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Artikel ; Online: Author Correction: Mapping the genomic landscape of CRISPR-Cas9 cleavage.

2023 Band 20, Heft 12, Seite(n) 2068

Sprache	Englisch
Erscheinungsdatum	2023-11-09
Erscheinungsland	United States
Dokumenttyp	Published Erratum
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/s41592-023-02114-4
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Allogeneic chimeric antigen receptor-T cells with CRISPR-disrupted programmed death-1 checkpoint exhibit enhanced functional fitness.

Cytotherapy

2023 Band 25, Heft 7, Seite(n) 750–762

Abstract: Background aims: Therapeutic disruption of immune checkpoints has significantly advanced the armamentarium of approaches for treating cancer. The prominent role of the programmed death-1 (PD-1)/programmed death ligand-1 axis for downregulating T cell ... ...

Abstract	Background aims: Therapeutic disruption of immune checkpoints has significantly advanced the armamentarium of approaches for treating cancer. The prominent role of the programmed death-1 (PD-1)/programmed death ligand-1 axis for downregulating T cell function offers a tractable strategy for enhancing the disease-modifying impact of CAR-T cell therapy. Methods: To address checkpoint interference, primary human T cells were genome edited with a next-generation CRISPR-based platform (Cas9 chRDNA) by knockout of the PDCD1 gene encoding the PD-1 receptor. Site-specific insertion of a chimeric antigen receptor specific for CD19 into the T cell receptor alpha constant locus was implemented to drive cytotoxic activity. Results: These allogeneic CAR-T cells (CB-010) promoted longer survival of mice in a well-established orthotopic tumor xenograft model of a B cell malignancy compared with identically engineered CAR-T cells without a PDCD1 knockout. The persistence kinetics of CB-010 cells in hematologic tissues versus CAR-T cells without PDCD1 disruption were similar, suggesting the robust initial debulking of established tumor xenografts was due to enhanced functional fitness. By single-cell RNA-Seq analyses, CB-010 cells, when compared with identically engineered CAR-T cells without a PDCD1 knockout, exhibited fewer T Conclusions: Genomic PD-1 checkpoint disruption in the context of allogeneic CAR-T cell therapy may provide a compelling option for treating B lymphoid malignancies.
Mesh-Begriff(e)	Humans ; Animals ; Mice ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Receptors, Antigen, T-Cell ; Programmed Cell Death 1 Receptor/metabolism ; Cell Line, Tumor ; T-Lymphocytes ; Immunotherapy, Adoptive ; Hematopoietic Stem Cell Transplantation
Chemische Substanzen	Receptors, Chimeric Antigen ; Receptors, Antigen, T-Cell ; Programmed Cell Death 1 Receptor
Sprache	Englisch
Erscheinungsdatum	2023-04-21
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2039821-9
ISSN	1477-2566 ; 1465-3249
ISSN (online)	1477-2566
ISSN	1465-3249
DOI	10.1016/j.jcyt.2023.03.011
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Generation of a Commercial-Scale Founder Population of Porcine Reproductive and Respiratory Syndrome Virus Resistant Pigs Using CRISPR-Cas.

Burger, Brian T / Beaton, Benjamin P / Campbell, Matthew A / Brett, Benjamin T / Rohrer, Melissa S / Plummer, Sarah / Barnes, Dylan / Jiang, Ke / Naswa, Sudhir / Lange, Jeremy / Ott, Alina / Alger, Elizabeth / Rincon, Gonzalo / Rounsley, Steven / Betthauser, Jeff / Mtango, Namdori R / Benne, Joshua A / Hammerand, Jessica / Durfee, Codie J /

Rotolo, Marisa L / Cameron, Peter / Lied, Alexandra M / Irby, Matthew J / Nyer, David B / Fuller, Chris K / Gradia, Scott / Kanner, Steven B / Park, Ki-Eun / Waters, Jerel / Simpson, Sean / Telugu, Bhanu P / Salgado, Brianna C / Brandariz-Nuñez, Alberto / Rowland, Raymond R R / Culbertson, Matt / Rice, Elena / Cigan, A Mark

The CRISPR journal

2024 Band 7, Heft 1, Seite(n) 12–28

Abstract: Disease resistance genes in livestock provide health benefits to animals and opportunities for farmers to meet the growing demand for affordable, high-quality protein. Previously, researchers used gene editing to modify the porcine CD163 gene and ... ...

