WO2014093661A2 - Crispr-cas systems and methods for altering expression of gene products - Google Patents

Crispr-cas systems and methods for altering expression of gene products Download PDF

Info

Publication number
WO2014093661A2
WO2014093661A2 PCT/US2013/074743 US2013074743W WO2014093661A2 WO 2014093661 A2 WO2014093661 A2 WO 2014093661A2 US 2013074743 W US2013074743 W US 2013074743W WO 2014093661 A2 WO2014093661 A2 WO 2014093661A2
Authority
WO
WIPO (PCT)
Prior art keywords
sequence
crispr
cell
expression
target
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2013/074743
Other languages
English (en)
French (fr)
Other versions
WO2014093661A3 (en
WO2014093661A9 (en
Inventor
Feng Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Massachusetts Institute of Technology
Broad Institute Inc
Original Assignee
Massachusetts Institute of Technology
Broad Institute Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=50441380&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2014093661(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to ES13824232.6T priority Critical patent/ES2552535T3/es
Priority to CN201380072715.1A priority patent/CN106170549B/zh
Priority to BR112015013785A priority patent/BR112015013785A2/pt
Priority to CA2894688A priority patent/CA2894688A1/en
Priority to PL13824232T priority patent/PL2764103T3/pl
Priority to EP13824232.6A priority patent/EP2764103B1/en
Priority to CN202010072631.XA priority patent/CN111187772B/zh
Priority to KR1020157018654A priority patent/KR20150107739A/ko
Priority to RU2015128100A priority patent/RU2687451C1/ru
Priority to CN202410963686.8A priority patent/CN118879746A/zh
Priority to AU2013359238A priority patent/AU2013359238B2/en
Application filed by Massachusetts Institute of Technology, Broad Institute Inc filed Critical Massachusetts Institute of Technology
Priority to DK13824232.6T priority patent/DK2764103T3/en
Priority to HK15101515.7A priority patent/HK1201290B/en
Priority to JP2015547555A priority patent/JP6545621B2/ja
Publication of WO2014093661A2 publication Critical patent/WO2014093661A2/en
Publication of WO2014093661A3 publication Critical patent/WO2014093661A3/en
Publication of WO2014093661A9 publication Critical patent/WO2014093661A9/en
Priority to US14/681,382 priority patent/US20150203872A1/en
Anticipated expiration legal-status Critical
Priority to US15/160,710 priority patent/US20160281072A1/en
Priority to AU2016244244A priority patent/AU2016244244B2/en
Priority to AU2019201608A priority patent/AU2019201608B2/en
Priority to AU2022201052A priority patent/AU2022201052B2/en
Priority to AU2025202729A priority patent/AU2025202729A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/90—Stable introduction of foreign DNA into chromosome
    • C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
    • C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/102—Mutagenizing nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/90—Stable introduction of foreign DNA into chromosome
    • C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • C12N9/222—Clustered regularly interspaced short palindromic repeats [CRISPR]-associated [CAS] enzymes
    • C12N9/226—Class 2 CAS enzyme complex, e.g. single CAS protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1082—Preparation or screening gene libraries by chromosomal integration of polynucleotide sequences, HR-, site-specific-recombination, transposons, viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPR]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/30—Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/80—Vectors containing sites for inducing double-stranded breaks, e.g. meganuclease restriction sites
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/90—Vectors containing a transposable element
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea

