The DOI matches its Crossref record; 73 of the 74 references it cites were found in a registry or an index; 29 of the 37 sources its claims cite were checked for support.
A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells
Open accessAbstract
Translation of the CRISPR–Cas9 system to human therapeutics holds high promise. However, specificity remains a concern especially when modifying stem cell populations. We show that existing rationally engineered Cas9 high-fidelity variants have reduced on-target activity when using the therapeutically relevant ribonucleoprotein (RNP) delivery method. Therefore, we devised an unbiased bacterial screen to isolate variants that retain activity in the RNP format. Introduction of a single point mutation, p.R691A, in Cas9 (high-fidelity (HiFi) Cas9) retained the high on-target activity of Cas9 while reducing off-target editing. HiFi Cas9 induces robust AAV6-mediated gene targeting at five therapeutically relevant loci (HBB, IL2RG, CCR5, HEXB, and TRAC) in human CD34+ hematopoietic stem and progenitor cells (HSPCs) as well as primary T cells. We also show that HiFi Cas9 mediates high-level correction of the sickle cell disease (SCD)-causing p.E6V mutation in HSPCs derived from patients with SCD. We anticipate that HiFi Cas9 will have wide utility for both basic science and therapeutic genome-editing applications. A bacterial screen yields a Cas9 variant that retains high on-target activity when delivered in the RNP format. As proof of principle, this Cas9 variant enables high-level correction of the sickle cell disease mutation in patient-derived HSPCs.
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Claims the paper makes
12 Own result · 6 Partly supported · 4 Supported · 1 No full text of the sources · 1 Own method · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Repurposing bacterial “CRISPR” systems to facilitate RNA-guided cleavage of complementary DNA has revolutionized the field of gene editing in mammalian cells 1–4.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > INTRODUCTION
What the sources say
- Partly supportedcites [1] Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012). sourceExperimental — accuracy not yet measured
The paper’s Abstract reports RNA-guided Cas9 cleavage of complementary DNA, and its Conclusions propose the system’s potential for genome editing. It does not report editing in mammalian cells or state that this application had revolutionized the field; the reported cleavage experiments used DNA substrates in vitro. (LLM, conf=0.88)
- Supportedcites [2] Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013). source
The Abstract reports engineering prokaryotic CRISPR/Cas systems so that RNA-guided Cas9 cleaves genomic targets in human and mouse cells. It describes this as a new class of genome-engineering tools with wide applicability in mammalian cells; “revolutionized” is the citing authors’ characterization of that significance. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [3] Doudna, J. A. & Charpentier, E. Genome editing. The new frontier of genome engineering with CRISPR–Cas9. Science 346, 1258096 (2014). source
- Supportedcites [4] Hsu, P. D., Lander, E. S. & Zhang, F. Development and applications of CRISPR–Cas9 for genome engineering. Cell 157, 1262–1278 (2014). source
The Introduction identifies Cas9 as an RNA-guided nuclease derived from a microbial CRISPR system. “CRISPR-Cas9: From Yogurt to Genome Editing” reports that bacterial CRISPR systems were engineered to direct DNA cleavage and genome editing in mammalian cells, followed by rapid adoption. The paper thus supports the citing sentence’s broad characterization, though it does not use the word “revolutionized.” (LLM, conf=0.91)
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“If a homologous donor DNA template is provided during the DSB repair, the homologous recombination (HR) repair pathway can generate more precise changes to the target DNA, including single nucleotide changes to insertion of large gene cassettes8,9.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > INTRODUCTION
What the sources say
- Supportedcites [8] Porteus, M. H. Towards a new era in medicine: therapeutic genome editing. Genome Biol. 16, 286 (2015). source
The development of genome editing and the contemporary toolbox states that HR repair of a double-strand break using a provided donor can make precise changes ranging from a single base to a large gene cassette. Box 1 explains that the donor provides the homologous template used during repair. (LLM, conf=0.94)
- Supportedcites [9] Dever, D. P. & Porteus, M. H. The changing landscape of gene editing in hematopoietic stem cells: a step towards Cas9 clinical translation. Curr. Opin. Hematol. 24, 481–488 (2017). source
The section on genome-editing reagents states that HR repair of a double-strand break using an exogenous donor with homology arms can introduce specific DNA changes. It also says an rAAV6 donor can mediate precise nucleotide changes and insert gene cassettes up to 5.7 kb. No page number is provided in our copy. (LLM, conf=0.93)
