CRISPR-Cas12a Gene Editing of HBG1 and HBG2 Promoters to Treat β-Thalassemia
New England Journal of Medicine, 2026 · paper · Clinical trials
A phase 1–2 study of Cas12a-edited stem-cell therapy reni-cel in nine patients with transfusion-dependent β-thalassemia. All engrafted, fetal hemoglobin rose, and all were transfusion-free at last follow-up; the study ended early for sponsor priorities.
5 findings
Substance Table 1 unit for the dose row is printed with a negative exponent: "Median total reni-cel dose (range) — ×10−6 CD34+ cells/kg" (value 6.1 [3.3–11.9]).
- p. 4 Table 1, reni-cel dose row
Median total reni-cel dose (range) — ×10−6 CD34+ cells/kg
- p. 5 Results, Participant and Engraftment Characteristics
the median reni-cel dose was 6.1×106
- p. 5 Results, Participant and Engraftment Characteristics
the median reni-cel dose was 6.1×106 (range, 3.3×106 to 11.9×106) CD34+ cells per kilogram
- p. 3 Methods, Reni-cel Production and Infusion
a single minimum dose of 3×106 CD34+ cells per kilogram (post-thaw)
Judge's note: Viewed crops C008-a and C008-e and the full table on extract/png/main-p004.png: the row label shows a superscript with a minus sign before the 6, and the PDF text layer carries a true minus (U+2212) between "10" and "6", so it is not a fused-superscript extraction artefact. The Results on page 5 state "the median reni-cel dose was 6.1×106 (range, 3.3×106 to 11.9×106) CD34+ cells per kilogram" and the Methods on page 3 give a minimum dose of "3×106 CD34+ cells per kilogram", both with positive exponent 6; as printed the table's unit is off by a factor of 10^12. (The genotype-subheading point raised in one note of this cluster is adjudicated under C007.)
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Reference or label Table 1 genotype subheading reads "β0/β0 and non-β0/β0–like mutations" for the beta-null group, duplicating the wording of the second subheading "Non–β0/β0 and non-β0/β0–like mutations".
- p. 4 Table 1, genotype subheading
β0/β0 and non-β0/β0–like mutations
- p. 1 Abstract, Results
four β0/β0 or β0/β0-like
- p. 4 Table 1, second subheading
Non–β0/β0 and non-β0/β0–like mutations
- p. 1 Abstract, Results
four β0/β0 or β0/β0-like and five non–β0/β0 genotypes
Judge's note: Read crop C007-a and the full Table 1 on extract/png/main-p004.png. Under the first subheading are β0/β0 (3 [33]) and β+/β+, homozygous IVS-I-110 G→A (1 [11]), i.e. 4 participants; under the second are β0/β+ (4 [44]) and βE/β0 (1 [11]), i.e. 5. The abstract (extract/png/main-p001.png) describes the cohort as "four β0/β0 or β0/β0-like and five non–β0/β0 genotypes", and the Results (page 5) call the first group "homozygous beta-null or beta-null–like mutations". The word "non-" in the first subheading therefore describes the opposite category and makes the two subheadings read alike; the counts themselves are consistent.
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Reference or label Both beti-cel results are placed in one named trial: "In the phase 3 study of HGB-207, this approach resulted in transfusion independence in 20 of 22 participants (91%) with the non–β0/β0 genotype and 16 of 18 (89%) of those with a more severe genotype.13,14", although reference 14 names the severe-genotype trial as HGB-212.
- p. 2 Introduction, beti-cel paragraph
In the phase 3 study of HGB-207, this approach resulted in transfusion independence in 20 of 22 participants (91%) with the non–β0/β0 genotype and 16 of 18 (89%) of those with a more severe genotype.13,14
- p. 10 Reference 14
severe genotype β-thalassaemia (HGB-212)
- p. 10 Reference 14
Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β-thalassaemia (HGB-212)
- p. 10 Reference 13
Betibeglogene autotemcel gene therapy for non-β0/β0 genotype β-thalassemia
Judge's note: Read the sentence on the page image (crop C002-a, page extract/png/main-p002.png) and the reference list on extract/png/main-p010.png. Ref 13 is Locatelli et al., "Betibeglogene autotemcel gene therapy for non-β0/β0 genotype β-thalassemia," N Engl J Med 2022; ref 14 is Kwiatkowski et al., "Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β-thalassaemia (HGB-212): a non-randomised, multicentre, single-arm, single-dose, phase 3 trial," Lancet 2024. The paper's own reference list therefore identifies two distinct phase 3 trials, while the sentence names only HGB-207 as the setting of both figures. The percentages themselves check out.