Definitions

  • the present invention generally relates to systems, methods and compositions used for the control of gene expression involving sequence targeting, such as genome perturbation or gene-editing, that may use vector systems related to Clustered Regularly Interspaced Short Palindromic Repeats (CRJSPR) and components thereof,
  • sequence targeting such as genome perturbation or gene-editing
  • CRJSPR Clustered Regularly Interspaced Short Palindromic Repeats
  • the CRISPR/Cas or the CRISPR-Cas system does not require the generation of customized proteins to target specific sequences but rather a single Cas enzyme can be programmed by a short RNA molecule to recognize a specific DNA target, in other words the Cas enzyme can be recruited to a specific DNA target using said short RNA molecule.
  • Adding the CRISPR-Cas system to the repertoire of genome sequencing techniques a d analysis methods may significantly simplify the methodology and accelerate the ability to catalog and map genetic factors associated with a diverse range of biological functions and diseases.
  • the invention provides a method of altering or modifying expression of one or more gene products that may comprise introducing into a cell containing and expressing DNA molecules encoding the one or more gene products an engineered, non-naturally occurring CRISPR-Cas system that may comprise a Cas protein and one or more guide RNAs that target the DNA molecules, whereby the one or more guide RNAs target the genomic loci of the DNA molecules encoding the one or more gene products and the Cas protein cleaves the genomic loci, of the DNA molecules encoding the one or more gene products, whereby expression of the one or more gene products is altered or modified; and, wherein the Cas protein and the guide RNA do not naturally occur together.
  • an engineered, non-naturally occurring CRISPR-Cas system that may comprise a Cas protein and one or more guide RNAs that target the DNA molecules, whereby the one or more guide RNAs target the genomic loci of the DNA molecules encoding the one or more gene products and the Cas protein cleaves the genomic loci,
  • the invention comprehends that the expression of two or more gene products may be altered or modified.
  • the guide RNA comprises a guide sequence fused to a tracr sequence.
  • the cell is a eukaryotic cell, in a more preferred embodiment the ceil is a mammalian ceil and in a yet more preferred embodiment the mammalian cell is a human cell.
  • the Cas protein may comprise one or more nuclear localization signal (s) (NLS(s)).
  • the Cas protein is a type II CRISPR system enzyme.
  • the Cas protein is a Cas9 protein.
  • the Cas9 protein is S. pneumoniae, S.
  • the protein may be a Cas9 homo log or ortholog.
  • the Cas protein is codoii-optimized for expression in a eukaryotic cell.
  • the Cas protein directs cleavage of one or two strands at the location of the target sequence.
  • the expression of the gene product is decreased and the gene product is a protein.
  • the invention comprehends that the introducing into the cell is by a delivery system that may comprise viral particles, liposomes, electroporation, microinjection or conjugation.
  • the invention provides a method of altering or modifying expression of one or more gene products comprising introducing into a. cell containing and expressing DNA molecules encoding the one or more gene products an engineered, non-naturally occurring vector system thai may comprise one or more vectors comprising: a) a first regulatory element operably linked to one or more CRISPR-Cas system guide RNAs that hybridize with target sequences in genomic loci of the DN A molecules encoding the one or more gene products, b) a second regulatory element operably linked to a Cas protein, wherein components (a) and (b) are located on same or different vectors of the system, whereby the guide RNAs target the genomic loci of the DNA molecules encoding the one or more gene products and the Cas protein cleaves the genomic loci of the DNA molecules encoding the one or more gene products, whereby expression of the one or more gene products is altered or modified; and, wherein the Cas protein and the guide RNAs do not naturally occur
  • the invention comprehends that the expression of two or more gene products may be altered or modified.
  • the guide RNA comprises a guide sequence fused to a traer sequence.
  • the cell is a eukaryotic cell, in a more preferred embodiment the cell is a mammalian ceil and in a yet more preferred embodiment the mammalia cell is a human cell.
  • the vectors of the system may further comprise one or more ' NLS(s).
  • the Cas protein is a type II CR ISPR system enzyme.
  • the Cas protein is a Cas9 protein.
  • the Cas9 protein is S. pneumoniae, S. pyogenes, or S.
  • thermophilic Cas9 and may include mutated Cas9 derived from these organisms.
  • the protein may be a Cas9 homo log or ortholog.
  • the Cas protein is codon-optimized for expression in a eukaryotic cell.
  • the Cas protein directs cleavage of one or two strands at the location of the target sequence, hi a further aspect of the invention, the expression of the gene product is decreased and the gene product is a protein.
  • the invention comprehends that the introducing into the cell is by a delivery system that may comprise viral particles, liposomes, electroporation, microinjection or conjugation.
  • the invention also provides an engineered, non-naturally occurring vector system that may comprise one or more vectors comprising: a) a first regulatory element operably linked to one or more CRISPR-Cas system guide RNAs that hybridize with target sequences in genomic loci of DNA molecules encoding one or more gene products, b) a second regulatory element operably linked to a Cas protein, wherein components (a) and (b) are located on same or different vectors of the system, whereby the guide RNAs target the genomic loci of the DNA molecules encoding the one or more gene products in a cell and the Cas protein cleaves the genomic loci of the DNA molecules encoding the one or more gene products, whereby expression of the one or more gene products is altered or modified; and, wherein the Cas protein and the guide RNAs do not naturally occur together.
  • the invention comprehends thai the expression of two or more gene products may be altered or modified.
  • the guide RNA comprises a guide sequence fused to a tracr sequence.
  • the cell is a eukaryotic cel l, in a more preferred embodiment t e ceil is a mammalian cell and in a yet more preferred embodiment the mammalian cell is a human cell.
  • the in ven tion also comprehends that the vectors of the system may further comprise one or more NLS(s).
  • the Cas protein is a type II CRISPR system enzyme.
  • the Cas protein is a Cas9 protein.
  • the Cas9 protein is S. pneumoniae, S.
  • the protein may be a Cas9 homolog or ortholog.
  • the Cas protein is coders -optimized for expression in a eukaryotic cell. Irs some embodiments, the Cas protein directs cleavage of one or two strands at the location of the target sequence.
  • the expression of the gene product is decreased and the gene product is a protein.
  • the invention comprehends that the introducing into the cell is by a delivery system that may comprise viral particles, liposomes, electroporation, microinjection or conjugation.
  • the invention provides an engineered, programmable, non ⁇ naturally occurring CRISPR-Cas system that may comprise a Cas protein and one or more guide RNAs that target the genomic loci of DNA molecules encoding one or more gene products in a cel l and the Cas protein cleaves the genomic loci of the DNA molecules encoding the one or more gene products, whereby expression of the o e or more gene products is altered or modified; and, wherein the Cas protein and the guide RNAs do not naturally occur together.
  • the invention comprehends that the expression of two or more gene products may be altered or modified.
  • the guide RNA comprises a guide sequence fused to a tracr sequence.
  • the cell is a eukaryotic cell, in a more preferred embodiment the cell is a mammalian cell and in a yet more preferred embodiment the mammalian cell is a human cell.
  • the CRISPR-Cas system may further comprise o e or more NLS(s).
  • the Cas protein is a type II CRISPR system enzyme.
  • the Cas protein is a Cas9 protein.
  • the Cas9 protein is S, pneumoniae, S. pyogenes, or S. merm.opb.il us Cas9, and may include mutated Cas9 derived from these organisms.
  • the protein may be a Cas9 homolog or ortholog.
  • the Cas protein is codon-optimized for expression in a eukaryotic cell.
  • the Cas protein directs cleavage of one or two strands at the location of the target sequence.
  • the expression of the gene product is decreased and the gene product is a protein.
  • the invention comprehends that the introducing into the cell is by a delivery system that may comprise viral particles, liposomes, eleetroporaiion, microinjection or conjugation.
  • the invention provides a vector system comprising one or more vectors.
  • the system comprises: (a) a first regulatory element operably linked to a tracr mate sequence and one or more insertion sites for inserting one or more guide sequences upstream of the tracr mate sequence, wherein when expressed, the guide sequence directs sequence-specific binding of a CRISPR complex to a target sequence in a eukaryotic cel l, wherein the CRISPR complex comprises a CRISPR enzyme complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the tracr mate sequence that is hybridized to the tracr sequence; and (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said CRISPR.
  • component (a) further comprises the tracr sequence downstream of the tracr mate sequence under the control of the first regulatory element.
  • component (a) further comprises two or more guide sequences operably linked to the first regulatory element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a CRISPR complex to a different target sequence in a eukaryotic cell.
  • the system comprises the tracr sequence under the control of a third regulatory element, such as a polymerase III promoter.
  • the tracr sequence exhibits at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% of sequence complementarity along the length of the tracr mate sequence when optimally aligned. Determining optimal alignment is within the purview of one of skill in the art. For example, there are publ.ical.ly and commercially available alignment algorithms and programs such as, but not limited to, ClustalW, Smith-Waterman in matlab, Bowtie, Geneious, Biopython and SeqMan,
  • the CRISPR complex comprises one or more nuclear localization sequences of sufficient strength to drive accumulation of said CRISPR complex in a detectable amount in the nucleus of a eukaryotic cell.
  • the CRISPR enzyme is a type II CRISPR system enzyme.
  • the CRISPR enzyme is a Cas9 enzyme.
  • the Cas9 enzyme is S. pneumoniae, S. pyogenes, or S. thermophiius Cas9, and may include mutated Cas9 derived from these organisms.
  • the enzyme may be a Cas9 homoiog or orthoiog.
  • the CRISPR enzyme is codon-optimized for expression in a eukaryotic cell. In some embodiments, the CRISPR. enzyme directs cleavage of one or two strands at the location of the target sequence.
  • the first regulatory element is a polymerase III promoter. In some embodiments, the second regulatory element is a polymerase II promoter.
  • the guide sequence is at least 15, 16, 17, 18, 19, 20, 25 nucleotides, or between 10-30, or between 15-25, or between 15-20 nucleotides in length.
  • the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • Vectors include, but are not limited to, nucleic acid .molecules that are single-stranded, double- stranded, or partially double-stranded; nucleic acid molecules that comprise one or more free ends, no free ends (e.g. circular); nucleic acid molecules that comprise DNA, RNA, or both; and other varieties of polynucleotides known in the art.
  • a "plasmid” which refers to a circular double stranded DNA loop into which additional DNA segments can be inserted, such as by standard molecular cloning techniques.
  • Another type of vector is a viral vector, wherein virally-derived DNA or RNA sequences are present in the vector for packaging into a vims (e.g.
  • Viral vectors also include polynucleotides carried by a virus for transfection into a host cell.
  • Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g. bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
  • Other vectors e.g., non-episomal mammalian vectors
  • certain vectors are capable of directing the expression of genes to which they are operatively- 1 inked. Such vectors are referred to herein as "expression vectors," Common expression vectors of utility in recombinant DNA techniques are often in the form of piasmids.
  • Recombinant expression vectors can comprise a nucleic acid of the invention in a form suitable for expression of the maceic acid in a host ceil, which means that the recombinant expression vectors include one or more regulatory elements, which may be selected on the basis of the host eel is to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed.
  • "operably linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory element(s) in a manner that allows for expression of the nucleotide sequence (e.g. in an in vitro transcription'translation system or in a host cell when the vector is introduced into the host cell).
  • regulators are intended to include promoters, enhancers, internal ribosomal entry sites (IRES), and other expression control elements (e.g. transcription termination signals, such as polyadenyiation signals and poly-U sequences).
  • IRES internal ribosomal entry sites
  • regulatory elements include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences).
  • a tissue-specific promoter may direct expression primarily in a desired tissue of interest, such as muscle, neuron, bone, skin, blood, specific organs (e.g. liver, pancreas), or particular cell types (e.g. lymphocytes). Regulatory elements may also direct expression in a temporal-dependent manner, such as in a cell-cycle dependent or developmental stage-dependent manner, which may or may not also be tissue or cell-type specific.
  • a vector comprises one or more pol III promoter (e.g. 1, 2, 3, 4, 5, or more pol III promoters), one or more pol II promoters (e.g. 1, 2, 3, 4, 5, or more pol II promoters), one or more pol I promoters (e.g.
  • pol III promoters include, but are not limited to, U6 and HI promoters.
  • pol II promoters include, but are not limited to, the retroviral Rous sarcoma vims (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optional y with the CMV enhancer) [see, e.g., Boshart et ai, Cel l, 41 :521 -530 (1985)], the SV40 promoter, the dihydrofolate reductase promoter, the ⁇ -actin promoter, the phosphoglycerol kinase (PGR) promoter, and the EFl promoter.
  • RSV Rous sarcoma vims
  • CMV cytomegalovirus
  • enhancer elements such as WPRE; CMV enhancers; the R-U5' segment in LTR of HTLV-I (Mol. Cell. Biol., Vol. 8(1), p. 466-472, 1988); SV40 enhancer; and the intron sequence between exons 2 and 3 of rabbit ⁇ -globin (Proc. Natl. Acad. Sci. USA., Vol. 78(3), p. 1527-31, 1 81). It wil l be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host ceil to be transformed, the level of expression desired, etc.
  • a vector can be introduced into host cells to thereby produce transcripts, proteins, or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., clustered regularly interspersed short palindromic repeats (CRISPR) transcripts, proteins, enzymes, mutant forms thereof, fusion proteins thereof, etc.).
  • CRISPR clustered regularly interspersed short palindromic repeats
  • Advantageous vectors include lenti viruses and adeno-associated viruses, and types of such vectors can also be selected for targeting particular types of cells.
  • the invention provides a eukaryotic host ceil comprising (a) a first regulatory element o erably linked to a tracr mate sequence and one or more insertion sites for inserting one or more guide sequences upstream of the tracr mate sequence, wherein when expressed, the guide sequence directs sequence-specific binding of a CRISPR complex to a target sequence in a eukaryotic cell, wherein the CRISPR complex comprises a CRISPR enzyme complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the tracr mate sequence that is hybridized to the tracr sequence; and/or (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said CRISPR enzyme comprising a nuclear localization sequence
  • the host cell comprises components (a) and (b).
  • component (a), component (b), or components (a) and (b) are stably integrated into a genome of the host eukaryotic cell.
  • component (a) further comprises the tracr sequence downstream of the tracr mate sequence under the control of the first regulatory element.
  • component (a) further comprises two or more guide sequences operably linked to the first regulatory element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a CRISPR. complex to a different target sequence in a eukaryotic cell.
  • the eukaryotic host cell further comprises a third regulatory element, such as a polymerase III promoter, operably linked to said tracr sequence.
  • the tracr sequence exhibits at least 50%, 60%, 70%), 80%, 90%, 95%, or 99% of sequence complementarity along the length of the tracr mate sequence when optimally aligned.
  • the enzyme may be a Cas9 homoiog or ortholog.
  • the CRISPR. enzyme is codon -optimized for expression in a eukaryotic cell.
  • the CRIS PR enzyme directs cleavage of one or two strands at the location of the target sequence.
  • the CRISPR enzyme lacks DNA strand cleavage activity.
  • the first regulator)? element is a polymerase III promoter.
  • the second regulatory element is a polymerase II promoter.
  • the guide sequence is at least 15, 16, 17, 18, 19, 20, 25 nucleotides, or between 10-30, or between 15-25, or between 15-20 nucleotides in length.
  • the invention provides a non-human eukaryotic organism; preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell according to any of the described embodiments.
  • the invention provides a eukaryotic organism; preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell according to any of the described embodiments.
  • the organism in some embodiments of these aspects may be an animal; for example a mammal. Also, the organism may be an arthropod such as an insect. The organism also may be a plant. Further, the organism may be a fungus,
  • the invention provides a kit compri sing one or more of the components described herein.
  • the kit comprises a vector system and instructions for using the kit.
  • the vector system comprises (a) a first regulatory element operably linked to a tracr mate sequence and one or more insertion sites for inserting one or more guide sequences upstream of the tracr male sequence, wherein when expressed, the guide sequence directs sequence-specific binding of a CRISPR complex to a target sequence in a eukaryotic cell, wherein the CRISPR complex comprises a CRISPR enzyme complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the tracr mate sequence that is hybridized to the tracr sequence; and/or (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said CRISPR enzyme comprising a nuclear localization sequence.
  • the kit comprises components (a) and (b) located on the same or different vectors of the system .
  • component (a) further comprises the tracr sequence downstream of the tracr mate sequence under the control of the first regulatory element.
  • component (a) further comprises two or more guide sequences operably linked to the first regulator)? element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a CRISPR complex to a different target sequence in a eukaryotic cell.
  • the system further comprises a third regulatory element, such as a polymerase HI promoter, operably linked to said tracr sequence.
  • the tracr sequence exhibits at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% of sequence complementarity along the length of the tracr mate sequence when optimally aligned.
  • the CRISPR enzyme comprises one or more nuclear localization sequences of sufficient strength to drive accumulation of said CRISPR enzyme in a detectable amount in the nucleus of a eukaryotic cell.
  • the CR ISPR enzyme is a type II CRISPR system enzyme.
  • the CRISPR enzyme is a Cas9 enzyme.
  • the Cas9 enzyme is S. pneumoniae, S, pyogenes or S.
  • thermophilus Cas9 and may include mutated Cas9 derived from these organisms.
  • the enzyme may be a Cas9 homolog or orthoiog.
  • the CRISPR enzyme is codon-optimized for expression in a eukaryotic cell.
  • the CRISPR enzyme directs cleavage of one or two strands at the location of the target sequence.
  • the CRISPR enzyme Sacks DNA strand cleavage activity.
  • the first regulatory element is a polymerase III promoter.
  • the second regulatory element is a polymerase II promoter.
  • the guide sequence is at least 15, 16, 17, 1 8, 19, 20, 25 nucleotides, or between 10-30, or between 15-25, or between 15-20 nucleotides in length.
  • the invention provides a method of modifying a target polynucleotide in a eukaryotic cell.
  • the method comprises allowing a CRISPR complex to bind to the target polynucleotide to effect cleavage of said target polynucleotide thereby modifying the target polynucleotide, wherein the CRISPR complex comprises a CRISPR enzyme complexed with a guide sequence hybridized to a target sequence within said target polynucleotide, wherein said guide sequence is linked to a tracr mate sequence which in turn hybridizes to a tracr sequence.
  • said cleavage comprises cleaving one or two strands at the location of the target sequence by said CRISPR enzyme. In some embodiments, said cleavage results in decreased transcription of a target gene. In some embodiments, the method further comprises repairing said cleaved target polynucleotide by homologous recombination with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of said target polynucleotide. In some embodiments, said mutation results in one or more amino acid changes in a protein expressed from a gene comprising the target sequence.
  • the method further comprises delivering one or more vectors to said eukaryotic cell, wherein the one or more vectors drive expression of one or more of: the CRISPR enzyme, the guide sequence linked to the tracr mate sequence, and the tracr sequence.
  • said vectors are delivered to the eukaryotic cell in a subject.
  • said modifying takes place in said eukaryotic cel l in a cell culture.
  • the method further comprises isolating said eukaryotic cell from a subject prior to said modifying.
  • the method further comprises returning said eukaryotic ceil and/or cells derived therefrom to said subject.
  • the invention provides a method of modifying expression of a polynucleotide in a eukaryotic cell.
  • the method comprises allowing a CRISPR complex to bind to the polynucleotide such that said binding results in increased or decreased expression of said polynucleotide; wherein the CRISPR complex comprises a CRISPR enzyme compiexed with a guide sequence hybridized to a target sequence within said polynucleotide, wherein said guide sequence is linked to a tracr mate sequence which in turn hybridizes to a tracr sequence.
  • the method further comprises delivering one or more vectors to said eukaryotic cells, wherein the one or more vectors drive expression of one or more of: the CRISPR enzyme, the guide sequence linked to the tracr mate sequence, and the tracr sequence.
  • the invention provides a method of generating a model eukaryotic cell comprising a mutated disease gene.
  • a disease gene is any gene associated an increase in the risk of having or developing a disease.
  • the method comprises (a) introducing one or more vectors into a eukaryotic cell, wherein the one or more vectors drive expression of one or more of: a CRI SPR enzyme, a guide sequence linked to a tracr mate sequence, and a tracr sequence; and (b) allowing a CRISPR complex to bind to a target polynucleotide to effect cleavage of the target polynucleotide within said disease gene, wherein the CRISPR complex comprises the CRISPR enzyme compiexed with (1) the guide sequence that is hybridized to the target sequence within the target polynucleotide, and (2) the tracr mate sequence that is hybridized to the tracr sequence, thereby generating a model euk
  • said cleavage comprises cleaving one or two strands at the location of the target sequence by said CRISPR enzyme. In some embodiments, said cleavage results in decreased transcription of a target gene. In some embodiments, the method further comprises repairing said cleaved target polynucleotide by homologous recombination with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of said target polynucleotide. In some embodiments, said mutation results in one or more amino acid changes in a protein expression from a gene comprising the target sequence.
  • the invention provides a method for developing a biologically active agent that modulates a cell signaling event associated with a disease gene.
  • a disease gene is any gene associated an increase in the risk of having or developing a disease.
  • the method comprises (a) contacting a test compound with a model cell of any one of the described embodiments; and (b) detecting a change in a readout that is indicative of a reduction or an augmentation of a cell signaling event associated with said mutation in said disease gene, thereby developing said biologically active agent that modulates said cell signaling event associated with said disease gene.
  • the invention provides a recombinant polynucleotide comprising a guide sequence upstream of a tracr mate sequence, wherein the guide sequence when expressed directs sequence-specific binding of a CRISPR complex to a corresponding target sequence present in a eukaryotic cell.
  • the target sequence is a viral sequence present in a eukaryotic cell.
  • the target sequence is a proto-oncogene or an oncogene.
  • the invention provides for a method of selecting one or more cell(s) by introducing one or more mutations in a gene in the one or more cell is), the method comprising: introducing one or more vectors into the cell (s). wherein the one or more vectors drive expression of one or more of: a CR ISPR enzyme, a guide sequence linked to a tracr mate sequence, a tracr sequence, and an editing template; wherein the editing template comprises the one or more mutations that abolish CRISPR enzyme cleavage; allowing homologous recombination of the editing template with the target polynucleotide in the cell(s) to be selected; allowing a CRISPR complex to bind to a target polynucleotide to effect cleavage of the target polynucleotide within said gene, wherein the CRISPR complex comprises the CRISPR enzyme complexed with (1) the guide sequence that is hybridized to the target sequence within the target polynucleotide, and (2) the
  • the CR1SPR enzyme is a type ⁇ CRISPR system enzyme.
  • the CRISPR enzyme is a Cas9 protein.
  • the Cas9 protein is S. pneumoniae, S. pyogenes, or S. thermophilus Cas9, and may include mutated Cas9 derived from these organisms.
  • the enzyme may be a Cas9 homo log or ortholog.
  • the enzyme is codon-optimized for expression in a eukaryotic cell.
  • the enzyme directs cleavage of one or two strands at the location of the target sequence.
  • the CRISPR enzyme is Cas9.
  • the cell to be selected may be a eukaryotic cell. Aspects of the invention allow for selection of specific cells without requiring a selection marker or a two-step process that may include a counter-selection system.
  • aspects of the invention comprehend site-specific gene knockout in the endogenous genome:
  • the present invention is advantageous over using site-specific nuclease technologies based on zinc finger and TAL effectors as it does not require elaborate design and may be used to simultaneously knockout multiple genes within the same genome.
  • the invention comprehends site-specific genome editing.
  • the present invention is advantageous over using natural or artificial site-specific nucleases or recombinases as it may be able to introduce site-specific double strand breaks to facilitate homologous recombination at the targeted genome loci.
  • the invention comprehends DNA sequence-specific interference.
  • the invention may be used to inactivate the genome of deleterious DNA-based organisms, such as microbes, viruses, or even cancerous cells, by directly introducing breaks at specific sites in the genome of these organisms.
  • the invention provides methods and compositions for multiplexed genome engineering as the CR ISPR-Cas system of the invention can be easil targeted to multiple sites in the genome through the use of multiple sequence-specific CRISPR spacer elements or guide sequences.
  • FIG. 1 shows a schematic model of the CRISPR system.
  • the Cas9 nuclease from Streptococcus pyogenes (yellow) is targeted to genomic DNA by a synthetic guide RNA (sgRNA) consisting of a 20-nt guide sequence (blue) and a scaffold (red).
  • the guide sequence base-pairs with the DNA target (blue), directly upstream of a requisite 5'-NGG protospacer adjacent motif (PA ; magenta), and Cas9 mediates a double-stranded break (DSB) ⁇ 3 bp upstream of the PAM (red triangle).
  • sgRNA synthetic guide RNA
  • PA magenta
  • DSB double-stranded break
  • Figure 2A-F shows an exemplary CRISPR system, a possible mechanism of action, an example adaptation for expression in eukaryotic ceils, and results of tests assessing nuclear localization and CRISPR activity.
  • Figure 2C discloses SEQ ID NQS 23-24, respectively, in order of appearance.
  • Figure 2E discloses SEQ ID NOS 25-27, respectively, in order of appearance.
  • Figure 2.F discloses SEQ ID NOS 28-32, respectively, in order of appearance.
  • Figure 3A-D shows results of an evaluation of SpCas9 specificity for an example target.
  • Figure 3 A discloses SEQ ID NOS 33, 26 and 34-44, respectively, in order of appearance.
  • Figure 3C discloses SEQ ID NO: 33.
  • Figure 4A-G shows an exemplary vector system and results for its use in directing homologous recombination in eukaryotic cells.
  • Figure 4E discloses SEQ ID NO: 45
  • Figure 4F discloses SEQ ID NOS 46-47, respectively, in order of appearance.
  • Figure 4G discloses SEQ ID NOS 48-52, respectively, in order of appearance,
  • Figure 5 provides a table of protospacer sequences (SEQ ID NOS 16, 15, 14, 53-58, 18, 17 and 59-63, respectively, in order of appearance) and summarizes modification efficiency results for protospacer targets designed based on exemplar S. pyogenes and 5.