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The GUIDE-seq procedure10 can be used to empirically identify real off-target sites in cells.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > RESULTS > Quantitative reduction in off-target editing using the HiFi mutant
What the sources say
- Supportedcites [10] Tsai, S. Q. et al. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR–Cas nucleases. Nat. Biotechnol. 33, 187–197 (2015). source
The Discussion describes GUIDE-Seq as an experimental method that identifies bona fide off-target sites genome-wide. It also states that GUIDE-Seq is performed on living cells, matching the claim that it can empirically identify actual off-target sites in cells. (LLM, conf=0.94)
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“RNP delivery results in an initially high level of the genome editing machinery followed by rapid decay, leading to a “fast on, fast off” strategy that results in highly efficient editing while minimizing OTEs13–19.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > INTRODUCTION
What the sources say
- Partly supportedcites [13] Gundry, M. C. et al. Highly efficient genome editing of murine and human hematopoietic progenitor cells by CRISPR/Cas9. Cell Reports 17, 1453–1461 (2016). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) describes RNP electroporation as a transient “hit-and-run” approach that enables efficient editing and reduces concerns about off-target cleavage. The paper does not establish the claimed initially high level followed by rapid decay of editing machinery, or demonstrate that this time course causes fewer off-target effects. (LLM, conf=0.85)
- Supportedcites [14] Gundry, M. C. et al. Technical considerations for the use of CRISPR/Cas9 in hematology research. Exp. Hematol. 54, 4–11 (2017). source
The ‘Cas9 and sgRNA reagents and delivery’ section says RNP delivery produces editing rates exceeding 85% in hematopoietic cells and may minimize off-target effects by delivering only a brief pulse of Cas9. The ‘CRISPR/Cas9 for gene disruption’ summary likewise says the RNP’s short half-life minimizes off-target cleavage. No page numbers are provided in our copy. (LLM, conf=0.91)
- Partly supportedcites [15] Dever, D. P. et al. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016). sourceExperimental — accuracy not yet measured
The Abstract reports efficient HBB editing in human HSPCs using Cas9 RNPs, and the Extended Data report greater on-target versus off-target specificity for RNP delivery than for an all-RNA system. Neither passage establishes an initially high level of editing machinery followed by rapid decay, or shows that this timing causes the improved specificity. (LLM, conf=0.86)
- Partly supportedcites [16] DeWitt, M. A. et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci. Transl. Med. 8, 360ra134 (2016). sourceExperimental — accuracy not yet measured
The Discussion reports efficient editing in human HSPCs with minimal genic off-target activity and notes that RNP delivery has been associated with reduced off-target effects. But our copy does not establish an initial high level followed by rapid decay, or show that such a pulse causes fewer off-target effects. The Results also report substantial activity at one intergenic off-target site, so the off-target finding needs that qualification. (LLM, conf=0.86)
- Supportedcites [17] Hultquist, J. F. et al. A Cas9 ribonucleoprotein platform for functional genetic studies of HIV–host interactions in primary human t cells. Cell Reports 17, 1438–1452 (2016). source
The Introduction (page unavailable) describes Cas9 RNP delivery as transient, says it enables high-efficiency editing, and identifies low rates of off-target editing as an advantage over traditional approaches. This supports the attributed brief-delivery, efficient-editing, low-off-target account. (LLM, conf=0.88)
- Partly supportedcites [18] Schumann, K. et al. Generation of knock-in primary human T cells using Cas9 ribonucleoproteins. Proc. Natl. Acad. Sci. USA 112, 10437–10442 (2015). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) describes fast editing, rapid Cas9 turnover and efficient editing in human T cells. The Results (page unavailable) found rare indels at two predicted off-target sites at rates comparable to controls. But the paper does not establish that RNP delivery minimizes off-target effects compared with other delivery methods; the Discussion says further testing is needed. (LLM, conf=0.86)
- Supportedcites [19] Kim, S., Kim, D., Cho, S. W., Kim, J. & Kim, J. S. Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Res. 24, 1012–1019 (2014). source
The Results sections on kinetics and off-target effects report that RNPs begin editing almost immediately, Cas9 is barely detectable after 24 hours, and editing remains highly efficient while off-target mutations are reduced relative to plasmid delivery. This supports the citing sentence’s “fast on, fast off” paraphrase. (LLM, conf=0.94)
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While cleavage at sites with perfect complementarity to the protospacer domain of the gRNA typically occurs with highest efficiency, cleavage at sites having one to several bases of mismatch with the gRNA can occur. These undesired cleavage events are called “off-target effects” (OTEs)10, and their existence should be minimized for therapeutic applications of genome editing technologies.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > INTRODUCTION
