.03.056 · Cited by 62
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Self-citationCurrent insights into the bone marrow niche: From biology in vivo to bioengineering ex vivo
Xiao, Y., McGuinness, C. S., Doherty-Boyd, W. S., Salmerón‐Sánchez, M., Donnelly, H., & Dalby, M. J. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121568 · Cited by 65
Enhancer-gene specificity in development and disease
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Khan, M. (2024) · Polymers · doi:10.3390/polym16182629 · Cited by 64
A call to action to scale up research and clinical genomic data sharing
Stark, Z., Glazer, D., Hofmann, O., Rendon, A., Marshall, C. R., Ginsburg, G. S., Lunt, C., Allen, N. E., Effingham, M., Ward, J. H., et al. (2024) · Nature Reviews Genetics · doi:10.1038/s41576-024-00776-0 · Cited by 60
“In turn, this has led to unprecedented acceleration in the development of precision treatments 6,7 .”
Manling, W., Wang, M., Jia, H., & Wu, P. (2022) · Drug Delivery · doi:10.1080/10717544.2022.2104404 · Cited by 62
“DNA The CRISPR/Cas9 vector, as a functional genome editing system, has been successfully applied to the treatment of some human refractory diseases (Frangoul et al., 2021).”
MethodCRISPR nuclease off-target activity and mitigation strategies
Wienert, B., & Cromer, M. K. (2022) · Frontiers in Genome Editing · doi:10.3389/fgeed.2022.1050507 · Cited by 66
“, 2020) and hematopoietic stem and progenitor cells (HSPCs) (Frangoul et al., 2021).”
BackgroundTracking-seq reveals the heterogeneity of off-target effects in CRISPR–Cas9-mediated genome editing
Zhu, M., Xu, R., Yuan, J., Wang, J., Ren, X., Cong, T., You, Y., Ju, A., Xu, L., Wang, H., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02307-y · Cited by 62
“The first US Food and Drug Administration (FDA)-approved CRISPR-based therapy, exagamglogene autotemcel (exa-cel, formerly CTX001), targets the BCL11A erythroid-specific enhancer in CD34 + HSPCs, including long-term hematopoietic stem cells (LT-HSCs) 34 .”
CRISPR–Cas9 delivery strategies for the modulation of immune and non-immune cells
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“Editing of these cells makes them produce more fetal haemoglobin, which prevents the sickling of red blood cells 55 .”
Emerging Role of Long Non-Coding RNAs in Diabetic Vascular Complications
Tanwar, V. S., Reddy, M. A., & Natarajan, R. D. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.665811 · Cited by 58
ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases
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Ensuring a future for gene therapy for rare diseases
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Current trends of clinical trials involving CRISPR/Cas systems
Zhang, S., Wang, Y., Mao, D., Wang, Y., Zhang, H., Pan, Y., Wang, Y., Teng, S., & Huang, P. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1292452 · Cited by 62
“In summary, even if ex vivo editing of CD34 + HSPCs decreases their stemness, CTX001 still “homes” to the bone marrow to exert its therapeutic function (76).”
BackgroundInfluentialKim, H. S., Kweon, J., & Kim, Y. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01212-3 · Cited by 68
Lipid- and polymer-based nanoparticle systems for the delivery of CRISPR/Cas9
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The power and the promise of CRISPR/Cas9 genome editing for clinical application with gene therapy
Guo, N., Liu, J., Li, W., Ma, Y., & Fu, D. (2021) · Journal of Advanced Research · doi:10.1016/j.jare.2021.11.018 · Cited by 64
The Role of Recombinant AAV in Precise Genome Editing
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In vivo CRISPR gene editing in patients with herpetic stromal keratitis
Wei, A., Yin, D., Zhai, Z., Ling, S., Le, H., Tian, L., Xu, J., Paludan, S. R., Cai, Y., & Hong, J. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.08.021 · Cited by 65
CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
Meisel, R. (2021) · New England Journal of Medicine · doi:10.1056/nejmc2103481 · Cited by 70
Current Strategies for Increasing Knock-In Efficiency in CRISPR/Cas9-Based Approaches
Leal, A., Herreno-Pachón, A., Benincore-Flórez, E., Karunathilaka, A., & Tomatsu, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052456 · Cited by 58
“By knocking out the BCL11A gene (80%), the authors found a significant increase in fetal hemoglobin synthesis [46].”