  • thermophilus CRISPR systems with corresponding PAMs against loci in human and mouse genomes. Cells were transfected with Cas9 and either pre-crRN A/ tracr N A or chimeric RNA, and analyzed 72 hours after transfection.
  • Percent indels are calculated based on Surveyor assay results from indicated cell lines (N :::: 3 for all protospacer targets, errors are S.E.M., N,D, indicates not detectable using the Surveyor assay, and N.T. indicates not tested in this study).
  • Figure 6A-C shows a comparison of different tracrRNA transcripts for Cas9- mediated gene targeting.
  • Figure 6A discloses SEQ ID NOS 64-65, respectively, in order of appearance.
  • Figure 7 shows a schematic of a surveyor nuclease assay for detection of double strand break-induced micro-insertions and --deletions.
  • Figure 8A-B shows exemplary bicistronic expression vectors for expression of CRISPR system elements in eukaryotic cells.
  • Figure 8A discloses SEQ ID NOS 66-68, respectively, in order of appearance.
  • Figure 8B discloses SEQ ID NOS 69-71 , respectively, in order of appearance,
  • Figure 9A-C shows histograms of distances between adjacent S. pyogenes SF370 locus 1 PAM (NGG) ( Figure 9A) and S. thermophilus LMD9 locus 2 PAM ( NAGAAW) ( Figure 9B) in the human genome; and distances for each PAM by chromosome (Chr) ( Figure 9C).
  • Figure 10A-D show r s an exemplary CRISPR system, an example adaptation for expression in eukaryotic cells, and results of tests assessing CRISPR activity.
  • Figure 1GB discloses SEQ ID NOS 72-73, respectively, in order of appearance.
  • Figure IOC discloses SEQ ID NO: 74,
  • Figure 11A-C shows exemplary manipulations of a CRISPR system for targeting of genomic loci in mammalian cells.
  • Figure 1 1 A discloses SEQ ID NO: 75.
  • Figure 11B discloses SEQ ID NOS 76-78, respectively, in order of appearance.
  • Figure 12A-B shows the results of a Northern blot analysis of crRNA processmg in mammalian cells.
  • Figure 12A discloses SEQ ID NO: 79.
  • Figure 13A-B shows an exemplary selection of protospacers in the human PVALB and mouse Th loci.
  • Figure 13 A discloses SEQ ID NO: 80.
  • Figure 13B discloses SEQ ID NO: 81.
  • Figure 14 shows example protospacer and corresponding PAM sequence targets of the S. thermophilus CRISPR system in the human EMX1 locus.
  • Figure 14 discloses SEQ ID NO: 74.
  • Figure 15 provides a table of sequences (SEQ ID NOS 82-93, respectively, in order of appearance) for primers and probes used for Surveyor, RFLP, genomic sequencing, and Northern blot assays.
  • Figure 16A-C shows exemplary ma ipulation of a CRISPR system with chimeric R As and results of SURVEYOR assays for system activity in eukaryotic cells.
  • Figure 16A discloses SEQ ID NO: 94.
  • Figure 17A-B shows a graphical representation of the results of SURVEYOR assays for CRISPR system activity in eukaryotic ceils.
  • Figure 18 shows an exemplary visualization of some S. pyogenes Cas9 target sites in the human genome using the UCSC genome browser.
  • Figure 18 discloses SEQ ID NOS 95-173, respectively, in order of appearance.
  • Figure 19A-0 shows a circular depiction of the phylogenetic analysis revealing fi ve families of Cas9s, including three groups of large Cas9s (-1400 amino acids) and two of small Cas9s ( ⁇ 1 100 amino acids).
  • Figure 20A-F shows the linear depiction of the phylogenetic analysis revealing five families of Cas9s, including three groups of large Cas9s (-1400 amino acids) and two of small Cas9s ( ⁇ 1100 amino acids).
  • Figure 21A-D shows genome editing via homologous recombination, (a) Schematic of SpCas9 nickase, with D10A mutation in the RuvC I catalytic domain, (b) Schematic representing homologous recombination (HR) at the human EMX1 locus using either sense or antisense single stranded oligonucleotides as repair templates. Red arrow above indicates sgRNA cleavage site; PCR primers for genotyping (Tables J and ) are indicated as arrows in right panel.
  • Figure 21C discloses SEQ ID NOS 174-176, 1 74, 177 and 176, respectively, in order of appearance, (c) Sequence of region modified by HR.
  • d SURVEYOR assay for wild type (wt) and nickase (DIOA) SpCas9-mediated indels at the ⁇ target 1 locus (n ⁇ -3). Arrows indicate positions of expected fragment sizes.
  • Figure 22A-B shows single vector designs for SpCas9.
  • Figure 22A discloses SEQ ID NO:
  • Figure 22B discloses SEQ ID NO: 181.
  • polynucleotide refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof.
  • Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown.
  • polynucleotides coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • loci locus defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched poly
  • a polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
  • chimeric RNA refers to the polynucleotide sequence comprising the guide sequence, the tracr sequence and the tracr mate sequence.
  • guide sequence refers to the about 20bp sequence within the guide RNA that specifies the target site and may be used interchangeably with the terms “guide” or “spacer”.
  • traer mate sequence may also be used interchangeably with the term “direct repeat(s)”.
  • An exemplary CRISPR-Cas system is illustrated in Figure 1.
  • wild type is a term of the art understood by skilled persons and means the typical form of an organism, strain, gene or characteristic as it occurs in nature as distinguished from mutant or variant forms.
  • variable should be taken to mean the exhibition of qualities that have a pattern that deviates from what occurs in nature.
  • nucleic acid molecules or polypeptides mean that the nucleic acid molecule or the polypeptide is at least substantially free from at least one other component with which they are naturally associated in nature and as found in nature.
  • Complementarity refers to the ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types.
  • a percent complementarity indicates the percentage of residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%», and 100% complementary).
  • Perfectly complementary means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.
  • Substantially complementary refers to a degree of complementarity that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% over a region of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, or more nucleotides, or refers to two nucleic acids that hybridize under stringent conditions.
  • stringent conditions for hybridization refer to conditions under which a nucleic acid having complementarity to a target sequence predominantly hybridizes with the target sequence, and substantially does not hybridize to non-target sequences. Stringent conditions are generally sequence-dependent, and vary depending on a number of factors. In general, the longer the sequence, the higher the temperature at which the sequence specifically hybridizes to its target sequence. Non-limiting examples of stringent conditions are described in detail in Tijssen (1993), Laboratory Techniques In Biochemistry And Molecular Biology- Hybridization With Nucleic Acid Probes Part I, Second Chapter “Overview of principles of hybridization and the strategy of nucleic acid probe assay", Elsevier, N,Y,
  • Hybridization refers to a reaction in which one or more polynucleotides react to form a complex tha is stabilized via hydrogen bonding between the bases of the nucleotide residues.
  • the hydrogen bonding may occur by Watson Crick base pairing, Hoogstein binding, or in any other sequence specific manner.
  • the complex may comprise two strands forming a duplex structure, three or more strands forming a multi stranded complex, a single self hybridizing strand, or any combination of these.
  • a hybridization reaction may constitute a step in a more extensive process, such as the initiation of PGR, or the cleavage of a polynucleotide by an enzyme.
  • a sequence capable of hybridizing with a given sequence is referred to as the "complement" of the given sequence.
  • expression refers to the process by which a polynucleotide is transcribed from a DNA template (such as into and mRNA or other RNA transcript) and/or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins.
  • Transcripts and encoded polypeptides may be collectively referred to as "gene product.” If the polynucleot de is deri ved from genomic DNA, expression may include splicing of the mRNA in a cukaryotie cell.
  • polypeptide refers to polymers of amino acids of any length.
  • the polymer may he linear or branched, it may comprise modified amino acids, and it may be interrupted by non amino acids.
  • the terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosyiation, iipidation, acetylation. phosphorylation, or any other manipulation, such as conjugation with a labeling component.
  • amino acid includes natural and/or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.
  • the terms "subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
  • the terms "therapeutic agent”, “therapeutic capable agent” or “treatment agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject.
  • the beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.
  • treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment.
  • the compositions may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested.
  • the term "effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to effect beneficial or desired results.
  • the therapeutical ly effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will provide an image for detection by any one of the imaging methods described herein.
  • the specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried,
  • Vectors can be designed for expression of CRISPR transcripts (e.g. nucleic acid transcripts, proteins, or enzymes) in prokaryotic or eukaryotic cells.
  • CRISPR transcripts e.g. nucleic acid transcripts, proteins, or enzymes
  • CRISPR transcripts can be expressed in bacterial cells such as Escherichia coli, insect cells (using haeulovirus expression vectors), yeast cells, or mammalian cells. Suitable host cel ls are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990).
  • the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.
  • Vectors may be introduced and propagated in a prokaryote.
  • a prokaryote is used to amplify copies of a vector to be Introduced into a eukaryotic celi or as an intermediate vector in the production of a vector to be introduced into a eukaryotic cel l (e.g. amplifying a plasmid as part of a viral vector packaging system).
  • a prokaryote is used to amplify copies of a vector and express one or more nucleic acids, such as to provide a source of one or more proteins for delivery to a host cell or host organism.
  • Fusion vectors add a number of amino acids to a protein encoded therein, such as to the amino terminus of the recombinant protein.
  • Such fusion vectors may serve one or more purposes, such as: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification.
  • a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombmant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein.
  • Such enzymes, and their cognate recognition sequences include Factor Xa, thrombin and enterokinase.
  • Example fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988.
  • pMAL New England Biolabs, Beverly, Mass.
  • pR!T5 Pharmacia, Piscataway, N.J.
  • GST glutathione S-transferase
  • suitable inducible non-fusion E. co!i expression vectors include pTrc (Amrami et al, (1988) Gene 69:301 -315) and pET l i d (Studier et al, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89).
  • a vector is a yeas'; expression vector.
  • yeast Saccharomyces cerivisae examples include pYepSecl (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kuijan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.).
  • a vector drives protein expression in insect cells using baculovirus expression vectors.
  • Baculovirus vectors available for expression of proteins in cultured insect ceils include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).
  • a vector is capable of driving expression of one or more sequences in mammalian cells using a mammalian expression vector.
  • mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187- 195).
  • the expression vector's control functions are typically provided by one or more regulatory elements.
  • commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, simian virus 40, and others disclosed herein and known in the art.
  • the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid).
  • tissue-specific regulatory elements are known in the art.
  • suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1 : 268-277), lymphoid-speeific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J.
  • y- regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the a-fetoprotein promoter (Campes and Tilghman, 1989. G .'"k'v Dev. 3: 537-546).
  • a regulatory element is operably linked to one or more elements of a CRISPR system so as to drive expression of the one or more elements of the CRISPR system.
  • CRISPRs Clustered Regularly Interspaced Short Palindromic Repeats
  • SP!DRs SPacer Interspersed Direct Repeats
  • SSRs interspersed short sequence repeats
  • the CRISPR loci typically differ from other SSRs by the structure of the repeats, which have been termed short regularly spaced repeats (SRSRs) (Janssen et al., OMICS J. imeu. Biol., 6:23-33 [2002]; and Mojica et al., Mol. Microbiol., 36:244-246 [2000]).
  • SRSRs short regularly spaced repeats
  • the repeats are short elements that occur in clusters that are regularly spaced by unique intervening sequences with a substantially constant length (Mojica et al., [2000], supra).
  • the repeat sequences are highly conserved between strains, the number of interspersed repeats and the sequences of the spacer regions typically differ from strain to strain (van Embden et al., J.
  • CRISPR loci have been identified in more than 40 prokaryotes (See e.g., Jansen et al., Mol. Microbiol, 43:1565-1575 [2002]; and Mojica et al, [2005]) including, but not limited to Aeropyrum, Pyrobaculum, Sulfolobus, Archaeoglobus, Halocarcula, Methanobacterium, Methanococcus, Methanosarcina, Methanopyrus, Pyrococcus, Picrophilus, Thermoplasma, Corynebacterium, Mycobacterium, Streptomyces, Aquifex, Porphyromonas, Chlorobium, Thermus, Bacillus, Listeria, Staphylococcus, Clostridium, Thermoanaerobacter, Mycoplasma, Fusobacterium, Azarcus, Chromobacterium, Neisseria, Nitrosomonas
  • CRISPR system refers col lectively to transcripts and other elements involved in the expression of or directing the activity of CRISPR-associated (“Cas") genes, including sequences encoding a Cas gene, a tracr (trans -activating CRISPR) sequence (e.g. tracrRNA or an active partial tracrRNA), a tracr-mate sequence (encompassing a "direct repeat” and a tracrRNA-processed partial direct repeat in the context of an endogenous CRISPR system), a guide sequence (also referred to as a "spacer” in the context of an endogenous CRISPR system), or other sequences and transcripts from a CRISPR locus.
  • a tracr trans -activating CRISPR
  • tracr-mate sequence encompassing a "direct repeat” and a tracrRNA-processed partial direct repeat in the context of an endogenous CRISPR system
  • guide sequence also referred to as a "spacer” in the context of an endogenous C
  • one or more elements of a CRISPR system is derived from a type I, type II, or type III CRISPR system. In some embodiments, one or more elements of a CRISPR system is derived from a particular organism comprising an endogenous CRISPR system, such as Streptococcus pyogenes. In general, a CRISPR system is characterized by elements that promote the formation of a CRISPR complex at the site of a target sequence (also referred to as a protospaeer in the context of an endogenous CRISPR system).
  • target sequence refers to a sequence to which a guide sequence is designed to have complementarity, where hybridization between a target sequence and a guide sequence promotes the formation of a CRISPR complex. Full complementarity is not necessarily required, provided there is sufficient complementarity to cause hybridization and promote formation of a CRISPR complex.
  • a target sequence may comprise any polynucleotide, such as DNA or KNA polynucleotides.
  • a target sequence is located in the nucleus or cytoplasm of a cel l.
  • the target sequence may be within an organelle of a eukaryotic cell, for example, mitochondrion or chloroplast.
  • a sequence or template that may be used for recombination into the targeted locus comprising the target sequences is referred to as an "editing template” or “editing polynucleotide” or “editing sequence”.
  • an exogenous template polynucleotide may he referred to as an editing template.
  • the recombination is homologous recombination.
  • 0075j typically, in the context of an endogenous CRISPR system, formation of a CRISPR complex (comprising a guide sequence hybridized to a target sequence and complexed with one or more Cas proteins) results in cleavage of one or both strands in or near (e.g. within 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the target sequence.
  • the tracr sequence which may comprise or consist of all or a portion of a wild- type tracr sequence (e.g.
  • a CRISPR complex may also form part, of a CRISPR complex, such as by hybridization along at least a portion of the tracr sequence to all or a portion of a tracr mate sequence that is operably linked to the guide sequence.
  • the tracr sequence has sufficient complementarity to a tracr mate sequence to hybridize and participate in formation of a CRISPR complex. As with the target sequence, it is believed that complete complementarity is not needed, provided there is sufficient to be functional.
  • the tracr sequence has at least 50%, 60%, 70%, 80%, 90%, 95% or 99% of sequence com lementarity along the length of the tracr mate sequence when optimally aligned.
  • one or more vectors driving expression of one or more elements of a CRISPR system are introduced into a host cell such that expression of the elements of the CRISPR system direct formation of a CRISPR complex at one or more target sites.
  • a Cas enzyme, a guide sequence linked to a tracr-mate sequence, and a tracr sequence could each be operably linked to separate regulator ⁇ 7 elements on separate vectors.
  • two or more of the elements expressed from the same or different regulatory elements may be combined in a single vector, with one or more additional vectors providing any components of the CRISPR system not included in the first vector.
  • CRISPR system elements that are combined in a single vector may be arranged in any suitable orientation, such as one element located 5 " with respect to ("upstream” of) or 3' with respect to ("downstream” of) a second element.
  • the coding sequence of one element may be located on the same or opposite strand of the coding sequence of a second element, and oriented in the same or opposite direction.
  • a single promoter drives expression of a transcript encoding a CRISPR.
  • a vector comprises one or more insertion sites, such as a restriction endormclease recognition sequence (also referred to as a "cloning site").
  • one or more insertion sites are located upstream and/or downstream of one or more sequence elements of one or more vectors.
  • a vector comprises an msertion site upstream of a tracr mate sequence, and optionally downstream of a regulatory element operably linked to the tracr mate sequence, such that following insertion of a guide sequence into the insertion site and upon expression the guide sequence directs sequence-specific binding of a CRJSPR. complex to a target sequence in a eukaryotic cell.
  • a vector comprises two or more insertion sites, each insertion site being located between two tracr mate sequences so as to allow insertion of a guide seq uence at each site.
  • the two or more guide sequences may comprise two or more copies of a single guide sequence, two or more different guide sequences, or combinations of these.
  • a single expression construct may be used to target CRISPR activity to multiple different, corresponding target sequences within a cell.
  • a single vector may comprise about or more than about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more guide sequences. In some embodiments, about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more such guide-sequence-containing vectors may be provided, and optionally delivered to a cell.
  • a vector comprises a regulatory element operably linked to an enzyme-coding sequence encoding a CRISPR enzyme, such as a Cas protein.
  • Cas proteins include Casl, CasI B, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csnl and Csxl2), CaslO, Csyl, Csy2, Csy3, Csel, Cse2, Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, CsxlS, Csfl, Csf2, Csf3,
  • the unmodified CRISPR. enzyme has DNA cleavage activity, such as Cas9.
  • the CRISPR enzyme is Cas9, and may be Cas9 from S. pyogenes or S. pneumoniae.
  • the CRISPR enzyme directs cleavage of one or both strands at the location of a target sequence, such as within the target sequence and/or within the complement of the target sequence.
  • the CRISPR enzyme directs cleavage of one or both strands within about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence.
  • a vector encodes a CRISPR enzyme that is mutated to with respect to a corresponding wild-type enzyme such that the mutated CRISPR enzyme lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence.
  • D10A aspartate-to-alanine substitution
  • pyogenes converts Cas9 from a nuclease that cleaves both strands to a nickase (cleaves a single strand).
  • Other examples of mutations that render Cas9 a nickase include, without limitation, H840A, N854A, and N863A.
  • niekases may be used for genome editing via homologous recombination,
  • Figure 21 shows genome editing via homologous recombination.
  • a Cas9 nickase may be used in combination with guide sequence(s), e.g., two guide sequences, which target respectively sense and antisense strands of the DNA target. This combination allows both strands to be nicked and used to induce NHEJ.
  • guide sequence(s) e.g., two guide sequences, which target respectively sense and antisense strands of the DNA target.
  • This combination allows both strands to be nicked and used to induce NHEJ.
  • Applicants have demonstrated (data not shown) the efficacy of two nickase targets (i.e., sgRNAs targeted at the same location but to different strands of DNA) in inducing mutagenic NHEJ.
  • a single ickase (Cas9-D10A with a single sgRNA) is unable to induce NHEJ and create indels but Applicants have shown that double nickase (Cas9-D10A and two sgRNAs targeted to different stra ds at the same location) can do so in human embryonic stem cells (hESCs).
  • the efficiency is about 50% of nuclease (i.e., regular Cas9 without D10 mutation) in hESCs.
  • two or more catalytic domains of Cas9 may be mutated to produce a mutated Cas9 substantially lacking all DNA cleavage activity.
  • a D10A mutation is combined with one or more of H840A, N854A, or N863A mutations to produce a Cas9 e zyme substantially lacking ail DNA cleavage activity.
  • a CRISPR enzyme is considered to substantially lack all DNA cleavage activity when the DNA cleavage activity of the mutated enzyme is less tha about 25%, 10%, 5%, 1%, 0.1%, 0.01%, or lower with respect to its non-mutated form.
  • Other mutations may be useful; where the Cas9 or other CRISPR enzyme is from a species other than S. pyogenes, mutations in corresponding amino acids may be made to achieve similar effects.
  • an enzyme coding sequence encoding a CRISPR. enzyme is codon optimized for expression in particular cells, such as eukaryotic cells.
  • the eukaryotic cells may be those of or derived from a particular organism, such as a mammal, i cluding but not limited to human, mouse, rat, rabbit, dog, or non-human primate.
  • codon optimization refers to a process of modifying a nucleic acid sequence for enhanced expression in the host cells of interest by replacing at least one codon (e.g.
  • Codon bias differences in codon usage between organisms
  • mRNA messenger RNA
  • tRNA transfer RNA
  • genes can be tailored for optimal gene expression in a given organism based on codon optimization.
  • Codon usage tables are readily available, for example, at the "Codon Usage Database", and these tables can be adapted in a number of ways. See Nakamura, Y., et al. ''Codon usage tabul ated from the international DNA sequence databases: status for the year 20Q0"Nuel. Acids Res. 28:292 (2000).
  • Computer algorithms for codon optimizing a particular sequence for expression in a particular host cell are also available, such as Gene Forge ( Aptagen; Jacobus, PA), are also available.
  • one or more codons e.g. 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or more, or all codons
  • one or more codons e.g. 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or more, or all codons
  • a guide sequence is any polynucleotide sequence having sufficient complementarity with a target polynucleotide sequence to hybridize with the target sequence and direct sequence-specific binding of a CRISPR complex to the target sequence.
  • the degree of com lementarity between a guide sequence and its corresponding target sequence when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more.
  • Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limiting example of which include the Smith-Waterman algorithm, the Needleman-Wimsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g. the Burrows Wheeler Aligner), ClustalW, Clustai X, BLAT, Novoalign (Novocraft Technologies, ELAND (I!fumma, San Diego, CA), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net).
  • Burrows-Wheeler Transform e.g. the Burrows Wheeler Aligner
  • ClustalW Clustai X
  • BLAT BLAT
  • Novoalign Novocraft Technologies
  • SOAP available at soap.genomics.org.cn
  • Maq available at maq.sourceforge.net.
  • a guide sequence is about or more than about 5, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length. In some embodiments, a guide sequence is less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length. The ability of a guide sequence to direct sequence- specific binding of a CR1SPR complex to a target sequence may be assessed by any suitable assay.
  • the components of a CRJSPR system sufficient to form a CRISPR complex, including the guide sequence to be tested, may be provided to a host cell having the corresponding target sequence, such, as by transfection with vectors encoding the components of the CRISPR sequence, followed by an assessment of preferential cleavage within the target sequence, such as by Surveyor assay as described herein.
  • cleavage of a target polynucleotide sequence may be evaluated in a test tube by providing the target sequence, components of a CRISPR complex, including the guide sequence to be tested and a control guide sequence different from the test guide sequence, and comparing binding or rate of cleavage at the target sequence between the test and control guide sequence reactions.
  • Other assays are possible, and will occur to those skilled in the art.
  • a guide sequence may be selected to target any target sequence.
  • the target sequence is a sequence within a genome of a cell.
  • Exemplary target sequences include those that are unique in the target genome.
  • a unique target sequence in a genome may include a Cas9 target site of the form M MM MM MM MNNNNNNNNNNNNXGG where NNNNNNNNNNXGG (N is A , G, T, or C; and X can be anything) has a single occurrence in the genome.
  • a unique target sequence in a genome may include an S.
  • a unique target sequence in a genome may include a Cas9 target site of the form MMMMMMMMNNNNNNNNNNNNXXAGAAW (SEQ ID NO: 1 ) where NNNNNNNNNNXXAGAAW (SEQ ID NO: 2) (N is A, G, T, or C; X can be anything; and W is A or T) has a single occurrence in the genome.
  • a unique target sequence in a genome may include an S. thermophilus CRISPR1 Cas9 target site of the form MMMMMM MMMNNNNNNNNNNNXXAGAAW (SEQ ID NO: 3) where ⁇ m NNXXAGAAW (SEQ ID NO: 4) (N is A, G, T, or C; X can be anything; and W is A or T) has a single occurrence in the genome.
  • S. thermophilus CRISPR1 Cas9 target site of the form MMMMMM MMMNNNNNNNNNNNNNXXAGAAW (SEQ ID NO: 3) where ⁇ m NNXXAGAAW (SEQ ID NO: 4) (N is A, G, T, or C; X can be anything; and W is A or T) has a single occurrence in the genome.
  • S. thermophilus CRISPR1 Cas9 target site of the form MMMMMM MMMNNNNNNNNNNNXXAGAAW (SEQ ID NO: 3) where ⁇ m
  • a unique target sequence in a genome may include a Cas9 target site of the form MMMMMMMMNNNNNNNNNNNNXGGXG where NNNNNNNNNNXGGXG (N is A, G, T, or C; and X can be anything) has a single occurrence in the genome.
  • a unique target sequence in a genome may include an S. pyogenes Cas9 target site of the form MMM MM MMMMNNNNNNNNNNNXGGXG where NNNNNNNNNNNXGGXG (N is A, G, T, or C; and X can be anything) has a single occurrence in the genome.
  • M may be A, G, T, or C, and need not be considered in identifying a sequence as unique.
  • a guide sequence is selected to reduce the degree of secondary structure within the guide sequence.
  • Secondary structure may be determined by any suitable polynucleotide folding algorithm. Some programs are based on calculating the minimal Gibbs free energy. An example of one such algorithm is mFold, as described by Zuker and Stiegler (Nucleic Acids Res. 9 (1981), 133-148). Another example folding algorithm is the online webserver RNAfoId, developed at Institute for Theoretical Chemistry at the University of Vienna, using the centroid structure prediction algorithm (see e.g. A.R. Gruber et al, 2008, Cell 106(1): 23-24; and PA Carr and GM Church, 2009, Nature Biotechnology 27(12): 1151 -62). Further algorithms may be found in U.S. application Serial No. 61/836,080 (attorney docket 44790.1 3.2022; Broad Reference B1-2013/004A); incorporated herein by reference.
  • a tracr mate sequence includes any sequence that has sufficient complementarity with a tracr sequence to promote one or more of: (1) excision of a guide sequence flanked by tracr mate sequences in a cell containing the corresponding tracr sequence; and (2) formation of a CRISPR complex at a target sequence, wherein the CRISPR complex comprises the tracr mate sequence hybridized to the tracr sequence.
  • degree of complementarity is with reference to the optimal alignment of the tracr mate sequence and tracr sequence, along the length of the shorter of the two sequences.
  • Optimal alignment may be determined by any suitable alignment algorithm, and may further account for secondary structures, such as self-complementarity within either the tracr sequence or tracr mate sequence.