What the sources say
- Supportedcites [10] Tsai, S. Q. et al. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR–Cas nucleases. Nat. Biotechnol. 33, 187–197 (2015). source
The Abstract describes unintended cleavage at off-target sites with protospacer mismatches and says therapeutic use requires understanding off-target effects to minimize harmful outcomes. The Results section on off-target sequence characteristics likewise reports cleavage at sites with several guide–protospacer mismatches. The paper also identifies other kinds of off-target sites, so mismatched sites are an example rather than an exhaustive definition. (LLM, conf=0.91)
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“AAV6 homologous donor DNA templates are an efficient way to deliver donor templates for sensitive primary immune cells, including HSPCs and T-Cells15,35–40.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > RESULTS > The R691A HiFi Cas9 mutant delivered as RNP is highly active and specific in CD34+ HSPCs
What the sources say
- Partly supportedcites [15] Dever, D. P. et al. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016). sourceExperimental — accuracy not yet measured
The section “CRISPR/Cas9 targeted HBB gene editing in HSPCs” reports high HSPC transduction and stable GFP expression in an average of 29% of HSPCs after delivery of homologous ssAAV6 donors. The paper supports the HSPC part of the claim, but the passages found do not establish efficient donor delivery in T cells. (LLM, conf=0.88)
- Partly supportedcites [35] Wang, J. et al. Homology-driven genome editing in hematopoietic stem and progenitor cells using ZFN mRNA and AAV6 donors. Nat. Biotechnol. 33, 1256–1263 (2015). sourceExperimental — accuracy not yet measured
The Results section ('HDR-mediated editing in HSPCs by ZFN mRNA and AAV6 donors'; page unavailable) identifies AAV6 as an effective vehicle for delivering homologous donor templates to CD34+ HSPCs. The paper also reports T cells arising after edited HSPCs were transplanted, but does not establish efficient donor-template delivery directly into T cells. That extension is not supported by this source. (LLM, conf=0.88)
- Partly supportedcites [36] Wang, J. et al. Highly efficient homology-driven genome editing in human T cells by combining zinc-finger nuclease mRNA and AAV6 donor delivery. Nucleic Acids Res. 44, e30 (2016). sourceExperimental — accuracy not yet measured
The Results (page unavailable) state that AAV6 vectors effectively delivered homologous donor DNA templates to CD4+ and CD8+ T cells. The paper does not establish the same result for HSPCs, so the claim’s inclusion of that cell population is unsupported by this source. (LLM, conf=0.88)
- Partly supportedcites [37] De Ravin, S. S. et al. Targeted gene addition in human CD34+ hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat. Biotechnol. 34, 424–429 (2016). sourceExperimental — accuracy not yet measured
The Methods section (AAV6 Donor Construction and Virus Production; page unavailable) describes AAV donor constructs flanked by homology arms. The results report efficient targeted integration in primary human HSPCs using AAV6 donor delivery. Our copy does not report AAV6 donor delivery in T cells, so it supports the HSPC example but not the T-cell example. (LLM, conf=0.87)
- Supportedcites [38] Sather, B. D. et al. Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template. Sci. Transl. Med. 7, 307ra156 (2015). source
The Discussion (page unavailable) identifies AAV6 as the optimal serotype for primary T cells and CD34+ progenitors and says it was used successfully to deliver rAAV donors in these cells. It also discusses donors with homology arms and reports approximately 14% HDR in CD34+ cells, though this was less robust than in T cells. (LLM, conf=0.90)
- Partly supportedcites [39] Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017). sourceExperimental — accuracy not yet measured
The Methods (AAV and Gene targeting; page not provided) describe an AAV6 donor with homologous TRAC sequences delivered to primary T cells. A results passage indexed under Abstract (page not provided) reports more than 40% CAR knock-in, supporting efficiency in T cells. The paper does not demonstrate this approach in HSPCs, so that extension is unsupported by this source. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [40] Schiroli, G. et al. Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1. Sci. Transl. Med. 9, eaan0820 (2017). source
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recent studies have shown that disease-causing genetic errors can be corrected using CRISPR/Cas9 in long-term engrafting HSPCs that are preserved in downstream effector lineages15,16,24,25.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > INTRODUCTION
What the sources say
- Partly supportedcites [15] Dever, D. P. et al. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016). sourceExperimental — accuracy not yet measured