BackgroundSystematic decomposition of sequence determinants governing CRISPR/Cas9 specificity
Fu, R., He, W., Dou, J., Villarreal, O. D., Bedford, E., Wang, H. H., Hou, C., Zhang, L., Wang, Y., Ma, D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28028-x · Cited by 59
Self-citationPrecision genome editing in the eye
Suh, S., Choi, E. H., Raguram, A., Liu, D. R., & Palczewski, K. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2210104119 · Cited by 56
“gies for treating cancers, blood disorders, chronic infections, protein-folding disorders, and eye diseases (16).”
BackgroundFoley, R. A., Sims, R. A., Duggan, E. C., Olmedo, J. K., Ma, R., & Jonas, S. J. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.973326 · Cited by 60
“Recently announced phase I and II clinical trials that leverage CRISPR/Cas9-based strategies to treat transfusion-dependent β-thalassemia (NCT03655678), sickle cell disease (NCT03745287) (Frangoul et al., 2021), transthyretin amyloidosis (NCT04601051) (Gillmore et al.”
BackgroundCRISPR/Cas9 Delivery Systems to Enhance Gene Editing Efficiency
Seijas, A., Cora, D., Novo, M., Al‐Soufi, W., Sanchez, L. E., & Arana, Á. J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094420 · Cited by 68
“The clinical success of CASGEVY TM demonstrates the therapeutic viability of CRISPR/Cas9 systems using non-viral delivery [9,10].”
InfluentialDarwinian genomics and diversity in the tree of life
Stephan, T., Burgess, S. M., Cheng, H., Danko, C. G., Gill, C. A., Jarvis, E. D., Koepfli, K.-P., Koltes, J. E., Lyons, E. H., Ronald, P. C., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2115644119 · Cited by 54
Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease
Germino-Watnick, P., Hinds, M., Le, A., Chu, R., Liu, X., & Uchida, N. (2022) · Cells · doi:10.3390/cells11111843 · Cited by 63
Hereditary spastic paraplegia: Genetic heterogeneity and common pathways
Panza, E., Meyyazhagan, A., & Orlacchio, A. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114203 · Cited by 55
In vivo delivery of CRISPR-Cas9 genome editing components for therapeutic applications
Huang, K. L., Zapata, D. A., Tang, Y., Teng, Y., & Li, Y. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121876 · Cited by 61
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“Recently, an additional autologous HSC gene-editing therapy strategy has been successfully applied clinically via the use of engineered endonucleases to reactivate HbF production 11,12 .”
Makkar, S. K. (2025) · Frontiers in Genetics · doi:10.3389/fgene.2025.1675209 · Cited by 72
“Riboswitches provide the prospect of built-in control mechanisms for therapeutic RNAs, contingent on achieving robust ligand – switch pairs (Wilson et al., 2023; Finkel et al., 2017; Frangoul et al., 2021; Jackson et al., 2006; Zhao et al., 2020).”
Künnapuu, J., Bokharaie, H., & Jeltsch, M. (2021) · Biology · doi:10.3390/biology10020167 · Cited by 54
“However, even cutting-edge trials limit themselves at the mom nt to cells that can be easily modified ex vivo (blood diseases such as ickle cell di ease and β-thalassemia) [152] or to very l calized targets [153].”
BackgroundBou‐Fakhredin, R., Franceschi, L. D., Motta, I., Cappellini, M. D., & Taher, A. T. (2022) · Pharmaceuticals · doi:10.3390/ph15060753 · Cited by 56
Self-citationGene therapy for inborn errors of immunity: past, present and future
Fischer, A. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00800-6 · Cited by 54
How data science and AI-based technologies impact genomics
Jing, L., & Ngiam, K. Y. (2023) · Singapore Medical Journal · doi:10.4103/singaporemedj.smj-2021-438 · Cited by 53
“[38] In contrast to ex vivo genome editing, in vivo genome‑editing approaches directly introduce the genome‑editing components into the patient via local or systemic delivery, and so the genome editing occurs inside the patient’s body.”