  • the degree of complementarity between the tracr sequence and tracr mate sequence along the length of the shorter of the two when optimally aligned is about or more than about 25%, 30%, 40%», 50%, 60%», 70%, 80%», 90%, 95%, 97.5%, 99%, or higher.
  • Example illustrations of optimal alignment between a tracr sequence and a tracr mate sequence are provided in Figures 10B and I IB.
  • the tracr sequence is about or more than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, or more nucleotides in length.
  • the tracr sequence and tracr mate sequence are contained within a single transcript, such that hybridization between the two produces a transcript having a secondary structure, such as a hairpin.
  • Preferred loop forming sequences for use in hairpin structures are four nucleotides in length, and most preferably have the sequence GAAA. However, longer or shorter loop sequences may be used, as may alternative sequences.
  • the sequences preferably include a nucleotide triplet (for example, AAA), and an additional nucleotide (for example C or G).
  • loop forming sequences include CAAA and AAAG.
  • the transcript or transcribed polynucleotide sequence has at least two or more hairpins.
  • the transcript has two, three, four or five hairpins.
  • the transcript has at most five hairpins.
  • the single transcript further includes a transcription termination sequence; preferably this is a polyT sequence, for example six T nucleotides. An example illustration of such a hairpin structure is provided in the lower portion of Figure 1 IB, where the portion of the sequence 5' of the final "N" and upstream of the loop corresponds to the tracr mate sequence, and the portion of the sequence 3' of the loop corresponds to the tracr sequence.
  • single polynucleotides comprising a guide sequence, a tracr mate sequence, and a tracr sequence are as follows (listed 5' to 3'), where "N" represents a base of a guide sequence, the first block of lower case letters represent the tracr mate sequence, and the second block of lower case letters represent the tracr sequence, and the final poly-T sequence represents the transcription terminator: (I)
  • sequences (1) to (3) are used in combination with Cas9 from S. thermophilus CR1SPR1.
  • sequences (4) to (6) are used in combination with Cas9 from S. pyogenes.
  • the tracr sequence is a separate transcript from a transcript comprising the tracr mate sequence (such as illustrated in the top portion of Figure 1 IB).
  • the CRISPR enzyme is part of a fusio protein comprising one or more heterologous protein domains (e.g. about or more than about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more domains in addition to the CRISPR enzyme).
  • a CRISPR enzyme fusion protein may comprise any additional protein sequence, and optionally a linker sequence between any two domains.
  • epitope tags include istidine (His) tags, V5 tags, FLAG tags, influenza hemagglutinin (HA) tags, Myc tags, VSV-G tags, and thioredoxin (Trx) tags.
  • reporter genes include, but are not limited to, glutathione-S-transferase (GST), horseradish peroxidase (HRP), chloramphenicol acetyltransferase (CAT) beta-galactosidase, beta-glucuronidase, luciferase, green fluorescent protein (GFP), HcRed, DsRed, cyan fluorescent protein (CFP), yellow fluorescent protei (YFP), and autofluorescent proteins including blue fluoresce t protein (BFP).
  • GST glutathione-S-transferase
  • HRP horseradish peroxidase
  • CAT chloramphenicol acetyltransferase
  • beta-galactosidase beta-galactosidase
  • beta-glucuronidase beta-galactosidase
  • luciferase green fluorescent protein
  • GFP green fluorescent protein
  • HcRed HcRed
  • DsRed cyan fluorescent
  • a CRISPR enzyme may be fused to a gene sequence encoding a protein or a fragment of a protein that bind DNA molecules or bind other cellular molecules, includi g but not limited to maltose binding protein (MBP), S-tag, Lex A DNA binding domain (DBD) fusions, GAL4 DNA binding domain fusions, and herpes simplex virus (HSV) BP 16 protein fusions. Additional domains that may form part of a fusion protein comprising a CRISPR enzyme are described in US2Q110059502, incorporated herein by reference. In some embodiments, a tagged CRISPR enzyme is used to identify the location of a target sequence.
  • MBP maltose binding protein
  • DBD Lex A DNA binding domain
  • HSV herpes simplex virus
  • a reporter gene which includes but is not limited to glutathione-S-transferase (GST), horseradish peroxidase (HRP), chloramphenicol acetyltransferase (CAT) beta-galactosidase, beta-glucuronidase, luciferase, green fluorescent protem (GFP), HcRed, DsRed, cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), and autofluorcsccnt proteins including blue fluorescent protein (BFP), may be introduced into a cell to encode a gene product which serves as a marker by which to measure the alteration or modification of expression of the gene product.
  • GST glutathione-S-transferase
  • HRP horseradish peroxidase
  • CAT chloramphenicol acetyltransferase
  • CAT chloramphenicol acetyltransferase
  • beta-galactosidase beta-galactosidas
  • the DNA molecule encoding the gene product may be introduced into the cell via a vector.
  • the gene product is luciferase.
  • the expression of the gene product is decreased.
  • the invention provides methods comprising delivering one or more polynucleotides, such as or one or more vectors as described herein, one or more transcripts thereof, and/or one or proteins transcribed therefrom, to a host cell.
  • the invention serves as a basic platform for enabling targeted modification of DNA -based genomes. It can interface with many devlivery systems, including but not limited to viral, liposome, electroporation, microinjection and conjugation.
  • the invention further provides cells produced by such methods, and organisms (such as animals, plants, or fungi) comprising or produced from such cells.
  • a CRISPR enzyme in combination with (and optionally complexed with) a guide sequence is delivered to a cell.
  • Non-viral vector delivery systems include DNA plasmids, RNA (e.g. a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery vehicle, such as a liposome.
  • Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes a ter delivery to the cell.
  • Methods of non-viral delivery of nucleic acids include lipofection, nucleofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conj ugates, naked DNA, artificial virions, and agent-enhanced uptake of DN A.
  • Lipofection is described in e.g., U.S. Pat. Nos. 5,049,386, 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., TransfectamTM and LipofectmTM).
  • Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91/17424; WO 91/16024. Delivery can be to cells (e.g. in vitro or ex vivo administration) or target tissues (e.g. in vivo administration).
  • lipid:nucleic acid complexes including targeted liposomes such as immunolipid complexes
  • Boese et al Cancer Gene Ther. 2:291 -297 (1995); Behr et al, Bioconjugate Chem. 5:382-389 (1994); Remy et al., Bioconjugate Chem. 5:647-654 (1994); Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et ai., Cancer Res. 52:4817-4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501 ,728, 4,774,085, 4,837,028, and 4,946,787).
  • RNA or DNA viral based systems for the delivery of nucleic acids take advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus.
  • Viral vectors can be administered directly to patients (in vivo) or they can be used to treat cells in vitro, and the modified cells may optionally be administered to patients (ex vivo).
  • Conventional viral based systems could include retroviral, lenti virus, adenoviral, adeno-associated and herpes simplex virus vectors for gene transfer. Integration in the host genome is possible with the retrovirus, ientivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene.
  • Retroviral vectors are retroviral vectors that are able to transduce or infect non-dividing ceils and typically produce high viral titers. Selection of a retroviral gene transfer system would therefore depend on the target tissue. Retroviral vectors are comprised of cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target ceil to provide permanent transgene expression.
  • Widely used retroviral vectors include those based upon murine leukemia vims (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency vims (SIV), human immuno deficiency vims (HIV), and combinations thereof (see, e.g., Buchscher et al, J. Virol. 66:2731 -2739 (1992); Johann et al., I. Virol. 66: 1635-1640 ( 1992); Sommnerfelt et al., Virol. 176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al, J. Virol.
  • adenoviral based systems may be used.
  • Adenoviral based vectors are capable of very high transduction efficiency in many cell types and do not require cell division. With such vectors, high titer and levels of expression have been obtained. This vector can be produced in large quantities in a relatively simple system.
  • Adeno-associated virus vectors may also be used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures (see, e.g., West et al, Virology 160:38-47 (1987); U.S. Pat. No. 4,797,368; WO 93/24641; otin, Human Gene Therapy 5:793-801 (1994); Muzyczka, .1. Clin. Invest. 94: 1351 (1994). Construction of recombinant AAV vectors are described in a number of publications, including U.S. Pat. No.
  • Packagmg ceils are typically used to form vims particles that are capable of infecting a host cell.
  • Such cells include 293 cells, which package adenovirus, and ⁇ 2 cells or PA317 cells, which package retrovirus.
  • Viral vectors used in gene therapy are usually generated by producing a cell line that packages a nucleic acid vector into a viral particle.
  • the vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, other viral sequences being replaced by an expression cassette for the polynucieotide(s) to be expressed.
  • the missing viral functions are typically supplied in trans by the packaging cell line.
  • AAV vectors used in gene therapy typically only possess ITR sequences from the AAV genome which are required for packaging and integration into the host genome.
  • Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences.
  • the cell line may also be infected with adenovirus as a helper.
  • the helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid.
  • the helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV. Additional methods for the delivery of nucleic acids to cells are known to those skilled in the art. See, for example, US20030087817, incorporated herein by reference.
  • a host cell is transiently or non-transiently transfected with one or more vectors described herein.
  • a ceil is transfected as it naturally occurs in a subject.
  • a cell that is transfected is taken from a subject.
  • the cell is derived from cells taken from a subject, such as a ceil line. A wide variety of cell lines for tissue culture are known in the art.
  • cell lines include, but are not limited to, C8161 , CCRF-CEM, MOLT, mI CD-3, NHDF, HeLa-S3, Huh l, i !uhA Huh7, HUVEC, HASMC, HEKn, HEKa, MiaPaCell, Panel , PC-3, TFI, CTLL-2, CiR, Rat6, CV l , RPTE, A10, T24, J82, A375, ARH-77, Calul, SW480, SW620, SKOV3, SK-UT, CaCo2, P388D1, SEM-K2, WEHI-231, HB56, TIB55, Jurkat, J45.01, LRMB, Bci-I, BC-3, IC21, DLD2, Raw264.7, NRK, NRK-52E, MRC5, MEF, Hep G2, HeLa B, HeLa T4, COS, COS-1 , COS-6, COS-M6A, BS-
  • a cell transfected with one or more vectors described herein is used to establish a new cell line comprising one or more vector-derived sequences
  • a cell transiently transfected with the components of a CRISPR system as described herein such as by transient transfection of one or more vectors, or transfection with RNA
  • RNA transient transfection of one or more vectors, or transfection with RNA
  • cells transiently or non-transiently transfected with one or more vectors described herein, or cell lines derived from such ceils are used in assessing one or more test compounds.
  • aspects of the invention relate to the generation of isogenic lines of mammalian cells for the study of genetic variations in disease.
  • a further aspect of the invention relates to the generation of genetically-modified animal models, either transgenic or viral -mediated delivery.
  • the invention also comprehends genome modification of microbes, cells, plants, animals or synthetic organisms for the generation of biomedically, agriculturally, and industrially useful products.
  • the invention comprehends gene therapy.
  • the invention may be used as a biological researc tool, for understanding the genome, e.g. gene knockout studies.
  • the inventions relates to many other methods and compositions that depend on the basic ability of editing and rewriting the DNA content of genomes, as well as targeted inactivation of DNA- based organisms.
  • the invention also may be used as therapeutic for targeting specific strains of bacterial infections, viral infection, etc.
  • one or more vectors described herein are used to produce a non-human transgenic animal or transgenic plant.
  • the transgenic animal is a mammal, such as a mouse, rat, or rabbit.
  • the organism or subject is a plant.
  • the organism or subject or plant is algae.
  • Methods for producing transgenic plants and animals are known in the art, and general ly begin with a method of cell transfection, such as described herein.
  • Transgenic animals are also provided, as are transgenic plants, especially crops and algae. The transgenic animal or plant may he useful in applications outside of providing a disease model.
  • transgenic plants especially pulses and tubers, and animals, especially mammals such as livestock (cows, sheep, goats and pigs), but also poultry and edible insects, are preferred.
  • Transgenic algae or other plants such as rape may be particularly useful in the production of vegetable oils or biofuels such as alcohols (especially methanol and ethaiiol), for instance. These may be engineered to express or overexpress high levels of oil or alcohols for use in the oil or biofuel industries.
  • alcohols especially methanol and ethaiiol
  • the invention provides for methods of modifying a target polynucleotide in a eukaryotic cell, which may be in vivo, ex vivo or in vitro.
  • the method comprises sampling a cell or population of cells from a human or non- human animal or plant (including micro-algae), and modifying the cell or cells. Culturing may occur at any stage ex vivo. The cell or cells may even be re -introduced into the non-human animal or plant (including micro-algae).
  • the invention provides for methods of modifying a target polynucleotide in a eukaryotic cell.
  • the method comprises allowing a CRISPR complex to bind to the target polynucleotide to effect cleavage of said target polynucleotide thereby modifying the target polynucleotide, wherein the CRISPR. complex comprises a CRISPR enzyme complexed with a guide sequence hybridized to a target sequence within said target polynucleotide, wherein said guide sequence is linked to a tracr mate sequence which in turn hybridizes to a tracr sequence.
  • the invention provides a method of modifying expression of a polynucleotide in a eukaryotic cell.
  • the method comprises allowing a CRISPR complex to bind to the polynucleotide such that said binding results in increased or decreased expression of said polynucleotide; wherein the CRISPR complex comprises a CRISPR enzyme complexed with a guide sequence hybridized to a target sequence within said polynucleotide, wherei said guide sequence is linked to a tracr mate sequence which i turn hybridizes to a tracr sequence.
  • pathogens are often host-specific.
  • Fusarium oxysporum f. sp. lycopersici causes tomato wilt but attacks only tomato
  • Plants have existing and induced defenses to resist most pathogens. Mutations and recombination events across plant generations lead to genetic variability that gives rise to susceptibility, especial!)? as pathogens reproduce with more frequency than plants.
  • there can be non-host resistance e.g., the host and pathogen are incompatible.
  • Horizontal Resistance e.g., partial resistance against all races of a pathogen, typically controlled by many genes
  • Vertical Resistance e.g., complete resistance to some races of a pathogen but not to other races, typically controlled by a few genes.
  • Plant and pathogens evolve together, and the genetic changes in one balance cha ges i other.
  • breeders combine most useful genes for Yield, Quality, Uniformity, Hardiness, Resistance.
  • the sources of resistance genes include native or foreign Varieties, Heirloom Varieties, Wild Plant Relatives, and Induced Mutations, e.g., treating plant material with mutagenic agents.
  • the invention provides kits containing any one or more of the elements disclosed in the above methods and compositions.
  • the kit comprises a vector system and instructions for using the kit.
  • the vector system comprises (a) a first regulatory element operably linked to a iracr mate sequence and one or more insertion sites for inserting a guide sequence upstream of the tracr mate sequence, wherein when expressed, the guide sequence directs sequence-specific binding of a CRISPR complex to a target sequence in a eukaryotic cell, wherein the CRISPR comple comprises a CRISPR enzyme complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the tracr mate sequence that is hybridized to the tracr sequence; and/or (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said CRISPR enzyme comprising a nuclear localization sequence.
  • Elements may be provided individually or in combinations, and may be provided in any suitable container, such as a vial, a bottle, or a tube.
  • the kit includes instructions in one or more languages, for example in more tha one language.
  • a kit comprises one or more reage ts for use in a process utilizing one or more of the elements described herein.
  • Reagents may be provided in any suitable container.
  • a kit may provide one or more reaction or storage buffers.
  • Reagents may be provided in a form that is usable in a particular assay, or in a form that requires addition of one or more other components before use (e.g. in concentrate or lyophilizcd form).
  • a buffer can be any buffer, including but not limited to a sodium carbonate buffer, a sodium bicarbonate buffer, a borate buffer, a Tris buffer, a MOPS buffer, a HEPES buffer, and combinations thereof.
  • the buffer is alkaline.
  • the buffer has a pH from about 7 to about 10.
  • the kit comprises one or more oligonucleotides corresponding to a guide sequence for insertion i to a vector so as to operably link the guide sequence and a regulatory element.
  • the kit comprises a homologous recombination template polynucleotide.
  • the invention provides methods for using one or more elements of a CRISPR system.
  • the CRISPR complex of the invention provides an effective means for modifying a target polynucleotide.
  • the CRISPR complex of the Invention has a wide variety of utility including modifying (e.g., deleting, inserting, translocating, inactivating, activating) a target polynucleotide in a multiplicity of cell types.
  • modifying e.g., deleting, inserting, translocating, inactivating, activating
  • the CRISPR complex of the invention has a broad spectrum of applications in, e.g., gene therapy, drug screening, disease diagnosis, and prognosis.
  • An exemplary CRISPR comple comprises a CR1SPR enzyme eomple ed with a guide sequence hybridized to a target sequence within the target polynucleotide.
  • the guide sequence is linked to a tracr mate sequence, which in turn hybridizes to a tracr sequence.
  • the target polynucleotide of a CRISPR complex can be any polynucleotide endogenous or exogenous to the eukaryotic cel l.
  • the target polynucleotide can be a polynucleotide residing in the nucleus of the eukaryotic celi.
  • the target polynucleotide can be a sequence coding a gene product (e.g., a protein) or a non-coding sequence (e.g., a regulator polynucleotide or a junk DNA).
  • the target sequence should be associated with a PAM (protospacer adjacent motif); that is, a short, sequence recognized by the CRISPR complex.
  • PAM protospacer adjacent motif
  • the precise sequence and length requirements for the PAM differ depending on the CRISPR enzyme used, but PAMs are typically 2-5 base pair sequences adjacent the protospacer (that is, the target sequence) Examples of PAM sequences are given in the examples section below, and the skilled person will be able to identify further PAM sequences for use with a given CRISPR enzyme.
  • the target polynucleotide of a CRISPR complex may include a number of disease- associated genes and polynucleotides as well as signaling biochemical pathway-associated genes and polynucleotides as listed in US provisional patent applications 61/736,527 and 61/748,427 having Broad reference BI-2011/008/WSGR Docket No. 44063-701.101 and BI ⁇ 201 1/008/WSGR Docket No. 44063-701 .102 respectively, both entitled SYSTEMS METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION filed on December 12, 2012 and January 2, 2013, respectively, the contents of all of which are herein incorporated by reference in their entirety.
  • target polynucleotides include a sequence associated with a signaling biochemical pathway, e.g., a signaling biochemical pathway-associated gene or polynucleotide.
  • target polynucleotides include a disease associated gene or polynucleotide.
  • a "disease-associated" gene or polynucleotide refers to any gene or polynucleotide which is yielding transcription or translation products at an abnormal level or in an abnormal form in cells derived from a disease-affected tissues compared with tissues or cel ls of a non disease control.
  • a disease-associated gene also refers to a gene possessing Sunation(s) or genetic variation that is directly responsible or is in linkage disequilibrium with a gene(s) thai is responsible for the etiology of a disease.
  • the transcribed or translated products may be known or unknown, and may be at a normal or abnormal level.
  • Parkinson's Disease x-Synuclein DJ-1 ; LRR 2; Parkin; PINK1
  • BCL7A BCL7
  • BCL7A BCL7
  • Leukemia TALI
  • oncology TCL5, SCL, TAL2, FLT3, NBS1 , NBS, ZNFN1A1, IK1, LYF1, diseases and disorders HOXD4, HOX4B.
  • RASK2 B-ceil non-Hodgkin lymphoma
  • GMPS GMPS, AF10, ARHGEF12, LARG, KIAA0382, CALM, CLTH, CEBPA, CEBP, CHIC 2, BTL, FLT3, KIT, PBT, LPP, NPMl , NUP214, D9S46E, CAN, CAIN, RUN 1, CBFA2, AM , WHSC 1L1 , NSD3, FLT3, AF1Q, NPMl , NUMA 1, ZNF145, PLZF, PML, MYL, STAT5B, AFIO, CALM, CLTH, ARL11, ARLTS1, P2RX7, P2X7, BCR, CML, PHL, ALL, GRAF, NF1 , VRNF, WSS, NFNS, PTPN 11, PTP2C, SHP2, NS1 , BCL2, CCND1 , PRAD1 , BCL1, TCRA, GATA1, GF1 , ERYF1 , NFE1, ABLL NQO
  • Inflammation and AIDS KIR3DLI, NKAT3, NKBI, AMB11, IR3DS1, IFNG, CXCL12, immune related SDF1; Autoimmune lymphoproiiferative syndrome (TNFRSF6,, ⁇ ' ⁇ , diseases and disorders FAS, CD95, ALPSIA); Combined immunodeficiencY, (IL2RG,
  • SCIDXl SCIDX, IMD4
  • HIV-1 CCL5, SCYA5, D17S136E, TCP2248
  • HIV susceptibility or infection HIV susceptibility or infection
  • CF CF, MRP7
  • Glycogen storage diseases SLC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM
  • Hepatic adenoma 142330 (TCF1 , HNFI A, MODY3), Hepatic failure, early onset, and neurologic disorder (SCOD1 , SCOl).
  • CIP Hepatic lipase deficiency
  • CTNNB1 Hepatic lipase deficiency
  • PDGFR L Hepatoblastoma
  • PDGRL Hepatoblastoma
  • PRLTS PRLTS
  • AXI 1 ⁇
  • CTNNB1 TP53, P53, LFS1, IGF2R, MPRJ, MET, CASP8, MCH5;
  • Medullary cystic kidney disease (UMOD, HNFJ, FJHN, MCKD2, ADMCKD2); Phenylketonuria (PAH, P U 1, QD R, DHPR, PTS); Polycystic kidney and hepatic disease (FCYT, PKHDl, ARPKD, PKDl, PKD2, PKD4, PKDTS, PR CSH, G19P1, PCLD, SEC63).
  • DMD Muscular / Skeletal Becker muscular dystrophy
  • DMD Muscular / Skeletal Becker muscular dystrophy
  • DMD Duchenne Muscular diseases and disorders Dystrophy
  • LMNA Emery-Dreifuss muscular dystrophy
  • LGMD2I LAMA2, LAMM, LARGE, KIAA0609, MDC I D, FCMD, TTID, MYOT, CAPN3, CANP3, DYSF, LGMD2B, SGCG, LGMD2C, DMDA1 , SCG3, SGCA, ADL, DAG2, LGMD2D, DMDA2, SGCB, LGMD2E, SGCD, SGD, LGMD2F, CMD1 L, TCAP, LGMD2G, CMD1 N, TRIM32, HT2A, LGMD2H, FKRP, MDC1C. LGMD2I, TTN.
  • LRP5 BMND1, LRP7, LR3, OPPG, VBCH2, CLC 7, CLC7, OPTA2, OSTM1, GL, TCIRG1, T1RC7, OC1 16, OPTB1
  • Muscular atrophy VAPB, VA
  • Neurological and ALS SOD1, ALS2, STEX, FUS, TARDBP, VEGF (VEGF-a, VEGF-b, neuronal diseases and VEGF-c); Alzheimer disease (APP, AAA, CVAP, AD1, APOE, AD2, disorders PSEN2, AD4, STM2, APBB2, FE65L1, NOS3, PLAU, UR , ACE,
  • SERPINA7 [seipiii peptidase inhibitor, clade A (alpha- 1 antiproteinase, antitrypsin), member 7];” AND “SERPINA6 (serpin peptidase inhibitor, clade A. (alpha- 1 antiproteinase, antitrypsin), member 6)
  • Trpal Pome; Cgrp; Of; Pica; Era; Nr2b; TRPM5; Prkaca;
  • Prkacb Prka l a
  • Prkar2a Prkacb
  • Wnt2b Wnt3a; Wnt4; Wnt5a; Wnt6; WntTb; Wnt8b;
  • Embodiments of the invention also relate to methods and compositions related to knocking out genes, amplifying genes and repairing particular mutations associated with DNA repeat instability and neurological disorders (Robert. D. Wells, Tetsuo Ashizawa, Genetic Instabilities and Neurological Diseases, Second Edition, Academic Press, Oct 13, 201 1 - Medical). Specific aspects of tandem repeal sequences have been found to be responsible for more than twenty human diseases (New insights into repeat instability: role of RNA'DNA hybrids, Mclvor EI, Polak U, Napieraia M. RNA Biol. 2010 Sep-Oct;7(5):551-8). The CRISPR- Cas system may be harnessed to con'ect these defects of genomic instability,
  • a further aspect of the invention relates to utilizing the CRISPR-Cas system for correcting defects in the EMP2A and EMP2B genes that have been identified to be associated with Lafora disease.
  • Lafora disease is an autosomal recessive condition which is characterized by progressive myoclonus epilepsy which may start as epileptic seizures in adolescence. A few cases of the disease may be caused by mutations in genes yet to be identified. The disease causes seizures, muscle spasms, difficulty walking, dementia, and eventually death. There is currently no therapy that has proven effective against disease progression.
  • the CRISP R-Cas system may be used to correct ocular defects that arise from several genetic mutations further described in Genetic Diseases of the Eye, Second Edition, edited by Elias I. Traboulsi, Oxford University Press, 2012.
  • the genetic brain diseases may include but are not limited to Adrenoleukodystrophy, Agenesis of the Corpus Callosum, Aicardi Syndrome, Alpers' Disease, Alzheimer's Disease, Barth Syndrome, Batten Disease, CADASIL, Cerebellar Degeneration, Fabry's Disease, Gerstmann-Straussler-Scheinker Disease, Huntington's Disease and other Triplet Repeat Disorders, Leigh's Disease, Lesch-Nyhan Syndrome, Menkes Disease, Mitochondrial Myopathies and NINDS Colpocephaly. These diseases are further described on the website of the National Institutes of Health under the subsection Genetic Brain Disorders.
  • the condition may be neoplasia.
  • the genes to be targeted are any of those listed in Table A (in this case PTEN asn so forth).
  • the condition may be Age-related Macular Degeneration.
  • the condition may be a Schizophrenic Disorder.
  • the condition may be a Trinucleotide Repeat Disorder.
  • the condition may be Fragile X Syndrome.
  • the condition may be a Secretase Related Disorder.
  • the conditio may be a Prion - related disorder.
  • the condition may be ALS.
  • the condition may be a dmg addiction. In some embodiments, the co dition may be Autism. In some embodiments, the condition may be Alzheimer's Disease. In some embodiments, the condition may be inflammation. In some embodiments, the condition may be Parkinson's Disease.
  • proteins associated with Parkinson's disease include but are not limited to a-synuclein, DJ-1, LRRK2, PINK! , Parkin, UCHL1, Synphilin-1, and NURRl .
  • Examples of addiction-related proteins may include ABAT for example,
  • inflammation-related proteins may include the monocyte chemoattractant protein- 1 (MCP1) encoded by the Ccr2 gene, the C-C chemokine receptor type 5 (CCR5) encoded by the Ccr5 gene, the IgG receptor ⁇ (FCGR2b, also termed CD32) encoded by the Fcgr2b gene, or the Fc epsilon R ig (FCER lg) protein encoded by the Fcerlg gene, for example.
  • MCP1 monocyte chemoattractant protein- 1
  • CCR5 C-C chemokine receptor type 5
  • FCGR2b also termed CD32
  • FCER lg Fc epsilon R ig
  • cardiovascular diseases associated proteins may include IL1B (interleukirs 1, beta), XDH (x an thine dehydrogenase), TP53 (tumor protein p53), PTG1S (prostagla din 12 (prostacyclin) synthase), MB (myoglobin), IL4 (interleukiii 4), ANGPTl (angiopoietin 1 ), ABCG8 (ATP-binding cassette, sub-family G (WHITE), member 8), or CTS (cathepsiii K), for example.
  • IL1B interleukirs 1, beta
  • XDH x an thine dehydrogenase
  • TP53 tumor protein p53
  • PTG1S prostagla din 12 (prostacyclin) synthase)
  • MB myoglobin
  • IL4 interleukiii 4
  • ANGPTl angiopoietin 1
  • ABCG8 ATP-binding cassette, sub-family G
  • Examples of A lzheimer's disease associated proteins may include the very low density lipoprotein receptor protein (VLDLR) encoded by the VLDLR gene, the ubiquitin-iike modifier activating enzyme 1 (UBA1) encoded by the UBA.1 gene, or the NEDD8-aetivating enzyme El catalytic subunit protem (UBEIC) encoded by the UBA3 gene, for example.
  • VLDLR very low density lipoprotein receptor protein
  • UBA1 ubiquitin-iike modifier activating enzyme 1
  • UBA3 NEDD8-aetivating enzyme El catalytic subunit protem
  • proteins associated Autism Spectrum Disorder may include the benzodiazepine receptor (peripheral ) associated protein 1 (BZRAPl ) encoded by the BZRAP! gene, the AF4/FMR2 family member 2 protein (AFF2) encoded by the AFF2 gene (also termed MFR2), the fragile X mental retardation autosomal homolog 1 protein (FXRl ) encoded by the FXR 1 gene, or the fragile X mental retardation autosomal homolog 2 protein (FXR2) encoded by the FXR2 gene, for example.
  • BZRAPl benzodiazepine receptor
  • AFF2 AF4/FMR2 family member 2 protein
  • FXRl fragile X mental retardation autosomal homolog 1 protein
  • FXR2 fragile X mental retardation autosomal homolog 2 protein
  • proteins associated Macular Degeneration may include the ATP-binding cassette, sub-family A (ABC1) member 4 protein (ABCA4) encoded by the ABCR gene, the apo lipoprotein E protein (APOE) encoded by the APOE gene, or the chemokine (C-C motif) Ligand 2 protein (CCL2) encoded by the CCL2 gene, for example.
  • ABC1 sub-family A
  • APOE apo lipoprotein E protein
  • CCL2 Ligand 2 protein