The “HBB gene correction in SCD HSPCs” section reports correction of the disease-causing E6V mutation in patient-derived HSPCs and expression of corrected β-globin in erythrocytes differentiated from them in vitro. The “HBB targeting in long-term repopulating HSCs” section reports edited cells in downstream lineages and secondary transplant recipients, but those experiments tracked HBB targeting with reporter donors, not correction of the disease-causing mutation. The paper therefore does not show that mutation-corrected cells themselves persisted through long-term engraftment into downstream lineages. (LLM, conf=0.90)
- Partly supportedcites [16] DeWitt, M. A. et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci. Transl. Med. 8, 360ra134 (2016). sourceExperimental — accuracy not yet measured
The Results sections report CRISPR/Cas9 correction of the sickle mutation in patient HSPCs and, separately, durable editing after HSPC engraftment in mice. But the engraftment experiment edited wild-type HSPCs to carry the sickle mutation, rather than testing corrected patient HSPCs in vivo. The paper therefore does not show that correction of a disease-causing mutation persisted in downstream lineages after long-term engraftment. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [24] De Ravin, S. S. et al. CRISPR–Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease. Sci. Transl. Med. 9, eaah3480 (2017). source
- Partly supportedcites [25] Traxler, E. A. et al. A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med. 22, 987–990 (2016). sourceExperimental — accuracy not yet measured
The main text (page unavailable) reports CRISPR/Cas9 editing of CD34+ HSPCs and increased fetal hemoglobin in their cultured erythroid progeny. It does not show correction of the disease-causing mutation or long-term engraftment; the Methods describe in-vitro differentiation rather than a transplantation study. (LLM, conf=0.88)
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Accordingly, several reports have shown efficient Glu6Val correction in SCD-HSPCs, although correction efficiency can sometimes be linked with off-target INDELs in the same edited population15,16,45,46.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > RESULTS > The R691A HiFi Cas9 delivered as RNP mediates high-level Glu6Val correction while reducing off-target activity in sickle cell disease-CD34+ HSPCs
What the sources say
- Partly supportedcites [15] Dever, D. P. et al. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016). sourceExperimental — accuracy not yet measured
The ‘HBB gene correction in SCD HSPCs’ section reports correction of an average of 50% of E6V alleles in patient-derived HSPCs, so this paper supports the efficient-correction part as one of the cited reports. The Extended Data describe off-target INDEL measurements in CD34+ HSPCs, but do not link those INDELs to correction in the same SCD-HSPC population; the INDELs reported alongside SCD correction were measured at the on-target HBB locus. No page numbers are available in our copy. (LLM, conf=0.85)
- Partly supportedcites [16] DeWitt, M. A. et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci. Transl. Med. 8, 360ra134 (2016). sourceExperimental — accuracy not yet measured
The Results section on correcting SCD HSPCs reports up to 25% of alleles corrected to wild type. A separate Results section on editing CD34+ HSPCs reports off-target indels, including 44% at an intergenic site, but does not establish that those indels occurred in the same SCD-HSPC population whose mutation was corrected. The paper therefore supports efficient correction and an off-target concern, but not that specific linkage. (LLM, conf=0.83)
- Partly supportedcites [45] Hoban, M. D. et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood 125, 2597–2604 (2015). sourceExperimental — accuracy not yet measured
The Gene correction in sickle BM section reports correction of the sickle mutation in patient-derived HSPCs. The Comprehensive ZFN specificity assessment reports off-target modification at the δ-globin gene in SCD bone-marrow CD34+ cells, but the passages do not establish that those off-target modifications were specifically INDELs; the indels shown alongside correction in Figure 5 are at the target β-globin cut site. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [46] Hoban, M. D. et al. CRISPR/Cas9-mediated correction of the sickle mutation in human CD34+ cells. Mol. Ther. 24, 1561–1569 (2016). source
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The lesion can be healed by the error-prone Non-Homologous End-Joining (NHEJ) pathway, which often results in creation of an insertion/deletion (INDEL) of one to several bases7.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > INTRODUCTION
What the sources say
- Partly supportedcites [7] Kass, E. M. & Jasin, M. Collaboration and competition between DNA double-strand break repair pathways. FEBS Lett. 584, 3703–3708 (2010). sourceExperimental — accuracy not yet measured
Section 4, “Repair by non-homologous end joining” (page not provided), says that processing DNA ends during NHEJ can produce insertions and deletions, making it more error-prone than homologous recombination. It does not establish that INDELs occur often or that they are typically one to several bases long. (LLM, conf=0.87)