Abstract	Disease resistance genes in livestock provide health benefits to animals and opportunities for farmers to meet the growing demand for affordable, high-quality protein. Previously, researchers used gene editing to modify the porcine CD163 gene and demonstrated resistance to a harmful virus that causes porcine reproductive and respiratory syndrome (PRRS). To maximize potential benefits, this disease resistance trait needs to be present in commercially relevant breeding populations for multiplication and distribution of pigs. Toward this goal, a first-of-its-kind, scaled gene editing program was established to introduce a single modified CD163 allele into four genetically diverse, elite porcine lines. This effort produced healthy pigs that resisted PRRS virus infection as determined by macrophage and animal challenges. This founder population will be used for additional disease and trait testing, multiplication, and commercial distribution upon regulatory approval. Applying CRISPR-Cas to eliminate a viral disease represents a major step toward improving animal health.
Mesh-Begriff(e)	Animals ; Swine ; Porcine respiratory and reproductive syndrome virus/genetics ; Porcine Reproductive and Respiratory Syndrome/genetics ; CRISPR-Cas Systems/genetics ; Disease Resistance/genetics ; Gene Editing ; Livestock
Sprache	Englisch
Erscheinungsdatum	2024-01-30
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	3017891-5
ISSN	2573-1602 ; 2573-1599
ISSN (online)	2573-1602
ISSN	2573-1599
DOI	10.1089/crispr.2023.0061
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Microfluidic affinity and ChIP-seq analyses converge on a conserved FOXP2-binding motif in chimp and human, which enables the detection of evolutionarily novel targets.

Nelson, Christopher S / Fuller, Chris K / Fordyce, Polly M / Greninger, Alexander L / Li, Hao / DeRisi, Joseph L

Nucleic acids research

2013 Band 41, Heft 12, Seite(n) 5991–6004

Abstract: The transcription factor forkhead box P2 (FOXP2) is believed to be important in the evolution of human speech. A mutation in its DNA-binding domain causes severe speech impairment. Humans have acquired two coding changes relative to the conserved ... ...

Abstract	The transcription factor forkhead box P2 (FOXP2) is believed to be important in the evolution of human speech. A mutation in its DNA-binding domain causes severe speech impairment. Humans have acquired two coding changes relative to the conserved mammalian sequence. Despite intense interest in FOXP2, it has remained an open question whether the human protein's DNA-binding specificity and chromatin localization are conserved. Previous in vitro and ChIP-chip studies have provided conflicting consensus sequences for the FOXP2-binding site. Using MITOMI 2.0 microfluidic affinity assays, we describe the binding site of FOXP2 and its affinity profile in base-specific detail for all substitutions of the strongest binding site. We find that human and chimp FOXP2 have similar binding sites that are distinct from previously suggested consensus binding sites. Additionally, through analysis of FOXP2 ChIP-seq data from cultured neurons, we find strong overrepresentation of a motif that matches our in vitro results and identifies a set of genes with FOXP2 binding sites. The FOXP2-binding sites tend to be conserved, yet we identified 38 instances of evolutionarily novel sites in humans. Combined, these data present a comprehensive portrait of FOXP2's-binding properties and imply that although its sequence specificity has been conserved, some of its genomic binding sites are newly evolved.
Mesh-Begriff(e)	Animals ; Base Sequence ; Binding Sites ; Cell Line ; Chromatin Immunoprecipitation ; Conserved Sequence ; DNA/chemistry ; DNA/metabolism ; Evolution, Molecular ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Humans ; Microfluidic Analytical Techniques ; Mutation ; Nucleotide Motifs ; Pan troglodytes/genetics ; Sequence Analysis, DNA
Chemische Substanzen	FOXP2 protein, human ; Forkhead Transcription Factors ; DNA (9007-49-2)
Sprache	Englisch
Erscheinungsdatum	2013-04-26
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkt259
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Sherlock: detecting gene-disease associations by matching patterns of expression QTL and GWAS.