  • proteins associated Schizophrenia may include R.G1 , ErbB4, CPLXl, TPHl, TPH2, NRXNl, GSK3A, BDNF, DISCI, GS 3B, and combmations thereof.
  • proteins involved in tumor suppression may include ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3 related), EGFR (epidermal growth factor receptor), ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2), ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3), ERBB4 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 4), Notch 1, Notch2, Notch 3, or Notch 4, for example.
  • ATM ataxia telangiectasia mutated
  • ATR ataxia telangiectasia and Rad3 related
  • EGFR epidermal growth factor receptor
  • ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2
  • ERBB3 v-erb-b2 erythroblastic leukemia viral
  • proteins associated with a secretase disorder may include PSENEN (presenilin enhancer 2 homolog (C. elegans)), CTSB (cathepsiii B), PSEN1 (preseiiilin 1), APP (amyloid beta (A4) precursor protein), APHI B (anterior pharynx defective 1 homolog B (C. elegans)), PSEN2 (presenilin 2 (Alzheimer disease 4)), or BACE1 (beta-site APP-cleaving enzyme 1), for example.
  • proteins associated with Amyotrophic Lateral Sclerosis may include SODl (superoxide dismutase 1 ), ALS2 (amyotrophic lateral sclerosis 2), FUS (fused in sarcoma), TARDBP (TAR DNA binding protein), VAGFA (vascular endothelial growth factor A), VAGFB (vascular endothelial growth factor B), and VAGFC (vascular endothelial growth factor C), and any combination thereof,
  • proteins associated with prion diseases may include SODl (superoxide dismutase 1), ALS2 (amyotrophic lateral sclerosis 2), FUS (fused in sarcoma), TARDBP (TAR DNA binding protein), VAGFA (vascular endothelial growth factor A), VAGFB (vascular endothelial growth factor B), and VAGFC (vascular endothelial growth factor C), and any combination thereof.
  • proteins related to neurodegenerative conditions in prion disorders may include A2M (Alpha-2-Macroglobulin), AATF (Apoptosis antagonizing transcription factor), ACPP (Acid phosphatase prostate), ACTA2 (Actin alpha 2 smooth muscle aorta), ADAM22 (ADAM metallopeptidase domain), ADORA3 (Adenosine A3 receptor), or ADRA 1D (Alpha-I D adrenergic receptor for A lpha- ID adrenoreeeptor), for example.
  • A2M Alpha-2-Macroglobulin
  • AATF Apoptosis antagonizing transcription factor
  • ACPP Acid phosphatase prostate
  • ACTA2 Actin alpha 2 smooth muscle aorta
  • ADAM22 ADAM metallopeptidase domain
  • ADORA3 Adosine A3 receptor
  • ADRA 1D Alpha-I D adrenergic receptor for A lpha- ID a
  • proteins associated with Immunodeficiency may include A2M [alpha-2- macroglobulin]; AANAT [arylalkylamine N -acet l transferase] ; ABCA! [ATP -binding cassette, sub-family A (ABCl ), member ! ]; ABCA2 [ATP-binding cassette, sub-family A (ABCl ), member 2]; or ABCA3 [ATP-binding cassette, sub-family A (ABCl), member 3]; for example.
  • proteins associated with Trinucleotide Repeat Disorders include A (androgen receptor), FMR1 (fragile X mental retardation 1), HTT (lumtingtin), or DMP (dystrophia myotonica-protein kinase), FXN (frataxin), ATXN2 (ataxin 2), for example.
  • proteins associated with Neurotransmission Disorders include SST (somatostatin), NQSl (nitric oxide synthase 1 (neuronal)), ADRA2A (adrenergic, a!pha-2A-, receptor), ADRA2C (adrenergic, alpha-2C-, receptor), TACR1 (tachykinin receptor 1), or HTR2c (5-hydroxytryptamine (serotonin) receptor 2C), for example.
  • neurodevelopn ental-associated sequences include A2BP1 [ataxin 2- binding protein 1], AADAT [aminoadipate aminotransferase], AANAT [arylalkylamine N- acetyltransferase], ABAT [4-aminobtityrate aminotransferase], ABCA1 [ATP-hmdmg cassette, sub-family A (ABC1), member 1], or ABC A i 3 [ATP-binding cassette, sub-family A (ABC1), member 13], for example.
  • A2BP1 ataxin 2- binding protein 1
  • AADAT aminoadipate aminotransferase
  • AANAT arylalkylamine N- acetyltransferase
  • ABAT 4-aminobtityrate aminotransferase
  • ABCA1 ATP-hmdmg cassette, sub-family A (ABC1), member 1]
  • ABC A i 3 ATP-binding cassette, sub-family A
  • FIG. 1 Aieardi-Goutieres Syndrome; Alexander Disease; Allan- Hern don- Dudiey Syndrome; POLG-Reiated Disorders; Alpha-Mannosldosis (Type II and III); Alstrom Syndrome; Angelman; Syndrome; Ataxia-Telangiectasia; Neuronal Ceroid-Lipofuscinoses; Beta- Thalassemia; Bilateral Optic Atrophy and (Infantile) Optic Atrophy Type 1; Retinoblastoma (bilateral); Canavan Disease; Cerebrooculofacioskeletal Syndrome 1 [COFSJ ]; Cerebrotcndinous Xanthomatosis; Cornelia de Lange Syndrome; MAPT-Reiated Disorders; Genetic Prion Diseases; Dravet Syndrome; Early-Onset Familial Alzheimer Disease; Friedreich Ataxia [FRDA]; Fryns Syndrome; Fucosidosis; Fukuyama Congenital Muscular Dyst
  • the present system can be used to target any polynucleotide sequence of interest.
  • Some examples of conditions or diseases that might be useful ly treated using the present system are included in the Tables above and examples of genes currently associated with those conditions are also provided there. However, the genes exemplified are not exhaustive.
  • Example 1 CRISPR Complex Activity in the Nucleus of a Eukaryotic Cell
  • An example type II CRISPR system is the type II CRISPR locus from Streptococcus pyogenes SF370, which contains a cluster of four genes Cas9, Cas l, Cas2, and Csn l, as well as two non-coding RNA elements, tracrRNA and a characteristic array of repetitive sequences (direct repeats) interspaced by short stretches of non-repetitive sequences (spacers, about 30bp each).
  • DSB targeted DNA double-strand break
  • Figure 2A First, two non-coding RNAs, the pre-crRNA array and tracrRNA, are transcribed from the CRISPR locus.
  • tracrRNA hybridizes to the direct repeats of pre- crRNA, which is then processed into mature crRNAs containing individual spacer sequences.
  • the mature crRNA rtracrRN A complex directs Cas9 to the DNA target consisting of the protospacer and the corresponding PAM via heterodupiex formation between the spacer region of the crRNA and the protospacer DNA.
  • Cas9 mediates cleavage of target DNA upstream of PAM to create a DSB within the protospacer ( Figure 2A),
  • This example describes an example process for adapting this RNA-programmable nuclease system to direct CR ISPR complex activity in the nuclei of eukaryotic cells.
  • HEK Human embryonic kidney
  • HEK 293 FT Human embryonic kidney (HEK) cell line HEK 293 FT (Life Technologies) was maintained in Duibecco's modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine seram (HyClone), 2mM GlutaMAX (Life Technologies), lOOU/mL penicillin, and IQOjtg mL streptomycin at 37°C with 5% CO2 incubation.
  • DMEM Duibecco's modified Eagle's Medium
  • Mouse neuro2A (N2A) cell line was maintained with DMEM supplemented with 5% fetal bovine serum (HyCSone), 2mM GlutaMAX (Life Technologies), lOOU/mL penicillin, and 100 ⁇ / ⁇ streptomycin at 37°C with 5% C0 2 .
  • HEK 293FT or N2A cells were seeded into 24-well plates (Corning) one day prior to transfection at a density of 200,000 ceils per well. Cells were transfected using Lipofectamine
  • HEK 293FT or N2A cells were transfected with plasmid DNA as described above.
  • the cells were incubated at 37°C for 72 hours before genomic DNA extraction.
  • the genomic region surrounding a CR!SPR target site for each gene was PGR amplified, and products were purified using QiaQuick Spin Column (Qiagen) following manufacturer's protocol.
  • a total of 4()()ng of the purified PGR products were mixed with 2 ⁇ 1 10X Taq polymerase PCR buffer (Enzymatics) and ultrapure water to a final volume of 20 ⁇ 1, and subjected to a re-annealing process to enable heteroduplex formation: 95°C for 10m in, 95°C to 85°C ramping at - 2°C/s, 85°C to 25°C at - 0.25°C/s, and 25°C hold for 1 minute.
  • HEK 293 FT and N2A ceils were transfected with plasmid DNA, and incubated at 37°C for 72 hours before genomic DNA extraction as described above.
  • the target genomic region was PCR amplified using primers outside the homology arms of the homologous recombination (HR) template.
  • PCR products were separated on a 1% agarose gel and extracted with MinElute Gel Extraction Kit (Qiagen), Purified products were digested with Hindll i (Fermentas) and analyzed on a 6% Novex TBE poly-acrylamide gel (Life Technologies).
  • RNA secondary structure prediction was performed using the online webserver RNAfold developed at Institute for Theoretical Chemistry at the University of Vienna, using the eentroid structure prediction algorithm (see e.g. A.R. Gruber et al, 2008, Cell 106( 1 ): 23-24; and PA Carr and GM Church, 2009, Nature Biotechnology 27(12): 1151-62).
  • HEK 293FT cells were maintained and transfected as stated above. Cells were harvested by trypsinization followed by washing in phosphate buffered saline (PBS). Total cell RNA was extracted with TRI reagent (Sigma) following manufacturer's protocol. Extracted total RNA was quantified using Naonodrop (Thermo Scientific) and normalized to same concentration.
  • RNAs were mixed with equal volumes of 2X loading buffer (Ambion), heated to 95°C for 5 min. chilled on ice for 1 mm, and then loaded onto 8% denaturing poiyacrylamide gels (SequaGel, National Diagnostics) after pre -running the gel for at least 30 minutes. The samples were electrophoresed for 1.5 hours at 40 W limit. Afterwards, the RNA was transferred to Hyboiid N+ membrane (GE Healthcare) at 300 mA in a semi-dry transfer apparatus (Bio-rad) at room temperature for 1 .5 hours. The RNA was crosslinked to the membrane using autocrosslink button on Stratagene IJY Crossliiiker the Stratalmker (Stratagene).
  • the membrane was pre-hybridized in ULTRAhyb-Oligo Hybridization Buffer (Ambion) for 30 min wit rotation at 42°C, and probes were then added and hybridized overnight. Probes were ordered from IDT and labeled with [gamma- "' P] ATP (Perkin Elmer) with T4 polynucleotide kinase (New England Biolabs). The membrane was washed once with pre-warmed (42°C) 2xSSC, 0,5% SDS for 1 min followed by two 30 minute washes at 2°C, The membrane was exposed to a phosphor screen for one hour or overnight at room temperature and then scanned with a phosphorimager (Typhoon).
  • CRISPR locus elements including tracrRNA, Cas9, and leader were PGR amplified from Streptococcus pyogenes SF370 genomic DNA with flanking homo fogy arms for Gibson Assembly. Two Bsal type IIS sites were introduced in between two direct repeats to facilitate easy insertion of spacers ( Figure 8). PGR products were cloned into EcoRV-digested pACYC184 downstream of the tet promoter using Gibson Assembly Master Mix (NEB). Other endogenous CRISPR system elements were omitted, with the exception of the last 50bp of Csn2.
  • Oligos Integrated DNA Technology
  • pDCGOO i&al-digested vector
  • T7 ligase Enzymatics
  • Challenge plasmids containing spacers with PAM [00152] expression in mammalian cells expression constructs illustrated in Figure 6A, with functionality as determined by results of the Surveyor assay shown in Figure 6B. Transcription start sites are marked as +1, and transcription terminator and the sequence probed by northern blot are also indicated. Expression of processed tracrRN A was also confirmed by Northern blot.
  • Figure 6C shows results of a Northern blot analysis of total RNA extracted from 293 FT cells transfected with U6 expression constructs carrying long or short tracrRNA, as well as SpCas9 and DR-EMX1(1)-DR.
  • Left and right panels are from 293FT cells transfected without or with SpRNase III, respectively.
  • U6 indicate loading control blotted with a probe targeting human U6 snRNA.
  • Transfection of the short tracrRNA expression construct led to abundant levels of the processed form of tracrRNA (-75bp). Very low amounts of long tracrRNA are detected on the Northern blot.
  • RNA polymerase Ill-based U6 promoter was selected to drive the expression of tracrRNA ( Figure 2C).
  • a U6 promoter-based construct was developed to express a pre-crRNA array consisting of a single spacer flanked by two direct repeats (DRs, also encompassed by the term "tracr-mate sequences"; Figure 2C).
  • the initial spacer was designed to target a 33-base-pair (bp) target site (30-bp protospacer plus a 3 -bp CRISPR motif (PAM) sequence satisfying the NGG recognition motif of Cas9) in the human EMXl locus ( Figure 2C), a key gene in the development of the cerebral cortex.
  • bp 33-base-pair
  • PAM 3 -bp CRISPR motif
  • HE 293FT cells were transfected with combinations of CRISPR components. Since DSBs in mammalian nuclei are partially repaired by the non-homologous end joining (NHEJ) pathway, which leads to the formation of indels, the Surveyor assay was used to detect potential cleavage activity at the target EMXl locus ( Figure 7) (see e.g. Guschin et al 2010, Methods Moi Biol 649: 247). Co-transfection of all four CRISPR.
  • NHEJ non-homologous end joining
  • Figure 12 provides an additional Northern blot analysis of crR A processing in mammalian cells.
  • Figure 12A illustrates a schematic showing the expression vector for a single spacer flanked by two direct repeats (DR-EMXl(l)-DR). The 30bp spacer targeting the human EMXl locus protospacer 1 (see Figure 6) and the direct repeat sequences are shown in the sequence beneath Figure 12A. The line indicates the region whose reverse-complement sequence was used to generate Northern blot probes for EMX1(1) crRNA detection.
  • Figure 12B shows a Northern blot analysis of total RNA extracted from 293FT cells transfected with U6 expression constructs carrying DR-EMX 1(1 )-DR.
  • DR-EMX1 (1 )-DR was processed into mature crRNAs only in the presence of SpCas9 and short tracrRNA and was not dependent on the presence of SpRNase III.
  • the mature crRNA detected from transfected 293FT total RNA is ⁇ 33bp and is shorter than the 39-42bp mature crRNA from S. pyogenes.
  • Figure 2 illustrates the bacterial CRISPR system described in this example.
  • Figure 2A il lustrates a schematic showing the CRISPR locus 1 from Streptococcus pyogenes SF370 and a proposed mechanism of CRISPR-mediated DNA cleavage by this system.
  • Mature crRNA processed from the direct repeat-spacer array directs Cas9 to genomic targets consisting of complimentary protospacers and a protospacer-adjacent motif (PAM).
  • PAM protospacer-adjacent motif
  • Cas9 mediates a double-strand break in the target DNA.
  • Figure 2B illustrates engineering of S.
  • FIG. 2C illustrates mammalian expression of SpCas9 and SpRNase ⁇ driven by the constitutive EFla promoter and tracrRNA and pre-crRNA array (DR-Spacer-DR) driven by the RNA Pol3 promoter U6 to promote precise transcription initiation and termination.
  • DR-Spacer-DR pre-crRNA array
  • FIG. 2D illustrates surveyor nuclease assay for SpCas9-mediated minor insertions and deletions.
  • SpCas9 was expressed with and without SpRNase III, tracrRNA, and a pre-crRNA array carrying the EMX1- target spacer.
  • Figure 2E illustrates a schematic representation of base pairing between target locus and EMXl -targeting crRNA, as well as an example chromatogram showing a micro deletion adjacent to the SpCas9 cleavage site.
  • Figure 2F illustrates mutated alleles identified from sequencing analysis of 43 clonal amplicons showing a variety of micro insertions and deletions. Dashes indicate deleted bases, and non-aligned or mismatched bases indicate insertions or mutations. Scale bar ::: ⁇ .
  • a chimeric crRNA-tracrRNA hybrid design was adapted, where a mature crRNA (comprising a guide sequence) may be fused to a partial tracrRNA via a stem-loop to mimic the natural crRNA :tracrRN A duplex.
  • a bicistronic expression vector was created to drive co -expression of a chimeric RNA and SpCas9 in transfected cells.
  • the bicistronic vectors were used to express a pre-crRNA (DR-guide sequence-DR) with SpCas9, to induce processing into crRNA with a separately expressed tracrRNA (compare Figure 1 I B top and bottom).
  • Figure 8 provides schematic illustrations of bicistronic expression vectors for pre-crRNA array ( Figure 8A) or chimeric crR A (represented by the short line downstream of the guide sequence insertion site and upstream of the EFla promoter in Figure 8B) with hSpCas9, showing location of various elements and the point of guide sequence insertion.
  • the expanded sequence around the location of the guide sequence insertion site in Figure 8B also shows a partial DR sequence (GTTTTAGAGCTA) (SEQ ID NO: 11) and a partial tracrRNA sequence (TAGCAAGTTAAAATAAGGCTAGTCCGTTTTT) (SEQ ID NO: 12).
  • Guide sequences can be inserted between Bbsl sites using annealed oligonucleotides.
  • FIG. 13 illustrates the selection of some additional targeted protospacers in human PVALB ( Figure 13 A) and mouse Th ( Figure 13B) loci. Schematics of the gene loci and the location of three protospacers within the last exon of each are provided. The underlined sequences include 30bp of protospacer sequence and 3bp at the 3' end corresponding to the PAM sequences.
  • Protospacers on the sense and anti-sense strands are indicated above and below the DNA sequences, respectively.
  • a modification rate of 6.3% and 0.75% was achieved for the human PVALB and mouse Th loci respectively, demonstrating the broad applicability of the CRISPR system in modifying different loci across multiple organisms (Figure 5). While cleavage was only detected with one out of three spacers for each locus using the chimeric constructs, all target sequences were cleaved with efficiency of indcl production reaching 27% when using the co- expressed pre-erRNA arrangement ( Figures 6 and 13).
  • Figure 11 provides a further illustration that SpCas9 can be reprogrammed to target multiple genomic loci in mammalian cells.
  • Figure 11A provides a schematic of the human ⁇ locus showing the location of five protospaeers, indicated by the underlined sequences.
  • Figure 11 B provides a schematic of the pre-crRNA/trcrRNA complex showing hybridization between the direct repeat region of the pre-erRNA and tracrRNA (top), and a schematic of a chimeric RNA design comprising a 20bp guide sequence, and tracr mate and tracr sequences consisting of partial direct repeat and tracrRNA sequences hybridized in a hairpin structure (bottom).
  • RNA Since the secondary structure of RNA can be crucial for intermolecular interactions, a structure prediction algorithm based on minimum free energy and Boltzmann-wcighted structure ensemble was used to compare the putative secondary structure of ail guide sequences used in the genome targeting experiment (see e.g. Gruber et al., 2008, Nucleic Acids Research, 36: WTO). Analysis revealed that in most cases, the effective guide sequences in the chimeric crRNA context were substantial ly free of secondary structure motifs, whereas the ineffective guide sequences were more likely to form internal secondary structures that could prevent base pairing with the target protospacer DNA. It is thus possible that variability in the spacer secondary structure might impact the efficiency of CRISPR-mediated interference when using a chimeric crRNA..
  • FIG 22 illustrates single expression vectors incorporating a U6 promoter linked to an insertion site for a guide oligo, and a Cbh promoter linked to SpCas9 coding sequence.
  • the vector shown in Figure 22b includes a tracrRNA coding sequence linked to an HI promoter.
  • Figure 3A illustrates results of a Surveyor nuclease assay comparing the cleavage efficiency of Cas9 when paired with different mutant chimeric RNAs.
  • Single-base mismatch up to 12-bp 5' of the PAM substantially abrogated genomic cleavage by SpCas9, whereas spacers with mutations at farther upstream positions retained activity against the original protospacer target ( Figure 3B).
  • SpCas9 has single-base specificity within the last 12-bp of the spacer. Furthermore, CRISPR is able to mediate genomic cleavage as efficiently as a pair of TALE nucleases (TALEN) targeting the same EMXl protospacer.
  • an aspartate-to-alanine substitution (D I OA) in the RuvC I catalytic domain of SpCas9 was engineered to convert the nuclease into a nickase (SpCas9n; illustrated in Figure 4A) (see e.g. Sapranausaks et al, 2011, Nucleic Acids Research, 39: 9275; Gasiunas et al, 2012, Proc. Natl. Acad. Sci. USA, 109:E2579), such that nicked genomic DNA undergoes the high-fidelity homo logy-directed repair (HDR). Surveyor assay confirmed that SpCas9n does not generate indels at the EMXl protospacer target.
  • D I OA aspartate-to-alanine substitution
  • Figure 4C provides a schematic il lustration of the HR strategy, with relative locations of recombination points and primer annealing sequences (arrows).
  • SpCas9 and SpCas9n indeed catalyzed integration of the HR template into the EMXl locus.
  • PCR. amplificatio of the target region followed by restriction digest with Hindlli revealed cleavage products corresponding to expected fragment sizes (arrows in restriction fragment length polymorphism gel analysis shown in Figure 4D), with SpCas9 and SpCas9n mediating similar levels of HR efficiencies.
  • Applicants further verified HR using Sanger sequencing of genomic amplicons (Figure 4E).
  • RNA to program sequence-specific DNA cleavage defines a new class of genome engineering tools for a variety of research and industrial applications.
  • CRISPR system can he further improved to increase the efficiency and versatility
  • Optimal Cas9 activity may depend on the availability of free Mg" at levels higher than that present in the mammalian nucleus (see e.g. Jinek et al., 2012, Science, 337:816), and the preference for an NGG motif immediately downstream of the protospacer restricts the ability to target on average every 12-bp in. the human genome ( Figure 9, evaluating both plus and minus strands of human chromosomal sequences).
  • FIG. 10 illustrates adaptation of the Type II CRISPR system from CRISPR 1 of Streptococcus thermophilus LMD-9 for heterologous expression in mammalian cells to achieve CRISP R-mediated genome editing.
  • Figure 10A provides a Schematic il lustration of CRISPR 1 from S. thermophilus LMD-9.
  • Figure 10B illustrates the design of an expression system for the S. thermophilus CRISPR system. Human codon-optimized hStCas9 is expressed using a constitutive EFla promoter. Mature versions of tracrRNA and crRNA are expressed using the U6 promoter to promote precise transcription initiation.
  • FIG. 1 A single base indicated by the lower case "a" in the crRNA sequence is used to remove the polyU sequence, which serves as a RNA polIII transcriptional terminator.
  • Figure IOC provides a schematic showing guide sequences targeting the human EMX1 locus.
  • Figure 10D shows the results of hStCas9-mediated cleavage in the target locus using the Surveyor assay.
  • RNA guide spacers 1 and 2 induced 14% and 6.4%, respectively.
  • Statistical analysis of cleavage activity across biological replica at these two protospacer sites is also provided in Figure 5.
  • Figure 14 provides a schematic of additional protospacer and corresponding PAM sequence targets of the S. thermophilus CRISPR system in the human ⁇ locus. Two protospacer sequences are highlighted and their corresponding PAM sequences satisfying NNAGAAW motif are indicated by underlining 3' with respect to the corresponding highlighted sequence. Both protospacers target the anti-sense strand.
  • a software program is designed to identify candidate CRISPR target sequences on both strands of an input DNA sequence based on desired guide sequence length and a CRISPR motif sequence (PAM) for a specified CRISPR enzyme.
  • PAM CRISPR motif sequence
  • target sites for Cas9 from S. pyogenes, with PAM sequences NGG may be identified by searching for 5'-N x -NGG-3' both on the input sequence and on the reverse-complement of the input.
  • target sites for Cas9 of S. thermophilus CRISPR 1, with PAM sequence NNAGAAW may be identified by searching for 5 ' -N X -NN AG AA W-3 ' both on the input sequence and on the reverse-complement of the input.
  • target sites for Cas9 of S. thermophilus CRISPR3, with PAM sequence NGGNG may be identified by searching for 5'-N x -NGGNG-3 ' both on the input sequence and on the reverse-complement of the input.
  • the value "x" in N x may be fixed by the program or specified by the user, such as 20.
  • the program filters out sequences based on the number of times they appear in the relevant reference genome.
  • the filtering step may be based on the seed sequence.
  • results are filtered based on the number of occurrences of the seed:PAM sequence in the relevant genome. The user may be al lowed to choose the length of the seed sequence.
  • the user may also be allowed to specify the number of occurrences of the seed:PAM sequence in a genome for purposes of passing the filter.
  • the default is to screen for unique sequences. Filtration level is altered by changing both the length of the seed sequence and the number of occurrences of the sequence in the genome.
  • the program may in addition or alternatively provide the sequence of a guide sequence complementary to the reported target sequencers ) by providing the reverse complement of the identified target sequence(s).
  • An example visualization of some target sites in the human genome is provided in Figure 18.
  • FIG. 16a illustrates a schematic of a bicistronic expression vector for chimeric RNA and Cas9. Cas9 is driven by the CBh promoter and the chimeric RNA is driven by a U6 promoter.
  • the chimeric guide RNA consists of a 20bp guide sequence (Ns) joined to the tracr sequence (running from the first "U" of the lower strand to the end of the transcript), which is truncated at various positions as indicated.
  • Protospacer IDs and their corresponding genomic target, protospacer sequence, PAM sequence, and strand location are provided in Table D.
  • Guide sequences were designed to be complementary to the entire protospacer sequence in the case of separate transcripts in the hybrid system, or only to the underlined portion in the case of chimeric RNAs, Table D:
  • chiRNA (+n) indicate that up to the +n nucleotide of wild-type tracrRNA is included i the chimeric RNA construct, with values of 48, 54, 67, and 85 used for n.
  • Chimeric RJMAs containing longer fragments of wild-type tracrRNA (chiRNA(+67) and chiRNA(+85)) mediated DNA. cleavage at all three EMX l target sites, with chiRNA(+85) in particular demonstrating significantly higher levels of DNA cleavage than the corresponding crRNA ' tracrRNA hybrids that expressed guide and tracr sequences in separate transcripts ( Figures 16b and 17a), Two sites in the PVALB locus that yielded no detectable cleavage using the hybrid system (guide sequence and tracr sequence expressed as separate transcripts) were also targeted using chiRNAs. chiRNA(+67) and chiRNA(+85) were able to mediate significant cleavage at the two PVALB protospacers ( Figures 16c and 17b).
  • the CRISPR-Cas system is an adaptive immune mechanism against invading exogenous DNA employed by diverse species across bacteria and archaea.
  • the type II CRISPR- Cas9 system consists of a set of genes encoding proteins responsible for the "acquisition" of foreign DNA into the CRISP R locus, as well as a set of genes encoding the "execution” of the DNA cleavage mechanism; these include the DNA nuclease (Cas9), a no -coding transactivating cr-RNA (tracrRNA), and an array of foreign DNA-derived spacers flanked by direct repeats (crR As).
  • the tracRNA and crRNA duplex guide the Cas9 nuclease to a target DNA sequence specified by the spacer guide sequences, and mediates double-stranded breaks in the DNA near a short sequence motif in the target DN A that is required for cleavage and specific to each CRISPR-Cas system.
  • the type II CRISPR-Cas systems are found throughout the bacterial kingdom and highly diverse in in Cas9 protein sequence and size, tracrRNA and crRNA direct repeat sequence, genome organization of these elements, and the motif requirement for target cleavage.
  • One species may have multiple distinct CRISPR-Cas systems.
  • Applicants analyzed Cas9 orthologs to identify the relevant PAM sequences and the corresponding chimeric guide RNA. Having an expanded set of PAMs provides broader targeting across the genome and also significant!)? increases the number of unique target sites and provides potential for identifying novel Cas9s with increased levels of specificity in the genome.
  • the specificity of Cas9 orthologs can be evaluated by testing the ability of each Cas9 to tolerate mismatches between the guide RNA and its DNA target. For example, the specificity of SpCas9 has been characterized by testing the effect of mutations in the guide RNA on cleavage efficiency. Libraries of guide RNAs were made with single or multiple mismatches between the guide sequence and the target DNA. Based on these findings, target sites for SpCas9 can be selected based on the following guidelines:
  • Example 7 Engineering of Plants (Micro-algae) using Cas9 to target and manipulate plant genes
  • Method 1 Applicants deliver Cas9 and guide RNA using a vector that expresses Cas9 under the control of a constitutive promoter such as Hsp70A-R.bc S2 or Beta2 -tubulin.
  • a constitutive promoter such as Hsp70A-R.bc S2 or Beta2 -tubulin.
  • Method 2 Applicants deliver Cas9 and T7 polymerase using vectors that expresses Cas9 and T7 polymerase under the control of a constitutive promoter such as Hsp70A ⁇ R.bc S2 or Beta2 -tubulin.
  • Guide RNA will be delivered using a vector containing T7 promoter driving the guide RNA.
  • Method 3 Applicants deliver Cas9 mRNA and in vitro transcribed guide RNA to algae cells, RNA can be in vitro transcribed , Cas9 mRNA will consist of the coding region for Cas9 as well as 3'UTR from Co l to ensure stabilization of the Cas9 mRNA.
  • Ci GGGAAAAGATCGAGAA ATC C f jAC ⁇ TCXXX ATCX XX " ⁇ ( ⁇ AC GTGGGi C ' ( " ! ' ( " ! '
  • gaaatTAATACGACTCACTATA NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
  • Chlamydomonas reinhardtii strain CC-124 and CC-125 from the Chlamydomonas Resource Center will be used for effectroporation. Electroporation protocol follows standard recommended protocol from the Gene Art Chlamydomonas Engineering kit.
  • Applicants generate a line of Chiamydomonas reinhardtii that expresses Cas9 constitutively. This can he done by using pChlamyl (linearized using Pvui) and selecting for hygromycin resistant colonies. Sequence for pChlamyl containing Cas9 is below. In this way to achieve gene knockout one simply needs to deliver RNA for the guideRNA. For homologous recombination Applicants deliver guideRNA as well, as a linearized homologous recombination template.
  • RNA length is measured by a ruler mechanism anchored at the precursor processing site.
  • CRISPR clustered regularly interspaced short palindromic repeat