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Reference or label Figure 1 legend: "Panels A and B show the changes in the total and fetal hemoglobin levels, respectively, after renizgamglogene autogedtemcel (reni-cel) infusion", although both panels display both measures.
- p. 5 Figure 1 legend
Panels A and B show the changes in the total and fetal hemoglobin levels, respectively
- p. 6 Figure 1 panel titles
Total Hemoglobin and Fetal Hemoglobin Levels
Judge's note: Read the legend on extract/png/main-p005.png (crop C010-a) and the figure itself on extract/png/main-p006.png. Panel A is titled "Changes in Total Hemoglobin and Fetal Hemoglobin Levels" and plots both a grey total-hemoglobin line and a blue fetal-hemoglobin line; Panel B is titled "Total Hemoglobin and Fetal Hemoglobin Levels" and shows paired blue (fetal) and grey (total) bars with a legend naming both. The panels differ in presentation (line plot with SD bars vs bar chart with printed values), not in which analyte each shows, so "respectively" pairs A with total and B with fetal incorrectly.
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Reference or label Figure 2 'Duration of Follow-up (mo)' column (21, 18, 18, 18, 15, 15, 12, 5, 3) disagrees with the bar labels, which the caption says represent 'the duration of postinfusion follow-up', and with the reported '17.5 months (range, 3.8 to 23.4)'.
- p. 7 Figure 2, right-hand column, participant 1
21
- p. 5 Results
17.5 months (range, 3.8 to 23.4)
Only the authors can say what is right here.
Judge's note: Checked Figure 2 on p7. Each row's bar labels add up to the reported follow-up: participant 1 0.7+22.7=23.4, which is the upper end of the range in the abstract, results and Table 1; participant 9 0.7+3.1=3.8, which is the lower end; the median of the nine bar totals is 17.5, which matches the text. The 'Duration of Follow-up' column instead reads 21…3, with median 15 and range 3–21. It probably shows the last scheduled visit month, but the column is labelled as follow-up duration and no footnote explains the difference. Only the authors can say which label or values were intended.
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12 minor (typos and the like; most checked by the judge only)
Reference or label Results: "In addition, six participants were followed for at least 15 months and could be evaluated for transfusion independence at 12 months (Table 1)." — Table 1 does not report that count.
- p. 5 Results, end of Participant and Engraftment Characteristics
six participants were followed for at least 15 months and could be evaluated for transfusion independence at 12 months (Table 1)
- p. 5 Results, Participant and Engraftment Characteristics
could be evaluated for transfusion independence at 12 months (Table 1)
Only the authors can say what is right here.
Judge's note: Read the sentence on extract/png/main-p005.png (crop C009-a) and checked every row of Table 1 on extract/png/main-p004.png: the only follow-up item is "Median follow-up duration (range) — mo 17.5 (3.8–23.4)"; there is no count of participants followed ≥15 months or evaluable for transfusion independence. Figure 2 (extract/png/main-p007.png) lists per-participant follow-up (21, 18, 18, 18, 15, 15, 12, 5, 3 months), from which six participants with ≥15 months can be read off. Rated minor because the Table 1 pointer does support the adjacent follow-up statement, but not the count as written.
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Wording Results: "Additional baseline clinical characteristics of the enrolled participants are summarized in Table 1 and Table S2", while Table 1 is headed "Participants (N=9)", i.e. the treated participants.
- p. 5 Results, genotype paragraph
Additional baseline clinical characteristics of the enrolled participants are summarized in Table 1 and Table S2.