He, Xin / Fuller, Chris K / Song, Yi / Meng, Qingying / Zhang, Bin / Yang, Xia / Li, Hao

American journal of human genetics

2013 Band 92, Heft 5, Seite(n) 667–680

Abstract: Genetic mapping of complex diseases to date depends on variations inside or close to the genes that perturb their activities. A strong body of evidence suggests that changes in gene expression play a key role in complex diseases and that numerous loci ... ...

Abstract	Genetic mapping of complex diseases to date depends on variations inside or close to the genes that perturb their activities. A strong body of evidence suggests that changes in gene expression play a key role in complex diseases and that numerous loci perturb gene expression in trans. The information in trans variants, however, has largely been ignored in the current analysis paradigm. Here we present a statistical framework for genetic mapping by utilizing collective information in both cis and trans variants. We reason that for a disease-associated gene, any genetic variation that perturbs its expression is also likely to influence the disease risk. Thus, the expression quantitative trait loci (eQTL) of the gene, which constitute a unique "genetic signature," should overlap significantly with the set of loci associated with the disease. We translate this idea into a computational algorithm (named Sherlock) to search for gene-disease associations from GWASs, taking advantage of independent eQTL data. Application of this strategy to Crohn disease and type 2 diabetes predicts a number of genes with possible disease roles, including several predictions supported by solid experimental evidence. Importantly, predicted genes are often implicated by multiple trans eQTL with moderate associations. These genes are far from any GWAS association signals and thus cannot be identified from the GWAS alone. Our approach allows analysis of association data from a new perspective and is applicable to any complex phenotype. It is readily generalizable to molecular traits other than gene expression, such as metabolites, noncoding RNAs, and epigenetic modifications.
Mesh-Begriff(e)	Algorithms ; Crohn Disease/genetics ; Diabetes Mellitus, Type 2/genetics ; Genetic Diseases, Inborn/genetics ; Genome-Wide Association Study/methods ; Humans ; Models, Genetic ; Quantitative Trait Loci/genetics ; Software
Sprache	Englisch
Erscheinungsdatum	2013-04-29
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2013.03.022
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: NmeCas9 is an intrinsically high-fidelity genome-editing platform

Amrani, Nadia / Gao, Xin D / Liu, Pengpeng / Edraki, Alireza / Mir, Aamir / Ibraheim, Raed / Gupta, Ankit / Sasaki, Kanae E / Wu, Tong / Donohoue, Paul D / Settle, Alexander H / Lied, Alexandra M / McGovern, Kyle / Fuller, Chris K / Cameron, Peter / Fazzio, Thomas G / Zhu, Lihua Julie / Wolfe, Scot A / Sontheimer, Erik J

Genome biology. 2018 Dec., v. 19, no. 1

2018

Abstract: BACKGROUND: The development of CRISPR genome editing has transformed biomedical research. Most applications reported thus far rely upon the Cas9 protein from Streptococcus pyogenes SF370 (SpyCas9). With many RNA guides, wildtype SpyCas9 can induce ... ...

Abstract	BACKGROUND: The development of CRISPR genome editing has transformed biomedical research. Most applications reported thus far rely upon the Cas9 protein from Streptococcus pyogenes SF370 (SpyCas9). With many RNA guides, wildtype SpyCas9 can induce significant levels of unintended mutations at near-cognate sites, necessitating substantial efforts toward the development of strategies to minimize off-target activity. Although the genome-editing potential of thousands of other Cas9 orthologs remains largely untapped, it is not known how many will require similarly extensive engineering to achieve single-site accuracy within large genomes. In addition to its off-targeting propensity, SpyCas9 is encoded by a relatively large open reading frame, limiting its utility in applications that require size-restricted delivery strategies such as adeno-associated virus vectors. In contrast, some genome-editing-validated Cas9 orthologs are considerably smaller and therefore better suited for viral delivery. RESULTS: Here we show that wildtype NmeCas9, when programmed with guide sequences of the natural length of 24 nucleotides, exhibits a nearly complete absence of unintended editing in human cells, even when targeting sites that are prone to off-target activity with wildtype SpyCas9. We also validate at least six variant protospacer adjacent motifs (PAMs), in addition to the preferred consensus PAM (5′-N4GATT-3′), for NmeCas9 genome editing in human cells. CONCLUSIONS: Our results show that NmeCas9 is a naturally high-fidelity genome-editing enzyme and suggest that additional Cas9 orthologs may prove to exhibit similarly high accuracy, even without extensive engineering.
Schlagwörter	Dependoparvovirus ; RNA ; Streptococcus pyogenes ; biomedical research ; engineering ; gene editing ; genome ; humans ; mutation ; nucleotides ; open reading frames
Sprache	Englisch
Erscheinungsverlauf	2018-12
Umfang	p. 214.
Erscheinungsort	BioMed Central
Dokumenttyp	Artikel
ZDB-ID	2040529-7
ISSN	1474-760X ; 1465-6906
ISSN (online)	1474-760X
ISSN	1465-6906
DOI	10.1186/s13059-018-1591-1
Datenquelle	NAL Katalog (AGRICOLA)