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • Medicinal Chemistry (AREA)
  • Mycology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Virology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Breeding Of Plants And Reproduction By Means Of Culturing (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Gastroenterology & Hepatology (AREA)
PCT/US2013/074743 2012-12-12 2013-12-12 Crispr-cas systems and methods for altering expression of gene products Ceased WO2014093661A2 (en)

Priority Applications (20)

Application Number Priority Date Filing Date Title
JP2015547555A JP6545621B2 (ja) 2012-12-12 2013-12-12 遺伝子産物の発現を変更するためのＣＲＩＳＰＲ−Ｃａｓ系および方法
DK13824232.6T DK2764103T3 (en) 2012-12-12 2013-12-12 CRISPR CAS systems and methods for altering the expression of gene products
BR112015013785A BR112015013785A2 (pt) 2012-12-12 2013-12-12 sistemas e métodos crispr-cas para alterar a expressão dos produtos de genes
CA2894688A CA2894688A1 (en) 2012-12-12 2013-12-12 Crispr-cas systems and methods for altering expression of gene products in eukaryotic cells
PL13824232T PL2764103T3 (pl) 2012-12-12 2013-12-12 Systemy crispr-cas i sposoby zmieniania ekspresji produktów genów
EP13824232.6A EP2764103B1 (en) 2012-12-12 2013-12-12 Crispr-cas systems and methods for altering expression of gene products
CN202010072631.XA CN111187772B (zh) 2012-12-12 2013-12-12 用于改变基因产物的表达的crispr-cas系统和方法
KR1020157018654A KR20150107739A (ko) 2012-12-12 2013-12-12 유전자 산물의 발현의 변경을 위한 ｃｒｉｓｐｒ―ｃａｓ 시스템 및 방법
RU2015128100A RU2687451C1 (ru) 2012-12-12 2013-12-12 Системы crispr-cas и способы изменения экспрессии продуктов генов
CN201380072715.1A CN106170549B (zh) 2012-12-12 2013-12-12 用于改变基因产物的表达的crispr-cas系统和方法
AU2013359238A AU2013359238B2 (en) 2012-12-12 2013-12-12 CRISPR-Cas systems and methods for altering expression of gene products
ES13824232.6T ES2552535T3 (es) 2012-12-12 2013-12-12 Sistemas de CRISPR-Cas y métodos para alterar la expresión de productos génicos
HK15101515.7A HK1201290B (en) 2012-12-12 2013-12-12 Crispr-cas systems and methods for altering expression of gene products
CN202410963686.8A CN118879746A (zh) 2012-12-12 2013-12-12 用于改变基因产物的表达的crispr-cas系统和方法
US14/681,382 US20150203872A1 (en) 2012-12-12 2015-04-08 Crispr-cas systems and methods for altering expression of gene products
US15/160,710 US20160281072A1 (en) 2012-12-12 2016-05-20 Crispr-cas systems and methods for altering expression of gene products
AU2016244244A AU2016244244B2 (en) 2012-12-12 2016-10-12 CRISPR-Cas systems and methods for altering expression of gene products
AU2019201608A AU2019201608B2 (en) 2012-12-12 2019-03-08 CRISPR-Cas systems and methods for altering expression of gene products
AU2022201052A AU2022201052B2 (en) 2012-12-12 2022-02-17 CRISPR-Cas systems and methods for altering expression of gene products
AU2025202729A AU2025202729A1 (en) 2012-12-12 2025-04-17 CRISPR-Cas systems and methods for altering expression of gene products

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US201261736527P 2012-12-12 2012-12-12
US61/736,527 2012-12-12
US201361748427P 2013-01-02 2013-01-02
US61/748,427 2013-01-02
US201361791409P 2013-03-15 2013-03-15
US61/791,409 2013-03-15
US201361835931P 2013-06-17 2013-06-17
US61/835,931 2013-06-17
US201361842322P 2013-07-02 2013-07-02
US61/842,322 2013-07-02
US14/054,414 US8697359B1 (en) 2012-12-12 2013-10-15 CRISPR-Cas systems and methods for altering expression of gene products
US14/054,414 2013-10-15

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US14/054,414 Continuation US8697359B1 (en) 2012-12-12 2013-10-15 CRISPR-Cas systems and methods for altering expression of gene products

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/681,382 Continuation US20150203872A1 (en) 2012-12-12 2015-04-08 Crispr-cas systems and methods for altering expression of gene products

Publications (3)

Publication Number Publication Date
WO2014093661A2 true WO2014093661A2 (en) 2014-06-19
WO2014093661A3 WO2014093661A3 (en) 2014-08-07
WO2014093661A9 WO2014093661A9 (en) 2014-10-16

Family

ID=50441380

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/074743 Ceased WO2014093661A2 (en) 2012-12-12 2013-12-12 Crispr-cas systems and methods for altering expression of gene products

Country Status (15)

Country Link
US (8) US8697359B1 (enExample)
EP (2) EP2998400A1 (enExample)
JP (6) JP6545621B2 (enExample)
KR (1) KR20150107739A (enExample)
CN (4) CN106480080B (enExample)
AU (5) AU2013359238B2 (enExample)
BR (1) BR112015013785A2 (enExample)
CA (1) CA2894688A1 (enExample)
DK (1) DK2764103T3 (enExample)
ES (1) ES2552535T3 (enExample)
HK (1) HK1216259A1 (enExample)
PL (1) PL2764103T3 (enExample)
PT (1) PT2764103E (enExample)
RU (1) RU2687451C1 (enExample)
WO (1) WO2014093661A2 (enExample)