- p. 4 Table 1 header
(N=9)
Judge's note: Read the sentence on extract/png/main-p005.png (crops C011-a, C012-a) and the Table 1 header on extract/png/main-p004.png. The same Results paragraph distinguishes the two populations: "a total of 11 participants had been enrolled across six sites... Of these, 9 participants... received treatment with reni-cel", and the paragraph's preceding sentences describe the nine treated participants. Table 1 is restricted to N=9, so "enrolled" is a loose label for the population tabulated; the data and counts are unaffected, hence minor wording.
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Wording The text gives fetal hemoglobin '12.0±1.5 g per deciliter at month 12 (among six participants)', but Figure 1A/1B shows a single No. of Participants row with 7 at month 12, shared by the total and fetal hemoglobin series.
- p. 7 Results, Total and Fetal Hemoglobin
12.0±1.5 g per deciliter at month 12 (among six participants)
- p. 6 Figure 1A/1B, No. of Participants row at month 12
7
- p. 7 Results, Total and Fetal Hemoglobin and F Cells
at month 12 (among six participants)
- p. 6 Figure 1A/1B, number-of-participants row
7 (month 12)
Only the authors can say what is right here.
Judge's note: In the p6 image, Figure 1A and 1B both show n=7 at month 12, and the fetal value 12.0 is plotted at that time point. The text on p7 says six for fetal hemoglobin and seven for total hemoglobin. At month 6 (7) and month 18 (4) the text and figure counts agree. The legend's general remark that 'Not all participants had samples that could be evaluated at each time point' could cover a missing month-12 sample, but the only count difference the legend spells out is the baseline fetal hemoglobin count of 8. The month-12 difference is therefore not disclosed, and it is unclear which count is right.
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Typo The Discussion prints '(ClinicalTrials.org number, NCT06363760)', but the abstract names the registry as 'ClinicalTrials.gov'.
- p. 9 Discussion, limitations paragraph
(ClinicalTrials.org number, NCT06363760)
- p. 1 Abstract
EdiThal ClinicalTrials.gov number, NCT05444894
- p. 9 Discussion, limitations paragraph
A long-term study (ClinicalTrials.org number, NCT06363760) is currently under way
- p. 1 Abstract, Conclusions
EdiThal ClinicalTrials.gov number, NCT05444894.
Judge's note: Rests on outside knowledge: NCT identifiers are issued by ClinicalTrials.gov. The p9 image shows 'ClinicalTrials.org', and the abstract on p1 uses 'ClinicalTrials.gov number, NCT05444894', so the paper names the same registry two ways.
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Typo Introduction misspells the gene symbol: "editing the BCL11A binding sites in the HGB1 and HBG2 promoters" (should be HBG1).
- p. 2 Introduction, paragraph on reni-cel
BCL11A binding sites in the HGB1 and
- p. 2 Introduction, paragraph beginning "Renizgamglogene autogedtemcel (reni-cel)"
editing the BCL11A binding sites in the HGB1 and HBG2 promoters
- p. 2 Introduction, last paragraph
HGB1 and
- p. 2 Introduction
HGB1 and HBG2 promoters
Judge's note: Viewed crop C001-b and full page extract/png/main-p002.png: the italic gene symbol is clearly set as "HGB1" immediately before a correctly set italic "HBG2". The same paragraph two sentences earlier prints "within the HBG1 and HBG2 promoters" correctly, as do the title, abstract, methods and Table/figure usage, so this is a letter transposition and not an extraction artefact. It is the only occurrence of "HGB1" in the article (the other "HGB-" strings are trial names HGB-207/HGB-212).
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Typo Genus name set in lower case and roman: "an engineered variant of the acidaminococcus species Cas12a (AsCas12a) gene-editing nuclease".