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Cas9/gRNA is directed to search for NGG protospacer adjacent motifs (PAMs) in the genome and if sufficient complementarity exists between the guide and the target, conformational changes occur and the now fully active Cas9 cleaves the DNA, resulting in a targeted double-stranded break (DSB)5,6.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > INTRODUCTION
What the sources say
- Supportedcites [5] Dagdas, Y. S. et al. A conformational checkpoint between DNA binding and cleavage by CRISPR–Cas9. Sci. Adv. 3, eaao0027 (2017). source
The Introduction states that S. pyogenes Cas9 target recognition requires an NGG PAM and guide-RNA base pairing, and that its nuclease domains cleave both DNA strands. The Results (Fig. 4G) describe a conformational checkpoint: sufficient RNA–DNA complementarity permits the HNH domain to enter its catalytically active conformation before cleavage. (LLM, conf=0.92)
- Supportedcites [6] Sternberg, S. H., LaFrance, B., Kaplan, M. & Doudna, J. A. Conformational control of DNA target cleavage by CRISPR–Cas9. Nature 527, 110–113 (2015). source
The paper’s discussion of its model says Cas9 identifies potential targets through PAM binding and guide–DNA complementarity, then undergoes an HNH conformational change that enables coordinated cleavage of both DNA strands. Extended Data Table 2 identifies the PAM as 5′-NGG-3′. (LLM, conf=0.92)
- Supported
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It worth mentioning that in several previous reports, LZ3 Cas9, Sniper Cas9, and HiFi Cas9 had comparable editing activity to the SpCas9-WT in human cells or other animal embryos.”
From Machine learning-based prediction models to guide the selection of Cas9 variants for efficient gene editing (2024) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“To further increase on-target efficiency and minimize off-target editing, S.p. HiFi Cas9 Nuclease was used77.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [77]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Compared to SpCas9, HiFi Cas9 shows similar editing efficiency but lower off-target effects in some genome sites.”
From Machine learning-based prediction models to guide the selection of Cas9 variants for efficient gene editing (2024) · cites this paper as [17]
In the citing paper
“The Cas9 nuclease is directed by a single-guide RNA (sgRNA) to modify a specific chromosomal DNA sequence by inducing a sequence-specific double-strand break (DSB) (3, 4).”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [4]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > RESULTS > The R691A high fidelity (HiFi) Cas9 mutant demonstrates superior on-target editing with RNP delivery
“HypaCas9 (R692A/M694A/Q695A/H698A)28”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > DISCUSSION
“HypaCas9, which included 4 mutations (N692A/M694A/Q695A/H698A) in the REC3 domain.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > RESULTS > The R691A high fidelity (HiFi) Cas9 mutant demonstrates superior on-target editing with RNP delivery
“HypaCas9 (R692A/M694A/Q695A/H698A)28.”
§ A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells > DISCUSSION
“HypaCas9, which included 4 mutations (N692A/M694A/Q695A/H698A) in the REC3 domain.”
Citations
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Spy-ing on nucleic acids: Atomic resolution of the S. pyogenes CRISPR-Cas9 surveillance state
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CRISPR-Cas9 and beyond: Expanding the Frontiers of Gene Editing
Pang, S., & Qu, J. (2025) · Advances in Bioscience and Biotechnology · doi:10.4236/abb.2025.165012
Development of new increased fidelity SpCas9 variants
Kulcsár, P. I. (2019) · SZTE Repository of Dissertations (University of Szeged) · doi:10.14232/phd.10317
Genetic Engineering Methods in Primary T Cells
Youssef, A., & Li, H.-S. (2025) · Advanced Therapeutics · doi:10.1002/adtp.202500149
Sen, P., Ansari, R., Chatterjee, A., Mondal, B., Sengupta, S., Ghorai, S., Bose, S., & Hazra, S. (2025) · Journal of Crop Science and Biotechnology · doi:10.1007/s12892-025-00301-7
New therapeutic options for the treatment of transfusion-dependent Diamond-Blackfan anemia
Bataev, A., Klyukhin, V. V., & Smetanina, N. S. (2025) · Pediatric Hematology/Oncology and Immunopathology · doi:10.24287/1726-1708-2025-24-2-140-146
Congenital dyserythropoietic anemias
Klyukhin, V. V., & Smetanina, N. S. (2025) · Pediatric Hematology/Oncology and Immunopathology · doi:10.24287/1726-1708-2025-24-2-130-139
Assessing Temperature-Dependent DNA Cleavage by CRISPR-Cas9
Knight, A. L., Luo, J., & Lisi, G. P. (2025) · BIO-PROTOCOL · doi:10.21769/bioprotoc.5463
Dua, P. H., Simon, B. M. J., Marley, C. B. E., Feliciano, C. M., Watry, H. L., Cowan, Q. T., Steury, D., Abraham, A., Gilbertson, E. N., Ramey, G. D., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.11.026 · Cited by 2
“17, 22, Our established allele-specific editing strategy used a single muta-tion-specific gRNA and high-fidelity Cas9 derived from Streptococcus pyogenes (HiFiCas9) 39 that allowed for the introduction of frameshift indels in the coding region of the mutant NEFL allele.”