Cited By (422)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2771468A1 (en) 2012-12-12 2014-09-03 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
EP2800811A1 (en) 2012-05-25 2014-11-12 The Regents of The University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
WO2014194190A1 (en) * 2013-05-30 2014-12-04 The Penn State Research Foundation Gene targeting and genetic modification of plants via rna-guided genome editing
WO2014186686A3 (en) * 2013-05-17 2015-01-08 Two Blades Foundation Targeted mutagenesis and genome engineering in plants using rna-guided cas nucleases
EP2784162B1 (en) 2012-12-12 2015-04-08 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
WO2015065964A1 (en) 2013-10-28 2015-05-07 The Broad Institute Inc. Functional genomics using crispr-cas systems, compositions, methods, screens and applications thereof
WO2015089364A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Crystal structure of a crispr-cas system, and uses thereof
WO2015089351A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
WO2015089419A2 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using particle delivery components
WO2015089486A2 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Systems, methods and compositions for sequence manipulation with optimized functional crispr-cas systems
WO2015089465A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
US9068179B1 (en) 2013-12-12 2015-06-30 President And Fellows Of Harvard College Methods for correcting presenilin point mutations
EP2764103B1 (en) 2012-12-12 2015-08-19 The Broad Institute, Inc. Crispr-cas systems and methods for altering expression of gene products
WO2015139008A1 (en) 2014-03-14 2015-09-17 Cibus Us Llc Methods and compositions for increasing efficiency of targeted gene modification using oligonucleotide-mediated gene repair
US9163284B2 (en) 2013-08-09 2015-10-20 President And Fellows Of Harvard College Methods for identifying a target site of a Cas9 nuclease
WO2015188109A1 (en) 2014-06-06 2015-12-10 Regeneron Pharmaceuticals, Inc. Methods and compositions for modifying a targeted locus
WO2015200805A2 (en) 2014-06-26 2015-12-30 Regeneron Pharmaceuticals, Inc. Methods and compositions for targeted genetic modifications and methods of use
US9228207B2 (en) 2013-09-06 2016-01-05 President And Fellows Of Harvard College Switchable gRNAs comprising aptamers
US9228208B2 (en) 2013-12-11 2016-01-05 Regeneron Pharmaceuticals, Inc. Methods and compositions for the targeted modification of a genome
US9234213B2 (en) 2013-03-15 2016-01-12 System Biosciences, Llc Compositions and methods directed to CRISPR/Cas genomic engineering systems
US9260752B1 (en) 2013-03-14 2016-02-16 Caribou Biosciences, Inc. Compositions and methods of nucleic acid-targeting nucleic acids
EP2931898B1 (en) 2012-12-12 2016-03-09 The Broad Institute, Inc. Engineering and optimization of systems, methods and compositions for sequence manipulation with functional domains
EP2898075B1 (en) 2012-12-12 2016-03-09 The Broad Institute, Inc. Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation
WO2016036754A1 (en) 2014-09-02 2016-03-10 The Regents Of The University Of California Methods and compositions for rna-directed target dna modification
WO2016049251A1 (en) 2014-09-24 2016-03-31 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for modeling mutations in leukocytes
WO2016049163A2 (en) 2014-09-24 2016-03-31 The Broad Institute Inc. Use and production of chd8+/- transgenic animals with behavioral phenotypes characteristic of autism spectrum disorder
WO2016061374A1 (en) 2014-10-15 2016-04-21 Regeneron Pharmaceuticals, Inc. Methods and compositions for generating or maintaining pluripotent cells
US9322006B2 (en) 2011-07-22 2016-04-26 President And Fellows Of Harvard College Evaluation and improvement of nuclease cleavage specificity
US9322037B2 (en) 2013-09-06 2016-04-26 President And Fellows Of Harvard College Cas9-FokI fusion proteins and uses thereof
WO2016069591A2 (en) 2014-10-27 2016-05-06 The Broad Institute Inc. Compositions, methods and use of synthetic lethal screening
WO2016081923A2 (en) 2014-11-21 2016-05-26 Regeneron Pharmaceuticals, Inc. METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATION USING PAIRED GUIDE RNAs
WO2016086227A2 (en) 2014-11-26 2016-06-02 The Regents Of The University Of California Therapeutic compositions comprising transcription factors and methods of making and using the same
WO2016086197A1 (en) 2014-11-25 2016-06-02 The Brigham And Women's Hospital, Inc. Method of identifying and treating a person having a predisposition to or afflicted with a cardiometabolic disease
WO2016083811A1 (en) 2014-11-27 2016-06-02 Imperial Innovations Limited Genome editing methods
US9359599B2 (en) 2013-08-22 2016-06-07 President And Fellows Of Harvard College Engineered transcription activator-like effector (TALE) domains and uses thereof
WO2016094867A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Protected guide rnas (pgrnas)
WO2016094880A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Delivery, use and therapeutic applications of crispr systems and compositions for genome editing as to hematopoietic stem cells (hscs)
WO2016094872A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Dead guides for crispr transcription factors
WO2016094874A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Escorted and functionalized guides for crispr-cas systems
WO2016100974A1 (en) 2014-12-19 2016-06-23 The Broad Institute Inc. Unbiased identification of double-strand breaks and genomic rearrangement by genome-wide insert capture sequencing
WO2016100857A1 (en) 2014-12-19 2016-06-23 Regeneron Pharmaceuticals, Inc. Stem cells for modeling type 2 diabetes
WO2016106236A1 (en) 2014-12-23 2016-06-30 The Broad Institute Inc. Rna-targeting system
WO2016106244A1 (en) 2014-12-24 2016-06-30 The Broad Institute Inc. Crispr having or associated with destabilization domains
WO2016108926A1 (en) 2014-12-30 2016-07-07 The Broad Institute Inc. Crispr mediated in vivo modeling and genetic screening of tumor growth and metastasis
JP2016521975A (ja) * 2013-05-15 2016-07-28 サンガモ バイオサイエンシーズ， インコーポレイテッド 遺伝的状態の処置のための方法および組成物
WO2016138488A2 (en) 2015-02-26 2016-09-01 The Broad Institute Inc. T cell balance gene expression, compositions of matters and methods of use thereof
WO2016138574A1 (en) 2015-03-02 2016-09-09 Sinai Health System Homologous recombination factors
EP2840140B1 (en) 2012-12-12 2016-11-16 The Broad Institute, Inc. Crispr-Cas component systems, methods and compositions for sequence manipulation
WO2016182893A1 (en) 2015-05-08 2016-11-17 Teh Broad Institute Inc. Functional genomics using crispr-cas systems for saturating mutagenesis of non-coding elements, compositions, methods, libraries and applications thereof
WO2016205728A1 (en) 2015-06-17 2016-12-22 Massachusetts Institute Of Technology Crispr mediated recording of cellular events
WO2016205764A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Novel crispr enzymes and systems
WO2016205745A2 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Cell sorting
US9526784B2 (en) 2013-09-06 2016-12-27 President And Fellows Of Harvard College Delivery system for functional nucleases
WO2017027910A1 (en) 2015-08-14 2017-02-23 The University Of Sydney Connexin 45 inhibition for therapy
EP3159407A1 (en) 2015-10-23 2017-04-26 Silence Therapeutics (London) Ltd Guide rnas, methods and uses
WO2017070605A1 (en) 2015-10-22 2017-04-27 The Broad Institute Inc. Type vi-b crispr enzymes and systems
WO2017069958A2 (en) 2015-10-09 2017-04-27 The Brigham And Women's Hospital, Inc. Modulation of novel immune checkpoint targets
EP3003392A4 (en) * 2013-06-04 2017-05-03 President and Fellows of Harvard College Rna-guideded transcriptional regulation
WO2017075451A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting pou2af1
WO2017075478A2 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by use of immune cell gene signatures
WO2017074788A1 (en) 2015-10-27 2017-05-04 The Broad Institute Inc. Compositions and methods for targeting cancer-specific sequence variations
WO2017075465A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting gata3
WO2017075294A1 (en) 2015-10-28 2017-05-04 The Board Institute Inc. Assays for massively combinatorial perturbation profiling and cellular circuit reconstruction
WO2017087708A1 (en) 2015-11-19 2017-05-26 The Brigham And Women's Hospital, Inc. Lymphocyte antigen cd5-like (cd5l)-interleukin 12b (p40) heterodimers in immunity
WO2017114497A1 (en) 2015-12-30 2017-07-06 Novartis Ag Immune effector cell therapies with enhanced efficacy
JP2017518075A (ja) * 2014-05-30 2017-07-06 ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー 潜伏性ウイルス感染を処置するための組成物および方法
WO2017147196A1 (en) 2016-02-22 2017-08-31 Massachusetts Institute Of Technology Methods for identifying and modulating immune phenotypes
EP3219799A1 (en) 2016-03-17 2017-09-20 IMBA-Institut für Molekulare Biotechnologie GmbH Conditional crispr sgrna expression
WO2017161325A1 (en) 2016-03-17 2017-09-21 Massachusetts Institute Of Technology Methods for identifying and modulating co-occurant cellular phenotypes
WO2017201476A1 (en) 2016-05-20 2017-11-23 Regeneron Pharmaceuticals, Inc. Methods for breaking immunological tolerance using multiple guide rnas
US9834791B2 (en) 2013-11-07 2017-12-05 Editas Medicine, Inc. CRISPR-related methods and compositions with governing gRNAS
US9834786B2 (en) 2012-04-25 2017-12-05 Regeneron Pharmaceuticals, Inc. Nuclease-mediated targeting with large targeting vectors
WO2017219027A1 (en) 2016-06-17 2017-12-21 The Broad Institute Inc. Type vi crispr orthologs and systems
JP2017537647A (ja) * 2014-12-16 2017-12-21 ダニスコ・ユーエス・インク 真菌ゲノム改変システムおよび使用方法
WO2018013840A1 (en) 2016-07-13 2018-01-18 Vertex Pharmaceuticals Incorporated Methods, compositions and kits for increasing genome editing efficiency
WO2018023014A1 (en) 2016-07-29 2018-02-01 Regeneron Pharmaceuticals, Inc. Mice comprising mutations resulting in expression of c-truncated fibrillin-1
US9885026B2 (en) 2011-12-30 2018-02-06 Caribou Biosciences, Inc. Modified cascade ribonucleoproteins and uses thereof
US9888673B2 (en) 2014-12-10 2018-02-13 Regents Of The University Of Minnesota Genetically modified cells, tissues, and organs for treating disease
WO2018035250A1 (en) 2016-08-17 2018-02-22 The Broad Institute, Inc. Methods for identifying class 2 crispr-cas systems
WO2018035364A1 (en) 2016-08-17 2018-02-22 The Broad Institute Inc. Product and methods useful for modulating and evaluating immune responses
WO2018049025A2 (en) 2016-09-07 2018-03-15 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses
WO2018048828A1 (en) 2016-09-06 2018-03-15 The Children's Medical Center Corporation Immune cells derived from induced pluripotent stem cell
WO2018054911A1 (en) 2016-09-23 2018-03-29 Bayer Cropscience Nv Targeted genome optimization in plants
US9938521B2 (en) 2014-03-10 2018-04-10 Editas Medicine, Inc. CRISPR/CAS-related methods and compositions for treating leber's congenital amaurosis 10 (LCA10)
WO2018067991A1 (en) 2016-10-07 2018-04-12 The Brigham And Women's Hospital, Inc. Modulation of novel immune checkpoint targets
US9957515B2 (en) 2013-03-15 2018-05-01 Cibus Us Llc Methods and compositions for targeted gene modification
WO2018083606A1 (en) 2016-11-01 2018-05-11 Novartis Ag Methods and compositions for enhancing gene editing
US9982278B2 (en) 2014-02-11 2018-05-29 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US9982279B1 (en) 2017-06-23 2018-05-29 Inscripta, Inc. Nucleic acid-guided nucleases
US10011849B1 (en) 2017-06-23 2018-07-03 Inscripta, Inc. Nucleic acid-guided nucleases
US10017760B2 (en) 2016-06-24 2018-07-10 Inscripta, Inc. Methods for generating barcoded combinatorial libraries
WO2018136758A1 (en) 2017-01-23 2018-07-26 Regeneron Pharmaceuticals, Inc. Hsd17b13 variants and uses thereof
EP3354732A1 (en) 2014-06-23 2018-08-01 Regeneron Pharmaceuticals, Inc. Nuclease-mediated dna assembly
EP2912175B1 (en) * 2012-10-23 2018-08-22 Toolgen Incorporated Composition for cleaving a target dna comprising a guide rna specific for the target dna and cas protein-encoding nucleic acid or cas protein, and use thereof
US10077453B2 (en) 2014-07-30 2018-09-18 President And Fellows Of Harvard College CAS9 proteins including ligand-dependent inteins
WO2018170515A1 (en) 2017-03-17 2018-09-20 The Broad Institute, Inc. Methods for identifying and modulating co-occurant cellular phenotypes
WO2018170333A1 (en) 2017-03-15 2018-09-20 The Broad Institute, Inc. Novel cas13b orthologues crispr enzymes and systems
WO2018191553A1 (en) 2017-04-12 2018-10-18 Massachusetts Eye And Ear Infirmary Tumor signature for metastasis, compositions of matter methods of use thereof
WO2018191388A1 (en) 2017-04-12 2018-10-18 The Broad Institute, Inc. Novel type vi crispr orthologs and systems
WO2018191750A2 (en) 2017-04-14 2018-10-18 The Broad Institute Inc. Novel delivery of large payloads
WO2018191520A1 (en) 2017-04-12 2018-10-18 The Broad Institute, Inc. Respiratory and sweat gland ionocytes
WO2018195486A1 (en) 2017-04-21 2018-10-25 The Broad Institute, Inc. Targeted delivery to beta cells
WO2018195019A1 (en) 2017-04-18 2018-10-25 The Broad Institute Inc. Compositions for detecting secretion and methods of use
US10113163B2 (en) 2016-08-03 2018-10-30 President And Fellows Of Harvard College Adenosine nucleobase editors and uses thereof
WO2018221685A1 (ja) 2017-05-31 2018-12-06 国立大学法人 東京大学 改変されたＣａｓ９タンパク質及びその用途
US10166255B2 (en) 2015-07-31 2019-01-01 Regents Of The University Of Minnesota Intracellular genomic transplant and methods of therapy
US10167457B2 (en) 2015-10-23 2019-01-01 President And Fellows Of Harvard College Nucleobase editors and uses thereof
WO2019005884A1 (en) 2017-06-26 2019-01-03 The Broad Institute, Inc. CRISPR / CAS-ADENINE DEAMINASE COMPOSITIONS, SYSTEMS AND METHODS FOR TARGETED NUCLEIC ACID EDITION
WO2019003193A1 (en) 2017-06-30 2019-01-03 Novartis Ag METHODS FOR TREATING DISEASES USING GENE EDITING SYSTEMS
JP2019500899A (ja) * 2015-11-23 2019-01-17 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア ＣＲＩＳＰＲ／Ｃａｓ９の核送達を通じた細胞ＲＮＡの追跡と操作
WO2019018440A1 (en) 2017-07-17 2019-01-24 The Broad Institute, Inc. HUMAN COLON CELL ATLAS IN GOOD HEALTH AND WITH HEMORRHAGIC RECTO-COLITIS
US10195273B2 (en) 2016-06-05 2019-02-05 Snipr Technologies Limited Selectively altering microbiota for immune modulation
WO2019028023A2 (en) 2017-07-31 2019-02-07 Regeneron Pharmaceuticals, Inc. METHODS AND COMPOSITIONS FOR EVALUATING CRISPR / CAS MEDIATED DISRUPTION OR EXCISION AND CRISPR / CAS INDUCED RECOMBINATION USING IN VIVO EXOGENIC DONOR NUCLEIC ACID
WO2019028029A1 (en) 2017-07-31 2019-02-07 Regeneron Pharmaceuticals, Inc. EVALUATION OF CRISPR / CAS INDUCED RECOMBINATION WITH IN VIVO EXOGENIC DONOR NUCLEIC ACID
WO2019028032A1 (en) 2017-07-31 2019-02-07 Regeneron Pharmaceuticals, Inc. EMBRYONIC STEM CELLS OF TRANSGENIC MOUSE CASES AND MICE AND USES THEREOF
WO2019049913A1 (ja) 2017-09-05 2019-03-14 国立大学法人 東京大学 改変されたＣａｓ９タンパク質及びその用途
WO2019060746A1 (en) 2017-09-21 2019-03-28 The Broad Institute, Inc. SYSTEMS, METHODS, AND COMPOSITIONS FOR THE TARGETED EDITING OF NUCLEIC ACIDS
WO2019067875A1 (en) 2017-09-29 2019-04-04 Regeneron Pharmaceuticals, Inc. NON-HUMAN ANIMALS COMPRISING A HUMANIZED TTR LOCUS AND METHODS OF USE
WO2019071054A1 (en) 2017-10-04 2019-04-11 The Broad Institute, Inc. METHODS AND COMPOSITIONS FOR MODIFYING THE FUNCTION AND STRUCTURE OF BUCKLES AND / OR CHROMATIN DOMAINS
WO2019070755A1 (en) 2017-10-02 2019-04-11 The Broad Institute, Inc. METHODS AND COMPOSITIONS FOR DETECTING AND MODULATING A GENETIC SIGNATURE OF IMMUNOTHERAPY RESISTANCE IN CANCER
WO2019087113A1 (en) 2017-11-01 2019-05-09 Novartis Ag Synthetic rnas and methods of use
WO2019094983A1 (en) 2017-11-13 2019-05-16 The Broad Institute, Inc. Methods and compositions for treating cancer by targeting the clec2d-klrb1 pathway
US10337001B2 (en) 2014-12-03 2019-07-02 Agilent Technologies, Inc. Guide RNA with chemical modifications
WO2019138083A1 (en) 2018-01-12 2019-07-18 Basf Se Gene underlying the number of spikelets per spike qtl in wheat on chromosome 7a
EP3514246A1 (en) 2014-02-27 2019-07-24 The Broad Institute Inc. T cell balance gene expression and methods of use thereof
WO2019143675A1 (en) 2018-01-17 2019-07-25 Vertex Pharmaceuticals Incorporated Dna-pk inhibitors
WO2019143677A1 (en) 2018-01-17 2019-07-25 Vertex Pharmaceuticals Incorporated Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
WO2019143678A1 (en) 2018-01-17 2019-07-25 Vertex Pharmaceuticals Incorporated Dna-pk inhibitors
US10377998B2 (en) 2013-12-12 2019-08-13 The Broad Institute, Inc. CRISPR-CAS systems and methods for altering expression of gene products, structural information and inducible modular CAS enzymes
US10385359B2 (en) 2013-04-16 2019-08-20 Regeneron Pharmaceuticals, Inc. Targeted modification of rat genome
WO2019183123A1 (en) 2018-03-19 2019-09-26 Regeneron Pharmaceuticals, Inc. Transcription modulation in animals using crispr/cas systems
US10428319B2 (en) 2017-06-09 2019-10-01 Editas Medicine, Inc. Engineered Cas9 nucleases
WO2019195611A1 (en) 2018-04-04 2019-10-10 Cibus Us Llc Fad2 genes and mutations
WO2019204585A1 (en) 2018-04-19 2019-10-24 Massachusetts Institute Of Technology Single-stranded break detection in double-stranded dna
EP3560330A1 (en) 2018-04-24 2019-10-30 KWS SAAT SE & Co. KGaA Plants with improved digestibility and marker haplotypes
WO2019210268A2 (en) 2018-04-27 2019-10-31 The Broad Institute, Inc. Sequencing-based proteomics
WO2019206236A1 (zh) * 2018-04-28 2019-10-31 中国科学院上海生命科学研究院 通过Tild-CRISPR实现高效精确的靶向整合
US10463049B2 (en) 2015-05-06 2019-11-05 Snipr Technologies Limited Altering microbial populations and modifying microbiota
WO2019213660A2 (en) 2018-05-04 2019-11-07 The Broad Institute, Inc. Compositions and methods for modulating cgrp signaling to regulate innate lymphoid cell inflammatory responses
US10494621B2 (en) 2015-06-18 2019-12-03 The Broad Institute, Inc. Crispr enzyme mutations reducing off-target effects
WO2019232542A2 (en) 2018-06-01 2019-12-05 Massachusetts Institute Of Technology Methods and compositions for detecting and modulating microenvironment gene signatures from the csf of metastasis patients
US10519468B2 (en) 2015-01-28 2019-12-31 Pioneer Hi-Bred International, Inc. Cells containing CRISPR hybrid DNA/RNA polynucleotides
WO2020006036A1 (en) 2018-06-26 2020-01-02 Massachusetts Institute Of Technology Crispr effector system based amplification methods, systems, and diagnostics
WO2020006049A1 (en) 2018-06-26 2020-01-02 The Broad Institute, Inc. Crispr/cas and transposase based amplification compositions, systems and methods
WO2020002592A1 (en) 2018-06-29 2020-01-02 Stichting Het Nederlands Kanker Instituut - Antoni Van Leeuwenhoek Ziekenhuis Traf2 inhibitors for use in the treatment of a cancer
WO2020028555A2 (en) 2018-07-31 2020-02-06 The Broad Institute, Inc. Novel crispr enzymes and systems
WO2020033601A1 (en) 2018-08-07 2020-02-13 The Broad Institute, Inc. Novel cas12b enzymes and systems
WO2020041387A1 (en) 2018-08-20 2020-02-27 The Brigham And Women's Hospital, Inc. Degradation domain modifications for spatio-temporal control of rna-guided nucleases
WO2020041380A1 (en) 2018-08-20 2020-02-27 The Broad Institute, Inc. Methods and compositions for optochemical control of crispr-cas9
US10577630B2 (en) 2013-06-17 2020-03-03 The Broad Institute, Inc. Delivery and use of the CRISPR-Cas systems, vectors and compositions for hepatic targeting and therapy
WO2020051507A1 (en) 2018-09-06 2020-03-12 The Broad Institute, Inc. Nucleic acid assemblies for use in targeted delivery
WO2020077236A1 (en) 2018-10-12 2020-04-16 The Broad Institute, Inc. Method for extracting nuclei or whole cells from formalin-fixed paraffin-embedded tissues
WO2020081730A2 (en) 2018-10-16 2020-04-23 Massachusetts Institute Of Technology Methods and compositions for modulating microenvironment
US10640789B2 (en) 2013-06-04 2020-05-05 President And Fellows Of Harvard College RNA-guided transcriptional regulation
EP3653229A1 (en) 2013-12-12 2020-05-20 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for genome editing
EP3653048A1 (en) 2014-12-19 2020-05-20 Regeneron Pharmaceuticals, Inc. Methods and compositions for targeted genetic modification through single-step multiple targeting
US10669320B2 (en) 2015-11-18 2020-06-02 The Regents Of The University Of Michigan Mps1 and KNL1 phosphorylation system
RU2722933C1 (ru) * 2019-06-11 2020-06-05 Автономная некоммерческая образовательная организация высшего образования Сколковский институт науки и технологий Средство разрезания днк на основе cas9 белка из бактерии demequina sediminicola
WO2020122195A1 (ja) 2018-12-12 2020-06-18 国立大学法人九州大学 ゲノム編集された細胞の製造方法
WO2020131862A1 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Crispr-associated transposase systems and methods of use thereof
WO2020131632A1 (en) 2018-12-20 2020-06-25 Regeneron Pharmaceuticals, Inc. Nuclease-mediated repeat expansion
WO2020131586A2 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Methods for identifying neoantigens
US10711285B2 (en) 2013-06-17 2020-07-14 The Broad Institute, Inc. Optimized CRISPR-Cas double nickase systems, methods and compositions for sequence manipulation
EP3686279A1 (en) 2014-08-17 2020-07-29 The Broad Institute, Inc. Genome editing using cas9 nickases
US10731181B2 (en) 2012-12-06 2020-08-04 Sigma, Aldrich Co. LLC CRISPR-based genome modification and regulation
US10745677B2 (en) 2016-12-23 2020-08-18 President And Fellows Of Harvard College Editing of CCR5 receptor gene to protect against HIV infection
WO2020168315A1 (en) 2019-02-15 2020-08-20 Just-Evotec Biologics, Inc. Automated biomanufacturing systems, facilities, and processes
US10760075B2 (en) 2018-04-30 2020-09-01 Snipr Biome Aps Treating and preventing microbial infections
US10767175B2 (en) 2016-06-08 2020-09-08 Agilent Technologies, Inc. High specificity genome editing using chemically modified guide RNAs
US10781444B2 (en) 2013-06-17 2020-09-22 The Broad Institute, Inc. Functional genomics using CRISPR-Cas systems, compositions, methods, screens and applications thereof
WO2020190932A1 (en) 2019-03-18 2020-09-24 Regeneron Pharmaceuticals, Inc. Crispr/cas screening platform to identify genetic modifiers of tau seeding or aggregation
WO2020190927A1 (en) 2019-03-18 2020-09-24 Regeneron Pharmaceuticals, Inc. Crispr/cas dropout screening platform to reveal genetic vulnerabilities associated with tau aggregation
WO2020206162A1 (en) 2019-04-03 2020-10-08 Regeneron Pharmaceuticals, Inc. Methods and compositions for insertion of antibody coding sequences into a safe harbor locus
WO2020206139A1 (en) 2019-04-04 2020-10-08 Regeneron Pharmaceuticals, Inc. Non-human animals comprising a humanized coagulation factor 12 locus
WO2020206036A1 (en) 2019-04-01 2020-10-08 The Broad Institute, Inc. Novel nucleic acid modifier
WO2020206134A1 (en) 2019-04-04 2020-10-08 Regeneron Pharmaceuticals, Inc. Methods for scarless introduction of targeted modifications into targeting vectors
WO2020229533A1 (en) 2019-05-13 2020-11-19 KWS SAAT SE & Co. KGaA Drought tolerance in corn
WO2020236972A2 (en) 2019-05-20 2020-11-26 The Broad Institute, Inc. Non-class i multi-component nucleic acid targeting systems
WO2020236967A1 (en) 2019-05-20 2020-11-26 The Broad Institute, Inc. Random crispr-cas deletion mutant
WO2020239680A2 (en) 2019-05-25 2020-12-03 KWS SAAT SE & Co. KGaA Haploid induction enhancer
WO2020243661A1 (en) 2019-05-31 2020-12-03 The Broad Institute, Inc. Methods for treating metabolic disorders by targeting adcy5
WO2020247812A1 (en) 2019-06-07 2020-12-10 Regeneron Pharmaceuticals, Inc. Non-human animals comprising a humanized albumin locus
WO2020247452A1 (en) 2019-06-04 2020-12-10 Regeneron Pharmaceuticals, Inc. Non-human animals comprising a humanized ttr locus with a beta-slip mutation and methods of use
WO2020252340A1 (en) 2019-06-14 2020-12-17 Regeneron Pharmaceuticals, Inc. Models of tauopathy
WO2021003432A1 (en) 2019-07-02 2021-01-07 Fred Hutchinson Cancer Research Center Recombinant ad35 vectors and related gene therapy improvements
US10912797B2 (en) 2016-10-18 2021-02-09 Intima Bioscience, Inc. Tumor infiltrating lymphocytes and methods of therapy
EP3772542A1 (en) 2019-08-07 2021-02-10 KWS SAAT SE & Co. KGaA Modifying genetic variation in crops by modulating the pachytene checkpoint protein 2
US20210040460A1 (en) 2012-04-27 2021-02-11 Duke University Genetic correction of mutated genes
US10920242B2 (en) 2011-02-25 2021-02-16 Recombinetics, Inc. Non-meiotic allele introgression
US10930367B2 (en) 2012-12-12 2021-02-23 The Broad Institute, Inc. Methods, models, systems, and apparatus for identifying target sequences for Cas enzymes or CRISPR-Cas systems for target sequences and conveying results thereof
WO2021041922A1 (en) 2019-08-30 2021-03-04 The Broad Institute, Inc. Crispr-associated mu transposase systems
US10946108B2 (en) 2013-06-17 2021-03-16 The Broad Institute, Inc. Delivery, use and therapeutic applications of the CRISPR-Cas systems and compositions for targeting disorders and diseases using viral components
WO2021050940A1 (en) 2019-09-13 2021-03-18 Regeneron Pharmaceuticals, Inc. Transcription modulation in animals using crispr/cas systems delivered by lipid nanoparticles
WO2021055874A1 (en) 2019-09-20 2021-03-25 The Broad Institute, Inc. Novel type vi crispr enzymes and systems
US10959414B2 (en) 2013-08-27 2021-03-30 Recombinetics, Inc. Efficient non-meiotic allele introgression
WO2021074367A1 (en) 2019-10-17 2021-04-22 KWS SAAT SE & Co. KGaA Enhanced disease resistance of crops by downregulation of repressor genes
US11001829B2 (en) 2014-09-25 2021-05-11 The Broad Institute, Inc. Functional screening with optimized functional CRISPR-Cas systems
WO2021092513A1 (en) 2019-11-08 2021-05-14 Regeneron Pharmaceuticals, Inc. Crispr and aav strategies for x-linked juvenile retinoschisis therapy
US11008588B2 (en) 2013-06-17 2021-05-18 The Broad Institute, Inc. Delivery, engineering and optimization of tandem guide systems, methods and compositions for sequence manipulation
WO2021108647A1 (en) 2019-11-27 2021-06-03 Crispr Therapeutics Ag Methods of synthesizing rna molecules
WO2021108363A1 (en) 2019-11-25 2021-06-03 Regeneron Pharmaceuticals, Inc. Crispr/cas-mediated upregulation of humanized ttr allele
US11028388B2 (en) 2014-03-05 2021-06-08 Editas Medicine, Inc. CRISPR/Cas-related methods and compositions for treating Usher syndrome and retinitis pigmentosa
US11033584B2 (en) 2017-10-27 2021-06-15 The Regents Of The University Of California Targeted replacement of endogenous T cell receptors
US11041173B2 (en) 2012-12-12 2021-06-22 The Broad Institute, Inc. Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
WO2021148447A1 (en) 2020-01-21 2021-07-29 Limagrain Europe Wheat haploid inducer plant and uses
WO2021150919A1 (en) 2020-01-23 2021-07-29 The Children's Medical Center Corporation Stroma-free t cell differentiation from human pluripotent stem cells
US11078481B1 (en) 2016-08-03 2021-08-03 KSQ Therapeutics, Inc. Methods for screening for cancer targets
US11078483B1 (en) 2016-09-02 2021-08-03 KSQ Therapeutics, Inc. Methods for measuring and improving CRISPR reagent function
US11092607B2 (en) 2015-10-28 2021-08-17 The Board Institute, Inc. Multiplex analysis of single cell constituents
US11098325B2 (en) 2017-06-30 2021-08-24 Intima Bioscience, Inc. Adeno-associated viral vectors for gene therapy
WO2021165508A1 (en) 2020-02-21 2021-08-26 Biogemma Prime editing technology for plant genome engineering
EP3872190A1 (en) 2020-02-26 2021-09-01 Antibodies-Online GmbH A method of using cut&run or cut&tag to validate crispr-cas targeting
US11111521B2 (en) 2011-12-22 2021-09-07 President And Fellows Of Harvard College Compositions and methods for analyte detection