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Artikel ; Online: NmeCas9 is an intrinsically high-fidelity genome-editing platform.

Genome biology

2018 Band 19, Heft 1, Seite(n) 214

Abstract: Background: The development of CRISPR genome editing has transformed biomedical research. Most applications reported thus far rely upon the Cas9 protein from Streptococcus pyogenes SF370 (SpyCas9). With many RNA guides, wildtype SpyCas9 can induce ... ...

Abstract	Background: The development of CRISPR genome editing has transformed biomedical research. Most applications reported thus far rely upon the Cas9 protein from Streptococcus pyogenes SF370 (SpyCas9). With many RNA guides, wildtype SpyCas9 can induce significant levels of unintended mutations at near-cognate sites, necessitating substantial efforts toward the development of strategies to minimize off-target activity. Although the genome-editing potential of thousands of other Cas9 orthologs remains largely untapped, it is not known how many will require similarly extensive engineering to achieve single-site accuracy within large genomes. In addition to its off-targeting propensity, SpyCas9 is encoded by a relatively large open reading frame, limiting its utility in applications that require size-restricted delivery strategies such as adeno-associated virus vectors. In contrast, some genome-editing-validated Cas9 orthologs are considerably smaller and therefore better suited for viral delivery. Results: Here we show that wildtype NmeCas9, when programmed with guide sequences of the natural length of 24 nucleotides, exhibits a nearly complete absence of unintended editing in human cells, even when targeting sites that are prone to off-target activity with wildtype SpyCas9. We also validate at least six variant protospacer adjacent motifs (PAMs), in addition to the preferred consensus PAM (5'-N Conclusions: Our results show that NmeCas9 is a naturally high-fidelity genome-editing enzyme and suggest that additional Cas9 orthologs may prove to exhibit similarly high accuracy, even without extensive engineering.
Mesh-Begriff(e)	Animals ; CRISPR-Associated Protein 9/metabolism ; Gene Editing/methods ; Humans ; Neisseria meningitidis/enzymology
Chemische Substanzen	CRISPR-Associated Protein 9 (EC 3.1.-) ; Cas9 endonuclease Streptococcus pyogenes (EC 3.1.-)
Sprache	Englisch
Erscheinungsdatum	2018-12-05
Erscheinungsland	England
Dokumenttyp	Comparative Study ; Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-018-1591-1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Harnessing type I CRISPR-Cas systems for genome engineering in human cells.

Cameron, Peter / Coons, Mary M / Klompe, Sanne E / Lied, Alexandra M / Smith, Stephen C / Vidal, Bastien / Donohoue, Paul D / Rotstein, Tomer / Kohrs, Bryan W / Nyer, David B / Kennedy, Rachel / Banh, Lynda M / Williams, Carolyn / Toh, Mckenzi S / Irby, Matthew J / Edwards, Leslie S / Lin, Chun-Han / Owen, Arthur L G / Künne, Tim /

van der Oost, John / Brouns, Stan J J / Slorach, Euan M / Fuller, Chris K / Gradia, Scott / Kanner, Steven B / May, Andrew P / Sternberg, Samuel H

Nature biotechnology

2019 Band 37, Heft 12, Seite(n) 1471–1477

Abstract: Type I CRISPR-Cas systems are the most abundant adaptive immune systems in bacteria and ... ...