Priyanka, S. S., Iqbal, G., Nidarshan, N. C., Kumari, K., Vanjre, S., Rasal, K. D., Sonwane, A., Brahmane, M. P., & Goswami, M. (2025) · Transgenic Research · doi:10.1007/s11248-025-00473-6
“Recent developments, such as high-fidelity Cas9 variants (e.g., HiFi Cas9, eSpCas9, and SpCas9-HF1), have demonstrated comparable on-target editing efficiencies to the original Cas9 enzyme while substantially reducing off-target activity (Vakulskas et al. 2018).”
Search-and-remove genome editing allows selection of cells by DNA sequence
Fast, L., Omar, M., Kanis, P., Schaffer, T., Chowdhury, D. T., Rakava, E., Pääbo, S., & Riesenberg, S. (2025) · Nature Communications · doi:10.1038/s41467-025-66896-1 · Cited by 1
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A guide RNA repeat checkpoint steers CRISPR-Cas9 catalysisPreprint
Chilamkurthy, R., Sudhakar, S., Pater, A. A., Bosmeny, M. S., Stabile, F., Katolik, A., Harikrishna, S., Turk, R., Damha, M. J., Leslie, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.02.691602
Self-citationGene-Editing-Based Approaches for Curing Sickle Cell Disease
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Self-citationThiamine Metabolism in Microbes and Strategies for Biomanufacturing
Zhang, Y., Liu, L., Hao, S., & Zhang, D. (2026) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c12462 · Cited by 1
TFU72 is a novel and potent DNA-PKcs inhibitor for enhancing homology-directed repair gene editingPreprint
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Self-citationHow Genomic and Structural Context Could Shape JAK-STAT Variant Pathogenicity
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“…et al., 2024; Du et al., 2023; Guo et al., 2019; Hibshman et al., 2024; Hou et al., 2013; Ikeda et al., 2019; H. K. Kim et al., 2020; Liang et al., 2022; Müller et al., 2016; Schmidheini et al., 2024; Slaymaker et al., 2016; Vakulskas et al., 2018; Wu et al., 2020; Yifei Zhang et al., 2020).”
Génotoxicité des systèmes CRISPR-Cas9.
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Study of bacterial conjugation from a practical and fundamental perspective
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Ex vivo gene therapy for β-hemoglobinpathies and metabolic disorders
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CRISPR-Cas9-based strategies for enhanced targeted integration
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“HiFi Cas9 protein was expressed in Rosetta™(DE3)pLysS Competent Cells (Novagen) and purified following established protocols ( 40 ).”
The genome takes the wheel: CAR T with built-in circuits
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“23 Encouragingly, early clinical studies evaluating CRISPR-engineered T cells, including those involving multiplex editing of up to three loci, have consistently reported low frequencies of off-target and chromosomal translocation events (NCT04557436, NCT03399448, and NCT03545815), 24 — 26…”
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Decoding the role of chromatin context in the off-target effects of CRISPR gene editing with EGOLD
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Site-specific DNA double-strand break induces local transcription in cis and protein expression
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CRISPR application in hematological disorders: from bench to bedside
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“High-fidelity SpCas9 variants, exemplified by SpCas9-HF1 (N497A/ R661A/Q695A/Q926A) 61-64 and later by Sniper2L, 65 substantially reduce off-target editing while largely preserving on-target activity, but generally do not expand the PAM repertoire.”
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Reading between the bases: technological advances in RNA modification detection
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Engineered targeted enhancement of translation in mammalian cell
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“Direct delivery approaches often result in non-physiological protein overexpression, lack endogenous regulatory control, and may trigger immune responses due to foreign nucleic acids or excessive protein levels [65, 66].”