BackgroundBiomaterial‐based gene therapy
Yu, Y., Gao, Y., He, L., Fang, B., Ge, W., Pu, Y., Ju, Y., Xie, X., & Lei, L. (2023) · MedComm · doi:10.1002/mco2.259 · Cited by 55
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Self-assembling protein nanoparticles for cytosolic delivery of nucleic acids and proteins
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Thalassemias: from gene to therapy
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Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs
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Recent Advances in CRISPR/Cas9 Delivery Approaches for Therapeutic Gene Editing of Stem Cells
Lotfi, M., Rad, D. M., Mashhadi, S., Ashouri, A., Mojarrad, M., Mozaffari‐Jovin, S., Farrokhi, S., Hashemi, M., Lotfi, M., Warkiani, M. E., et al. (2023) · Stem Cell Reviews and Reports · doi:10.1007/s12015-023-10585-3 · Cited by 54
“Abbreviations CRISPR/Cas9 : clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9; hPSCs : human pluripotent stem cells, indel: insertion or deletion; DSBs : double-strand breaks; NHEJ : non-homologous end-joining; HDR : homology-directed repair; TALENs :…”
Alves, C. R. R., Ha, L. L., Yaworski, R., Sutton, E. R., Lazzarotto, C. R., Christie, K. A., Reilly, A., Beauvais, A., Doll, R. M., de la Cruz, D., et al. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-023-01132-z · Cited by 72
CRISPR-DIPOFF: an interpretable deep learning approach for CRISPR Cas-9 off-target prediction
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“By knocking off the faulty gene and correcting it with a controlled repair mechanism CRISPR has opened up a new approach of treating sickle cell anemia [4] and its human clinical trial has also started [16].”
BackgroundEnhancer–promoter specificity in gene transcription: molecular mechanisms and disease associations
Friedman, M. J., Wagner, T., Lee, H., Rosenfeld, M. G., & Oh, S. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01233-y · Cited by 61
Chemical engineering of CRISPR–Cas systems for therapeutic application
Barber, H. M., Pater, A. A., Gagnon, K. T., Damha, M. J., & O’Reilly, D. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01086-0 · Cited by 57
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Progress of delivery methods for CRISPR-Cas9
Yang, W., Yan, J., Zhuang, P., Ding, T., Chen, Y., Zhang, Y., Zhang, H., & Cui, W. (2022) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2022.2100342 · Cited by 52
“A study by Frangoul et al. included a patient with SCD and a patient with TDT [130].”
BackgroundMethodInfluentialSelf-citationCRISPR/Cas9 assisted stem cell therapy in Parkinson's disease
Pinjala, P., Tryphena, K. P., Prasad, R., Khatri, D. K., Sun, W., Singh, S. B., Gugulothu, D. B., Srivastava, S., & Vora, L. K. (2023) · Biomaterials Research · doi:10.1186/s40824-023-00381-y · Cited by 57
“Thus, CRISPR/Cas9-based gene therapy has reached the clinical trial stage for many monogenic diseases such as sickle cell anemia [7], β-thalassemia [7], hereditary tyrosinemia type I [8] and is being applied in advanced preclinical testing stages of Duchenne muscular dystrophy (DMD), hemoglobinopathies, and hereditary…”
BackgroundOncogenic activation of PIK3CA in cancers: Emerging targeted therapies in precision oncology
Wang, Y., Rozen, V., Zhao, Y., & Wang, Z. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2024.101430 · Cited by 60
Lipid nanoparticle-mediated mRNA delivery to CD34+ cells in rhesus monkeys
Kim, H., Zenhausern, R., Gentry, K., Lian, L., Huayamares, S. G., Radmand, A., Loughrey, D., Podilapu, A. R., Hatit, M. Z. C., Ni, H., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02470-2 · Cited by 59
Self-citationCRISPR-Cas9 to induce fetal hemoglobin for the treatment of sickle cell disease
Demirci, S., Leonard, A. K., Essawi, K., & Tisdale, J. F. (2021) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2021.09.010 · Cited by 56
Gene therapy for cystic fibrosis: Challenges and prospects
Sui, H., Xu, X., Su, Y., Gong, Z., Yao, M., Liu, X., Zhang, T., Jiang, Z., Bai, T., Wang, J., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1015926 · Cited by 56
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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