Abstract	Type I CRISPR-Cas systems are the most abundant adaptive immune systems in bacteria and archaea
Mesh-Begriff(e)	CRISPR-Cas Systems/genetics ; Escherichia coli ; Gene Editing/methods ; Genome/genetics ; HEK293 Cells ; Humans ; Models, Genetic
Sprache	Englisch
Erscheinungsdatum	2019-11-18
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-019-0310-0
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Mapping the genomic landscape of CRISPR-Cas9 cleavage.

Nature methods

2017 Band 14, Heft 6, Seite(n) 600–606

Abstract: RNA-guided CRISPR-Cas9 endonucleases are widely used for genome engineering, but our understanding of Cas9 specificity remains incomplete. Here, we developed a biochemical method (SITE-Seq), using Cas9 programmed with single-guide RNAs (sgRNAs), to ... ...

Abstract	RNA-guided CRISPR-Cas9 endonucleases are widely used for genome engineering, but our understanding of Cas9 specificity remains incomplete. Here, we developed a biochemical method (SITE-Seq), using Cas9 programmed with single-guide RNAs (sgRNAs), to identify the sequence of cut sites within genomic DNA. Cells edited with the same Cas9-sgRNA complexes are then assayed for mutations at each cut site using amplicon sequencing. We used SITE-Seq to examine Cas9 specificity with sgRNAs targeting the human genome. The number of sites identified depended on sgRNA sequence and nuclease concentration. Sites identified at lower concentrations showed a higher propensity for off-target mutations in cells. The list of off-target sites showing activity in cells was influenced by sgRNP delivery, cell type and duration of exposure to the nuclease. Collectively, our results underscore the utility of combining comprehensive biochemical identification of off-target sites with independent cell-based measurements of activity at those sites when assessing nuclease activity and specificity.
Mesh-Begriff(e)	CRISPR-Cas Systems/genetics ; Chromosome Mapping/methods ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Genome/genetics ; High-Throughput Nucleotide Sequencing ; Sequence Analysis, DNA
Sprache	Englisch
Erscheinungsdatum	2017-05-01
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/nmeth.4284
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Harnessing type I CRISPR–Cas systems for genome engineering in human cells

Cameron, Peter / Coons, Mary M. / Klompe, Sanne E. / Lied, Alexandra M. / Smith, Stephen C. / Vidal, Bastien / Donohoue, Paul D. / Rotstein, Tomer / Kohrs, Bryan W. / Nyer, David B. / Kennedy, Rachel / Banh, Lynda M. / Williams, Carolyn / Toh, Mckenzi S. / Irby, Matthew J. / Edwards, Leslie S. / Lin, Chun Han / Owen, Arthur L.G. / Künne, Tim /

van der Oost, John / Brouns, Stan J.J. / Slorach, Euan M. / Fuller, Chris K. / Gradia, Scott / Kanner, Steven B. / May, Andrew P. / Sternberg, Samuel H.

Nature Biotechnology

2019 Band 37

Abstract: Type I CRISPR–Cas systems are the most abundant adaptive immune systems in bacteria and archaea1,2. Target interference relies on a multi-subunit, RNA-guided complex called Cascade3,4, which recruits a trans-acting helicase-nuclease, Cas3, for target ... ...

Abstract	Type I CRISPR–Cas systems are the most abundant adaptive immune systems in bacteria and archaea1,2. Target interference relies on a multi-subunit, RNA-guided complex called Cascade3,4, which recruits a trans-acting helicase-nuclease, Cas3, for target degradation5–7. Type I systems have rarely been used for eukaryotic genome engineering applications owing to the relative difficulty of heterologous expression of the multicomponent Cascade complex. Here, we fuse Cascade to the dimerization-dependent, non-specific FokI nuclease domain8–11 and achieve RNA-guided gene editing in multiple human cell lines with high specificity and efficiencies of up to ~50%. FokI–Cascade can be reconstituted via an optimized two-component expression system encoding the CRISPR-associated (Cas) proteins on a single polycistronic vector and the guide RNA (gRNA) on a separate plasmid. Expression of the full Cascade–Cas3 complex in human cells resulted in targeted deletions of up to ~200 kb in length. Our work demonstrates that highly abundant, previously untapped type I CRISPR–Cas systems can be harnessed for genome engineering applications in eukaryotic cells.
Schlagwörter	Life Science
Sprache	Englisch
Erscheinungsland	nl
Dokumenttyp	Artikel ; Online
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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