Pancreatic organoids and organoid-on-a-chip platforms: from disease modeling to precision therapy
Lin, M., Ma, W., Ma, T., He, Y., Shi, H., Ge, N., Guo, J., Xie, Y., Sun, S., & Yang, F. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08489-0
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Mushtaq, M. W., Bhat, R. A. H., Rather, M. A., Khan, I. A., & Bhat, I. A. (2026) · Ecological Genetics and Genomics · doi:10.1016/j.egg.2026.100498
Mundada, A. R., Badikol, A. R., & Mangu, K. (2026) · Neurogenetics · doi:10.1007/s10048-026-00921-3 · Cited by 1
“These proteins have been shown to decrease off-target cleavage in neurons while maintaining efficient editing at disease-relevant loci [119].”
Genome editing for aquaculture breeding: established applications and emerging directions
Wu, Y. N., Yang, L., Zhang, Y., Wu, M., Huang, S., Guo, X., Wang, D., Xu, J., & Zhou, L. J. (2026) · Water Biology and Security · doi:10.1016/j.watbs.2026.100683
Zaman, W., & Ayaz, A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27146467
“Off-target activity is closely linked to dose and exposure duration [101].”
AI identifies interactions in CRISPR complexes to improve specificity of DNA editing
Chu, H. Y., & Wong, A. S. L. (2026) · Nature · doi:10.1038/d41586-026-02042-1
Chesneau, A., Haccard, O., Benchetrit, A., Affaticati, P., Levraud, J., & Perron, M. (2026) · Scientific Reports · doi:10.1038/s41598-026-60601-y
Strategies for Packaging Macromolecules onto or into Virus-Like Particles
Hussain, T. A., Xie, M. S., Pérez-Segura, C., et al. (2026) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6c00172
Evaluating high-fidelity CRISPR-Cas nucleases in nucleosomal contexts using a quantitative framework
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“…in the field, with numerous variants being designed to enhance specificity while maintaining on-target activity for SpCas9 (Casini et al., 2018; Vakulskas et al., 2018; Slaymaker et al., 2016; Nathaniel Hunter Roberts and Anthony Vakulskas, 2023) and Cas12a (Zetsche et al., 2015; Kim et al.,…”
CRISPR RNA architecture steers Cas9 catalysis and fidelity via a guide repeat clasp motif
Chilamkurthy, R., Sudhakar, S., Pater, A. A., Bosmeny, M. S., Stabile, F., Katolik, A., Harikrishna, S., Elazzouzi, F., Turk, R., Damha, M. J., et al. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag710
“Editing events were quantified using the rhAmpSeq sys-tem (IDT), Illumina sequencing, and counting of reads with indels, as described previously [ 33 , 54 ].”
InfluentialSelf-citationUnlocking the curative potential of gene transfer and editing for hematopoietic disorders
Shiroshita, K., Stolz, A., Malouf, C., Tran, V. L., Li, J., Weiss, M. J., & Naldini, L. (2026) · Experimental Hematology · doi:10.1016/j.exphem.2026.105493 · Cited by 1
Rezaee, M., Izadi, F., Nobaharian, S., Hassani, L., Rezaei, E., Amini, S. S., Pourfathollah, A. A., Kowsari, A., Naeimi, S., Varnamkhasti, K. K., et al. (2026) · Beni-Suef University Journal of Basic and Applied Sciences · doi:10.1186/s43088-026-00824-0
“Electroporation (Table 1: >96% in HSPCs [26]) and AAV6 (Table 3: >90% [25]; 50% [64]) are the leading platforms.”
SLC25A38 gene modification mediated by CRISPR/Cas9 in HEK293T cell line
Yazdanparast, S., Galehdari, H., Khatami, S. R., & Hoveizi, E. (2026) · Journal of Applied Genetics · doi:10.1007/s13353-026-01108-0
Roman, G., Lauritzen, K. H., Smolkova, B., Almaas, R., Sandset, P. M., Stavik, B., Sullivan, G. J., & Chollet, M. E. (2026) · Stem Cell Reviews and Reports · doi:10.1007/s12015-026-11221-6
Retinal Degeneration and Regeneration in Xenopus laevis Tadpoles
Lun, J., Chesneau, A., Borday, C., et al. (2026) · Methods in molecular biology · doi:10.1007/978-1-0716-5360-9_21
Recent Advances in CRISPR/Cas Technologies for Biological Discovery, Therapeutics, and Diagnostics
Kim, M., Do, H. S., Jang, H. Y., Lee, K. E., & Lee, S. J. (2026) · Biomolecules · doi:10.3390/biom16091268
“However, increased fidelity can be accompanied by reduced editing activity at some target sites [41,42], highlighting the need to balance specificity and efficiency.”