- p. 2 Introduction
engineered variant of the acidaminococcus species Cas12a
- p. 2 Introduction, paragraph beginning "Renizgamglogene autogedtemcel (reni-cel)"
an engineered variant of the acidaminococcus species Cas12a (AsCas12a) gene-editing nuclease
- p. 2 Introduction, next paragraph
The AsCas12a nuclease was chosen over Streptococcus pyogenes
- p. 2 Introduction
acidaminococcus species Cas12a (AsCas12a)
Judge's note: Viewed crop C004-b and full page extract/png/main-p002.png. The printed text shows "acidaminococcus" in lower-case roman type, while the next paragraph on the same page sets "Streptococcus pyogenes" with an initial capital and in italics. The abbreviation AsCas12a derives from the genus Acidaminococcus, so the intended form is capitalised; this is an internal typographic inconsistency on the same page.
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Typo The Discussion says 'too short to evaluate participants for inefficient erythropoiesis', while the Introduction uses the standard term 'ineffective erythropoiesis'.
- p. 9 Discussion, limitations paragraph
follow-up was too short to evaluate participants for inefficient erythropoiesis or iron overload over time
- p. 2 Introduction, first paragraph
the severity of anemia and ineffective erythropoiesis
Judge's note: The p9 image shows 'ineffi-cient erythropoiesis', while the Introduction (p2) uses 'ineffective erythropoiesis' twice. This is a terminology inconsistency only; the meaning is clear.
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Typo Methods, Study End Points: "starting at 3 months after treament, without red-cell transfusion" misspells "treatment".
- p. 3 Study End Points
starting at 3 months after treament
- p. 3 Methods, Study End Points
starting at 3 months after treament, without red-cell transfusion
- p. 3 Study End Points
treament
- p. 7 Figure 2 column header
Tranfusion
Judge's note: Viewed crop C006-b and full page extract/png/main-p003.png: the printed line reads "starting at 3 months after treament, without red-cell transfusion". The same definition is given correctly in Statistical Analysis ("for at least 12 consecutive months from month 3 after reni-cel infusion", page 5). The Figure 2 header misspelling "Tranfusion" also listed in this cluster is adjudicated separately as C015.
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Typo Mixed number styles within one sentence: "...five (56%) had non–β0/β0 genotypes (4 had β0/β+ mutations, and one had a βE/β0 mutation)", against "(three had β0/β0 mutations, and one had a β+/β+...)" in the parallel clause.
- p. 5 Results, participant characteristics
(4 had β0/β+ mutations, and one had a
Judge's note: Read on crop C012-a and extract/png/main-p005.png. The parallel parenthetical for the first genotype group spells out "three" and "one", while the second uses the numeral "4" beside the spelled-out "one". Purely a house-style inconsistency; no number or count is affected (3+1=4 and 4+1=5 match Table 1 and the abstract).
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Typo Figure 1 Panel A y-axis label misspelled: "Mean Hemogloblin (g/dl)".
- p. 6 Figure 1A y-axis label
Mean Hemogloblin (g/dl)
Judge's note: Viewed crop C014-a and the full figure on extract/png/main-p006.png. The Panel A vertical axis reads "Mean Hemogloblin (g/dl)" with an extra "l", while the Panel B axis in the same figure reads "Mean Hemoglobin (g/dl)" correctly; the PDF text layer likewise contains both spellings on separate lines, so it is not an extraction artefact.
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Typo Figure 2 column header misspelled: "Prestudy Red-Cell Tranfusion Units per Year".
- p. 7 Figure 2 column header
Tranfusion
- p. 7 Figure 2, column header (left of the swim lanes)
Prestudy Red-Cell Tranfusion Units per Year
Judge's note: Viewed crop C015-b and the full figure on extract/png/main-p007.png: the third column header reads "Tranfusion" (missing s), while the key and legend of the same figure spell "transfusion" correctly ("Time without red-cell transfusions starting from the last transfusion", "The number of red-cell transfusion units received per year...").
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Typo Table 2 footnote † reads 'The relatedness of an adverse effect to reni-cel or busulfan', but the table and text otherwise say 'adverse event'.
- p. 9 Table 2 footnote †
The relatedness of an adverse effect to reni-cel or busulfan
Judge's note: The wording is visible in the p9 image of the Table 2 footnotes. The meaning is unchanged; this is a minor wording inconsistency.
Second check: none (judge only)