Iqbal, U., Khalid, K., Shaltout, M., Yükselten, Y., & Sutton, R. E. (2026) · Viruses · doi:10.3390/v18090972
High‐Content CRISPR Screening: Methods and Applications
Zhang, Y., Zhang, Y., Tang, X., Deng, X., Zhou, Y., Wu, Y., & Luo, J. (2026) · MedComm · doi:10.1002/mco2.70964
Nucleofection-Based CRISPR/Cas Delivery in Human T Cells for Immunotherapy Applications
Ortiz-Bueno, M., Millán-López, A., Labun, K., & Benabdellah, K. (2026) · Methods in molecular biology · doi:10.1007/978-1-0716-5547-4_20
Mohiuddin, M., & Ahsan, M. A. M. (2026) · Health Science Reports · doi:10.1002/hsr2.73308
“The delivery of ri-bonucleoproteins (RNPs) enables rapid genome modification and promotes their degradation soon after cellular delivery [96, 97].”
Reshaping the scissors: From directed evolution to AI-driven design for enhanced Cas performance
Cheng, X., 阮, 卫., Jin, Z., Suo, L., Ma, Y., Jiang, L., Zheng, W., Li, N., & Hu, W. (2026) · BioDesign Research · doi:10.1016/j.bidere.2026.100124
PTPN22 as a novel therapeutic target: a key intracellular checkpoint for NK cell therapy
Uong, T. N. T., Yoon, M. S., Nguyen, N. P. N. M., Lee, M., Koh, S. K., Jeong, J., Kim, Y.-H., & Cho, D. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2026-016896
Outcomes and challenges of stem cell transplantation in patients with ribosomopathies
Pierri, F., & Dufour, C. (2026) · Seminars in Hematology · doi:10.1053/j.seminhematol.2026.09.009
Metadata
- Authors
- Vakulskas, C. A., Dever, D. P., Rettig, G. R., Turk, R., Jacobi, A. M., Collingwood, M. A., Bode, N. M., McNeill, M. S., Yan, S., Camarena, J., Lee, C. M., Park, S. H., Wiebking, V., Bak, R. O., Gomez-Ospina, N., Pavel-Dinu, M., Sun, W., Bao, G., Porteus, M. H., & Behlke, M. A.
- Affiliations
- Integrated DNA Technologies (United States) (US)
- Stanford Medicine (US)
- Rice University (US)
- Aarhus University (DK)
- Corresponding author
- Porteus, Matthew H.
- Behlke, Mark A.
- ORCID
- Vakulskas, Christopher A.
- Dever, Daniel P.
- Rettig, Garrett R.
- Turk, Rolf
- Jacobi, Ashley M.
- Collingwood, Michael A.
- Bode, Nicole M.
- McNeill, Matthew S.
- Yan, Shuqi
- Camarena, Joab
- Lee, Ciaran M.
- Wiebking, Volker
- Bak, Rasmus O.
- Gomez-Ospina, Natalia
- Pavel-Dinu, Mara
- Sun, Wenchao
- Bao, Gang
- Porteus, Matthew H.
- Behlke, Mark A.
- Venue
- Nature Medicine
- Published
- 2018-08
- Volume
- 24
- Issue
- 8
- Pages
- 1216-1224
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6107069
- OpenAlex
- W2886819502
- Cited by
- 782
- References
- 74
- Citations by year
- 2026: 66 · 2025: 92 · 2024: 91 · 2023: 86 · 2022: 116 · 2021: 113 · 2020: 116 · 2019: 92 · 2018: 9
- FWCI
- 29.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Amon G. Carter Foundation
- Lundbeckfonden (R238‐2016‐3349)
- National Institutes of Health (5r01ai120766-02, R01-AI120766, AI120766)
- National Institute of Allergy and Infectious Diseases (R01-AI120766, R01AI097320)
- Topics
- 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
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- ribonucleoprotein delivery, CRISPR/Cas9 genome editing, hematopoietic stem and progenitor cells, sickle cell disease, off-target editing, HBB, IL2RG, CCR5, HEXB, TRAC, T cells
- MeSH terms
- Gene Editing, CRISPR-Associated Protein 9, Anemia, Sickle Cell, Base Sequence, Escherichia coli, Hematopoietic Stem Cells, Humans, Mutation, Ribonucleoproteins, Antigens, CD34, HEK293 Cells
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