WO2021178556A1 (en) 2020-03-04 2021-09-10 Regeneron Pharmaceuticals, Inc. Methods and compositions for sensitization of tumor cells to immune therapy
US11124796B2 (en) 2014-09-24 2021-09-21 The Broad Institute, Inc. Delivery, use and therapeutic applications of the CRISPR-Cas systems and compositions for modeling competition of multiple cancer mutations in vivo
WO2021195079A1 (en) 2020-03-23 2021-09-30 Regeneron Pharmaceuticals, Inc. Non-human animals comprising a humanized ttr locus comprising a v30m mutation and methods of use
WO2021202938A1 (en) 2020-04-03 2021-10-07 Creyon Bio, Inc. Oligonucleotide-based machine learning
US11141493B2 (en) 2014-03-10 2021-10-12 Editas Medicine, Inc. Compositions and methods for treating CEP290-associated disease
WO2021206054A1 (ja) 2020-04-06 2021-10-14 株式会社Ｌｏｇｏｍｉｘ ゲノム改変方法及びゲノム改変キット
CN113614247A (zh) * 2018-11-26 2021-11-05 拜奥卡德联合股份公司 Dna切割剂
US11180793B2 (en) 2015-04-24 2021-11-23 Editas Medicine, Inc. Evaluation of Cas9 molecule/guide RNA molecule complexes
US11180751B2 (en) 2015-06-18 2021-11-23 The Broad Institute, Inc. CRISPR enzymes and systems
WO2021239986A1 (en) 2020-05-29 2021-12-02 KWS SAAT SE & Co. KGaA Plant haploid induction
US11214800B2 (en) 2015-08-18 2022-01-04 The Broad Institute, Inc. Methods and compositions for altering function and structure of chromatin loops and/or domains
US11236313B2 (en) 2016-04-13 2022-02-01 Editas Medicine, Inc. Cas9 fusion molecules, gene editing systems, and methods of use thereof
US11242525B2 (en) 2014-03-26 2022-02-08 Editas Medicine, Inc. CRISPR/CAS-related methods and compositions for treating sickle cell disease
US11268082B2 (en) 2017-03-23 2022-03-08 President And Fellows Of Harvard College Nucleobase editors comprising nucleic acid programmable DNA binding proteins
WO2022069756A1 (en) 2020-10-02 2022-04-07 Limagrain Europe Crispr-mediated directed codon re-write
US11299767B2 (en) 2013-03-12 2022-04-12 President And Fellows Of Harvard College Method for generating a three-dimensional nucleic acid containing matrix
US11306309B2 (en) 2015-04-06 2022-04-19 The Board Of Trustees Of The Leland Stanford Junior University Chemically modified guide RNAs for CRISPR/CAS-mediated gene regulation
US11306324B2 (en) 2016-10-14 2022-04-19 President And Fellows Of Harvard College AAV delivery of nucleobase editors
US11319532B2 (en) 2017-08-30 2022-05-03 President And Fellows Of Harvard College High efficiency base editors comprising Gam
US11332736B2 (en) 2017-12-07 2022-05-17 The Broad Institute, Inc. Methods and compositions for multiplexing single cell and single nuclei sequencing
US11339437B2 (en) 2014-03-10 2022-05-24 Editas Medicine, Inc. Compositions and methods for treating CEP290-associated disease
EP4001429A1 (en) 2020-11-16 2022-05-25 Antibodies-Online GmbH Analysis of crispr-cas binding and cleavage sites followed by high-throughput sequencing (abc-seq)
US11352647B2 (en) 2016-08-17 2022-06-07 The Broad Institute, Inc. Crispr enzymes and systems
WO2022120022A1 (en) 2020-12-02 2022-06-09 Regeneron Pharmaceuticals, Inc. Crispr sam biosensor cell lines and methods of use thereof
US11359208B2 (en) 2018-01-09 2022-06-14 Cibus Us Llc Shatterproof genes and mutations
WO2022137760A1 (ja) 2020-12-25 2022-06-30 株式会社Logomix ゲノムｄｎａに大規模な欠失を生じさせる方法およびゲノムｄｎａの分析方法
US11390884B2 (en) 2015-05-11 2022-07-19 Editas Medicine, Inc. Optimized CRISPR/cas9 systems and methods for gene editing in stem cells
WO2022165001A1 (en) 2021-01-29 2022-08-04 Merck Sharp & Dohme Llc Compositions of programmed death receptor 1 (pd-1) antibodies and methods of obtaining the compositions thereof
US11414657B2 (en) 2015-06-29 2022-08-16 Ionis Pharmaceuticals, Inc. Modified CRISPR RNA and modified single CRISPR RNA and uses thereof
US11421251B2 (en) 2015-10-13 2022-08-23 Duke University Genome engineering with type I CRISPR systems in eukaryotic cells
US11427817B2 (en) 2015-08-25 2022-08-30 Duke University Compositions and methods of improving specificity in genomic engineering using RNA-guided endonucleases
WO2022186233A1 (ja) 2021-03-03 2022-09-09 株式会社Logomix ゲノムｄｎａを改変する方法および改変を検出する方法
US11447527B2 (en) 2018-09-18 2022-09-20 Vnv Newco Inc. Endogenous Gag-based capsids and uses thereof
US11447770B1 (en) 2019-03-19 2022-09-20 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
US11453891B2 (en) 2017-05-10 2022-09-27 The Regents Of The University Of California Directed editing of cellular RNA via nuclear delivery of CRISPR/CAS9
US11466271B2 (en) 2017-02-06 2022-10-11 Novartis Ag Compositions and methods for the treatment of hemoglobinopathies
WO2022221699A1 (en) 2021-04-16 2022-10-20 Beam Therapeutics, Inc. Genetic modification of hepatocytes
US11499151B2 (en) 2017-04-28 2022-11-15 Editas Medicine, Inc. Methods and systems for analyzing guide RNA molecules
US11512311B2 (en) 2016-03-25 2022-11-29 Editas Medicine, Inc. Systems and methods for treating alpha 1-antitrypsin (A1AT) deficiency
US11542554B2 (en) 2015-11-03 2023-01-03 President And Fellows Of Harvard College Method and apparatus for volumetric imaging
US11542509B2 (en) 2016-08-24 2023-01-03 President And Fellows Of Harvard College Incorporation of unnatural amino acids into proteins using base editing
US11542496B2 (en) 2017-03-10 2023-01-03 President And Fellows Of Harvard College Cytosine to guanine base editor
US11542515B2 (en) 2016-02-09 2023-01-03 Cibus Us Llc Methods and compositions for increasing efficiency of targeted gene modification using oligonucleotide-mediated gene repair
US11547614B2 (en) 2017-10-31 2023-01-10 The Broad Institute, Inc. Methods and compositions for studying cell evolution
WO2023287707A1 (en) 2021-07-15 2023-01-19 Just-Evotec Biologics, Inc. Bidirectional tangential flow filtration (tff) perfusion system
US11560566B2 (en) 2017-05-12 2023-01-24 President And Fellows Of Harvard College Aptazyme-embedded guide RNAs for use with CRISPR-Cas9 in genome editing and transcriptional activation
US11566263B2 (en) 2016-08-02 2023-01-31 Editas Medicine, Inc. Compositions and methods for treating CEP290 associated disease
WO2023006933A1 (en) 2021-07-30 2023-02-02 KWS SAAT SE & Co. KGaA Plants with improved digestibility and marker haplotypes
WO2023010135A1 (en) 2021-07-30 2023-02-02 Tune Therapeutics, Inc. Compositions and methods for modulating expression of methyl-cpg binding protein 2 (mecp2)
WO2023010133A2 (en) 2021-07-30 2023-02-02 Tune Therapeutics, Inc. Compositions and methods for modulating expression of frataxin (fxn)
US11578118B2 (en) 2017-10-20 2023-02-14 Fred Hutchinson Cancer Center Systems and methods to produce B cells genetically modified to express selected antibodies
US11578312B2 (en) 2015-06-18 2023-02-14 The Broad Institute Inc. Engineering and optimization of systems, methods, enzymes and guide scaffolds of CAS9 orthologs and variants for sequence manipulation
US11591601B2 (en) 2017-05-05 2023-02-28 The Broad Institute, Inc. Methods for identification and modification of lncRNA associated with target genotypes and phenotypes
US11597924B2 (en) 2016-03-25 2023-03-07 Editas Medicine, Inc. Genome editing systems comprising repair-modulating enzyme molecules and methods of their use
US11603544B2 (en) 2017-06-05 2023-03-14 Fred Hutchinson Cancer Center Genomic safe harbors for genetic therapies in human stem cells and engineered nanoparticles to provide targeted genetic therapies
WO2023077053A2 (en) 2021-10-28 2023-05-04 Regeneron Pharmaceuticals, Inc. Crispr/cas-related methods and compositions for knocking out c5
US11661590B2 (en) 2016-08-09 2023-05-30 President And Fellows Of Harvard College Programmable CAS9-recombinase fusion proteins and uses thereof
WO2023093862A1 (en) 2021-11-26 2023-06-01 Epigenic Therapeutics Inc. Method of modulating pcsk9 and uses thereof
US11667911B2 (en) 2015-09-24 2023-06-06 Editas Medicine, Inc. Use of exonucleases to improve CRISPR/CAS-mediated genome editing
WO2023108047A1 (en) 2021-12-08 2023-06-15 Regeneron Pharmaceuticals, Inc. Mutant myocilin disease model and uses thereof
US11680296B2 (en) 2017-10-16 2023-06-20 Massachusetts Institute Of Technology Mycobacterium tuberculosis host-pathogen interaction
US11680268B2 (en) 2014-11-07 2023-06-20 Editas Medicine, Inc. Methods for improving CRISPR/Cas-mediated genome-editing
WO2023137471A1 (en) 2022-01-14 2023-07-20 Tune Therapeutics, Inc. Compositions, systems, and methods for programming t cell phenotypes through targeted gene activation
WO2023137472A2 (en) 2022-01-14 2023-07-20 Tune Therapeutics, Inc. Compositions, systems, and methods for programming t cell phenotypes through targeted gene repression
US11713485B2 (en) 2016-04-25 2023-08-01 President And Fellows Of Harvard College Hybridization chain reaction methods for in situ molecular detection
EP4219699A1 (en) 2013-12-12 2023-08-02 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions with new architectures for sequence manipulation
WO2023150620A1 (en) 2022-02-02 2023-08-10 Regeneron Pharmaceuticals, Inc. Crispr-mediated transgene insertion in neonatal cells
US11732274B2 (en) 2017-07-28 2023-08-22 President And Fellows Of Harvard College Methods and compositions for evolving base editors using phage-assisted continuous evolution (PACE)
US11739156B2 (en) 2019-01-06 2023-08-29 The Broad Institute, Inc. Massachusetts Institute of Technology Methods and compositions for overcoming immunosuppression
EP4252759A2 (en) 2018-05-11 2023-10-04 Memorial Sloan Kettering Cancer Center T cell receptors targeting pik3ca mutations and uses thereof
WO2023191063A1 (ja) 2022-04-01 2023-10-05 株式会社Logomix 遺伝子工学、細胞工学、および細胞医薬に適した細胞およびその製造方法
US11795443B2 (en) 2017-10-16 2023-10-24 The Broad Institute, Inc. Uses of adenosine base editors
EP4268831A2 (en) 2018-09-12 2023-11-01 Fred Hutchinson Cancer Center Reducing cd33 expression to selectively protect therapeutic cells
WO2023212677A2 (en) 2022-04-29 2023-11-02 Regeneron Pharmaceuticals, Inc. Identification of tissue-specific extragenic safe harbors for gene therapy approaches
US11814624B2 (en) 2017-06-15 2023-11-14 The Regents Of The University Of California Targeted non-viral DNA insertions
WO2023220603A1 (en) 2022-05-09 2023-11-16 Regeneron Pharmaceuticals, Inc. Vectors and methods for in vivo antibody production
US11834670B2 (en) 2017-04-19 2023-12-05 Global Life Sciences Solutions Usa Llc Site-specific DNA modification using a donor DNA repair template having tandem repeat sequences
WO2023235726A2 (en) 2022-05-31 2023-12-07 Regeneron Pharmaceuticals, Inc. Crispr interference therapeutics for c9orf72 repeat expansion disease
WO2023235725A2 (en) 2022-05-31 2023-12-07 Regeneron Pharmaceuticals, Inc. Crispr-based therapeutics for c9orf72 repeat expansion disease
US11851690B2 (en) 2017-03-14 2023-12-26 Editas Medicine, Inc. Systems and methods for the treatment of hemoglobinopathies
WO2023250511A2 (en) 2022-06-24 2023-12-28 Tune Therapeutics, Inc. Compositions, systems, and methods for reducing low-density lipoprotein through targeted gene repression
WO2024005186A1 (ja) 2022-06-30 2024-01-04 リージョナルフィッシュ株式会社 ｔｒａｃｒＲＮＡユニット、及びゲノム編集方法
US11866726B2 (en) 2017-07-14 2024-01-09 Editas Medicine, Inc. Systems and methods for targeted integration and genome editing and detection thereof using integrated priming sites
US11866697B2 (en) 2017-05-18 2024-01-09 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
WO2024015881A2 (en) 2022-07-12 2024-01-18 Tune Therapeutics, Inc. Compositions, systems, and methods for targeted transcriptional activation
US11884915B2 (en) 2021-09-10 2024-01-30 Agilent Technologies, Inc. Guide RNAs with chemical modification for prime editing
WO2024026474A1 (en) 2022-07-29 2024-02-01 Regeneron Pharmaceuticals, Inc. Compositions and methods for transferrin receptor (tfr)-mediated delivery to the brain and muscle
US11897953B2 (en) 2017-06-14 2024-02-13 The Broad Institute, Inc. Compositions and methods targeting complement component 3 for inhibiting tumor growth
US11898179B2 (en) 2017-03-09 2024-02-13 President And Fellows Of Harvard College Suppression of pain by gene editing
WO2024040254A2 (en) 2022-08-19 2024-02-22 Tune Therapeutics, Inc. Compositions, systems, and methods for regulation of hepatitis b virus through targeted gene repression
WO2024039576A2 (en) 2022-08-19 2024-02-22 Memorial Sloan-Kettering Cancer Center T cell receptors targeting ras mutations and uses thereof
US11913075B2 (en) 2017-04-01 2024-02-27 The Broad Institute, Inc. Methods and compositions for detecting and modulating an immunotherapy resistance gene signature in cancer
US11913015B2 (en) 2017-04-17 2024-02-27 University Of Maryland, College Park Embryonic cell cultures and methods of using the same
US11911415B2 (en) 2015-06-09 2024-02-27 Editas Medicine, Inc. CRISPR/Cas-related methods and compositions for improving transplantation
US11912985B2 (en) 2020-05-08 2024-02-27 The Broad Institute, Inc. Methods and compositions for simultaneous editing of both strands of a target double-stranded nucleotide sequence
WO2024042199A1 (en) 2022-08-26 2024-02-29 KWS SAAT SE & Co. KGaA Use of paired genes in hybrid breeding
US11920128B2 (en) 2013-09-18 2024-03-05 Kymab Limited Methods, cells and organisms
WO2024064642A2 (en) 2022-09-19 2024-03-28 Tune Therapeutics, Inc. Compositions, systems, and methods for modulating t cell function
WO2024073606A1 (en) 2022-09-28 2024-04-04 Regeneron Pharmaceuticals, Inc. Antibody resistant modified receptors to enhance cell-based therapies
US11957695B2 (en) 2018-04-26 2024-04-16 The Broad Institute, Inc. Methods and compositions targeting glucocorticoid signaling for modulating immune responses
WO2024080067A1 (ja) 2022-10-14 2024-04-18 株式会社インプランタイノベーションズ ゲノム編集方法およびゲノム編集用組成物
US11963966B2 (en) 2017-03-31 2024-04-23 Dana-Farber Cancer Institute, Inc. Compositions and methods for treating ovarian tumors
US11963982B2 (en) 2017-05-10 2024-04-23 Editas Medicine, Inc. CRISPR/RNA-guided nuclease systems and methods
WO2024098002A1 (en) 2022-11-04 2024-05-10 Regeneron Pharmaceuticals, Inc. Calcium voltage-gated channel auxiliary subunit gamma 1 (cacng1) binding proteins and cacng1-mediated delivery to skeletal muscle
US11981922B2 (en) 2019-10-03 2024-05-14 Dana-Farber Cancer Institute, Inc. Methods and compositions for the modulation of cell interactions and signaling in the tumor microenvironment
WO2024107765A2 (en) 2022-11-14 2024-05-23 Regeneron Pharmaceuticals, Inc. Compositions and methods for fibroblast growth factor receptor 3-mediated delivery to astrocytes
WO2024105633A1 (en) 2022-11-18 2024-05-23 Kyoto Prefectural Public University Corporation Compositions for mitophagy induction and uses thereof
US11994512B2 (en) 2018-01-04 2024-05-28 Massachusetts Institute Of Technology Single-cell genomic methods to generate ex vivo cell systems that recapitulate in vivo biology with improved fidelity
US12031132B2 (en) 2018-03-14 2024-07-09 Editas Medicine, Inc. Systems and methods for the treatment of hemoglobinopathies
US12036240B2 (en) 2018-06-14 2024-07-16 The Broad Institute, Inc. Compositions and methods targeting complement component 3 for inhibiting tumor growth
US12037407B2 (en) 2021-10-14 2024-07-16 Arsenal Biosciences, Inc. Immune cells having co-expressed shRNAS and logic gate systems
US12049643B2 (en) 2017-07-14 2024-07-30 The Broad Institute, Inc. Methods and compositions for modulating cytotoxic lymphocyte activity
WO2024163678A2 (en) 2023-02-01 2024-08-08 Tune Therapeutics, Inc. Fusion proteins and systems for targeted activation of frataxin (fxn) and related methods
WO2024163683A2 (en) 2023-02-01 2024-08-08 Tune Therapeutics, Inc. Systems, compositions, and methods for modulating expression of methyl-cpg binding protein 2 (mecp2) and x-inactive specific transcript (xist)
US12058986B2 (en) 2017-04-20 2024-08-13 Egenesis, Inc. Method for generating a genetically modified pig with inactivated porcine endogenous retrovirus (PERV) elements
WO2024168253A1 (en) 2023-02-10 2024-08-15 Possible Medicines Llc Delivery of an rna guided recombination system
WO2024168265A1 (en) 2023-02-10 2024-08-15 Possible Medicines Llc Aav delivery of rna guided recombination system
US12076375B2 (en) 2022-06-29 2024-09-03 Snipr Biome Aps Treating and preventing E coli infections
US12098425B2 (en) 2018-10-10 2024-09-24 Readcoor, Llc Three-dimensional spatial molecular indexing
WO2024206911A2 (en) 2023-03-30 2024-10-03 Children's Hospital Medical Center Clinical-grade organoids
US12110545B2 (en) 2017-01-06 2024-10-08 Editas Medicine, Inc. Methods of assessing nuclease cleavage
WO2024211887A1 (en) * 2023-04-07 2024-10-10 Genentech, Inc. Modified guide rnas
WO2024220741A1 (en) 2023-04-19 2024-10-24 Flagship Pioneering Innovations Vii, Llc Compositions and methods for the production of libraries
WO2024228717A2 (en) 2022-09-07 2024-11-07 Quantitative Biosciences, Inc. Fentanyl-specific single variable-domain antibodies and use in a continuous agglutination assay
WO2024236547A1 (en) 2023-05-18 2024-11-21 Inceptor Bio, Llc Modified phagocytic cells expressing chimeric antigen receptors comprising a herpes virus entry mediator (hvem) co-stimulatory domain and uses thereof
WO2024238977A2 (en) 2023-05-18 2024-11-21 Children's Hospital Medical Center Liver organoids with intrahepatic sympathetic nerves, and methods of use thereof
US12157760B2 (en) 2018-05-23 2024-12-03 The Broad Institute, Inc. Base editors and uses thereof
US12161694B2 (en) 2017-03-24 2024-12-10 The Broad Institute, Inc. Methods and compositions for regulating innate lymphoid cell inflammatory responses
US12165743B2 (en) 2018-11-09 2024-12-10 The Broad Institute, Inc. Compressed sensing for screening and tissue imaging
US12171783B2 (en) 2017-11-13 2024-12-24 The Broad Institute, Inc. Methods and compositions for targeting developmental and oncogenic programs in H3K27M gliomas
WO2024263961A2 (en) 2023-06-23 2024-12-26 Children's Hospital Medical Center Methods of matrix-free suspension culture
WO2025006963A1 (en) 2023-06-30 2025-01-02 Regeneron Pharmaceuticals, Inc. Methods and compositions for increasing homology-directed repair
WO2025006419A1 (en) 2023-06-26 2025-01-02 Flagship Pioneering Innovations Vii, Llc Engineered plasmodia and related methods
US12203136B2 (en) 2020-08-17 2025-01-21 Readcoor, Llc Methods and systems for spatial mapping of genetic variants
US12201699B2 (en) 2014-10-10 2025-01-21 Editas Medicine, Inc. Compositions and methods for promoting homology directed repair
US12215366B2 (en) 2015-02-09 2025-02-04 Duke University Compositions and methods for epigenome editing
US12215345B2 (en) 2013-03-19 2025-02-04 Duke University Compositions and methods for the induction and tuning of gene expression
US12214056B2 (en) 2016-07-19 2025-02-04 Duke University Therapeutic applications of CPF1-based genome editing
WO2025029662A1 (en) 2023-07-28 2025-02-06 Regeneron Pharmaceuticals, Inc. Anti-tfr: acid sphingomyelinase for treatment of acid sphingomyelinase deficiency
WO2025029654A2 (en) 2023-07-28 2025-02-06 Regeneron Pharmaceuticals, Inc. Use of bgh-sv40l tandem polya to enhance transgene expression during unidirectional gene insertion
WO2025029835A1 (en) 2023-07-31 2025-02-06 Tune Therapeutics, Inc. Compositions and methods for modulating il-2 gene expression
WO2025029657A2 (en) 2023-07-28 2025-02-06 Regeneron Pharmaceuticals, Inc. Anti-tfr:gaa and anti-cd63:gaa insertion for treatment of pompe disease
WO2025029840A1 (en) 2023-07-31 2025-02-06 Tune Therapeutics, Inc. Compositions and methods for multiplexed activation and repression of t cell gene expression
US12221720B2 (en) 2017-11-13 2025-02-11 The Broad Institute, Inc. Methods for determining spatial and temporal gene expression dynamics during adult neurogenesis in single cells
US12227742B2 (en) 2017-10-23 2025-02-18 The Broad Institute, Inc. Nucleic acid modifiers
US12226479B2 (en) 2017-05-11 2025-02-18 The General Hospital Corporation Methods and compositions of use of CD8+ tumor infiltrating lymphocyte subtypes and gene signatures thereof
US12227578B2 (en) 2016-11-11 2025-02-18 The Broad Institute, Inc. Modulation of intestinal epithelial cell differentiation, maintenance and/or function through T cell action
WO2025038494A1 (en) 2023-08-11 2025-02-20 Tune Therapeutics, Inc. Compositions, systems, and methods for lymphoid cell differentiation using targeted gene activation
EP4512819A2 (en) 2015-08-12 2025-02-26 The General Hospital Corporation Compositions and methods that promote hypoxia or the hypoxia response for treatment and prevention of mitochondrial dysfunction and oxidative stress disorders
US12239646B2 (en) 2017-07-19 2025-03-04 Dana-Farber Cancer Institute, Inc. Cancer diagnostic and treatment
US12241090B2 (en) 2014-05-28 2025-03-04 Children's Hospital Medical Center Methods and systems for converting precursor cells into gastric tissues through directed differentiation
WO2025046513A1 (en) 2023-08-29 2025-03-06 Inceptor Bio, Llc Methods of manufacturing myeloid-derived cells from hematopoietic stem cells and compositions and uses thereof
WO2025049524A1 (en) 2023-08-28 2025-03-06 Regeneron Pharmaceuticals, Inc. Cxcr4 antibody-resistant modified receptors
WO2025059073A1 (en) 2023-09-11 2025-03-20 Tune Therapeutics, Inc. Epigenetic editing methods and systems for differentiating stem cells
US12258584B2 (en) 2010-05-06 2025-03-25 Children's Hospital Medical Center Methods and systems for converting precursor cells into intestinal tissues through directed differentiation
US12264323B2 (en) 2018-12-17 2025-04-01 The Broad Institute, Inc. CRISPR CPF1 direct repeat variants
WO2025072803A1 (en) 2023-09-29 2025-04-03 Children's Hospital Medical Center Ntrk2 signaling-mediated alveolar capillary injury and repair
US12281338B2 (en) 2018-10-29 2025-04-22 The Broad Institute, Inc. Nucleobase editors comprising GeoCas9 and uses thereof
US12281334B2 (en) 2017-04-14 2025-04-22 Children's Hospital Medical Center Multi donor stem cell compositions and methods of making same
US12286727B2 (en) 2016-12-19 2025-04-29 Editas Medicine, Inc. Assessing nuclease cleavage
WO2025096638A2 (en) 2023-10-30 2025-05-08 Turnstone Biologics Corp. Genetically modified tumor infilitrating lymphocytes and methods of producing and using the same
US12297457B2 (en) 2017-10-10 2025-05-13 Children's Hospital Medical Center Esophageal tissue and/or organoid compositions and methods of making same
US12297436B2 (en) 2017-05-18 2025-05-13 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
US12305204B2 (en) 2016-08-17 2025-05-20 The Broad Institute, Inc. CRISPR enzymes and systems
US12319938B2 (en) 2020-07-24 2025-06-03 The General Hospital Corporation Enhanced virus-like particles and methods of use thereof for delivery to cells
US12331347B2 (en) 2014-07-11 2025-06-17 President And Fellows Of Harvard College Methods for high-throughput labelling and detection of biological features in situ using microscopy
WO2025128343A1 (en) 2023-12-11 2025-06-19 Just-Evotec Biologics, Inc. Protein expression using trans-splicing and split selectable markers
US12338436B2 (en) 2018-06-29 2025-06-24 Editas Medicine, Inc. Synthetic guide molecules, compositions and methods relating thereto
US12351815B2 (en) 2019-06-13 2025-07-08 The General Hospital Corporation Engineered human-endogenous virus-like particles and methods of use thereof for delivery to cells
US12351837B2 (en) 2019-01-23 2025-07-08 The Broad Institute, Inc. Supernegatively charged proteins and uses thereof
US12379372B2 (en) 2017-12-21 2025-08-05 Children's Hospital Medical Center Digitalized human organoids and methods of using same
US12390514B2 (en) 2017-03-09 2025-08-19 President And Fellows Of Harvard College Cancer vaccine
US12402610B2 (en) 2018-11-09 2025-09-02 The Broad Institute, Inc. Methods and compositions for modulating innate lymphoid cell pathogenic effectors
US12406749B2 (en) 2017-12-15 2025-09-02 The Broad Institute, Inc. Systems and methods for predicting repair outcomes in genetic engineering
US12404514B2 (en) 2016-12-09 2025-09-02 The Broad Institute, Inc. CRISPR-systems for modifying a trait of interest in a plant
WO2025184567A1 (en) 2024-03-01 2025-09-04 Regeneron Pharmaceuticals, Inc. Methods and compositions for re-dosing aav using anti-cd40 antagonistic antibody to suppress host anti-aav antibody response
US12414967B2 (en) 2016-11-04 2025-09-16 Children's Hospital Medical Center Compositions and methods of treating liver disease
US12421500B2 (en) 2018-07-26 2025-09-23 Children's Hospital Medical Center Hepato-biliary-pancreatic tissues and methods of making same
US12428622B2 (en) 2018-09-12 2025-09-30 Children's Hospital Medical Center Organoid compositions for the production of hematopoietic stem cells and derivatives thereof
US12428631B2 (en) 2016-04-13 2025-09-30 Duke University CRISPR/Cas9-based repressors for silencing gene targets in vivo and methods of use
US12435330B2 (en) 2019-10-10 2025-10-07 The Broad Institute, Inc. Methods and compositions for prime editing RNA
WO2025212920A1 (en) 2024-04-03 2025-10-09 Children's Hospital Medical Center Multi-zonal liver organoids
WO2025217202A1 (en) 2024-04-08 2025-10-16 Children's Hospital Medical Center Bile duct organoid
US12454687B2 (en) 2012-12-12 2025-10-28 The Broad Institute, Inc. Functional genomics using CRISPR-Cas systems, compositions, methods, knock out libraries and applications thereof
US12460231B2 (en) 2014-04-02 2025-11-04 Editas Medicine, Inc. Crispr/CAS-related methods and compositions for treating primary open angle glaucoma
US12467086B2 (en) 2011-10-14 2025-11-11 President And Fellows Of Harvard College Sequencing by structure assembly
WO2025235388A1 (en) 2024-05-06 2025-11-13 Regeneron Pharmaceuticals, Inc. Transgene genomic identification by nuclease-mediated long read sequencing
US12473543B2 (en) 2019-04-17 2025-11-18 The Broad Institute, Inc. Adenine base editors with reduced off-target effects
US12492237B2 (en) 2019-06-20 2025-12-09 Memorial Sloan-Kettering Cancer Center T cell receptors targeting PIK3CA mutations and uses thereof
US12497597B2 (en) 2019-05-31 2025-12-16 Children's Hospital Medical Center Methods of generating and expanding hematopoietic stem cells
US12499971B2 (en) 2016-09-28 2025-12-16 The Broad Institute, Inc. Systematic screening and mapping of regulatory elements in non-coding genomic regions, methods, compositions, and applications thereof
WO2025260068A1 (en) 2024-06-14 2025-12-18 Tune Therapeutics, Inc. Lipid nanoparticle formulation for delivery of nucleic acids to cells
WO2025265017A1 (en) 2024-06-20 2025-12-26 Regeneron Pharmaceuticals, Inc. Ass1 gene insertion for the treatment of citrullinemia type i
US12522807B2 (en) 2018-07-09 2026-01-13 The Broad Institute, Inc. RNA programmable epigenetic RNA modifiers and uses thereof
WO2026015647A1 (en) 2024-07-09 2026-01-15 Tune Therapeutics, Inc. Compositions, systems, and methods for cell differentiation using targeted gene activation of dll4 and/or vcam1
US12534714B2 (en) 2019-03-18 2026-01-27 The Broad Institute, Inc. Type VII CRISPR proteins and systems
US12534709B2 (en) 2019-05-31 2026-01-27 Children's Hospital Medical Center Shaped organoid compositions and methods of making same
US12559790B2 (en) 2020-01-29 2026-02-24 10X Genomics, Inc. Compositions and methods for analyte detection
US12565671B2 (en) 2016-08-31 2026-03-03 President And Fellows Of Harvard College Methods of combining the detection of biomolecules into a single assay using fluorescent in situ sequencing
WO2026047626A1 (en) 2024-08-30 2026-03-05 Inceptor Bio, Llc Compositions and methods involving immune cells engineered for binding bispecific antibodies for use in cell therapy
EP4711442A1 (en) 2024-09-15 2026-03-18 Quantitative Biosciences, Inc. Microfluidic chip for the parallel culture of microbial biosensor strains
WO2026064753A1 (en) 2024-09-23 2026-03-26 Tune Therapeutics, Inc. Dna methyltransferase-like protein (dnmt3l) or dna methyltransferase 3a (dnmt3a) repressor systems for epigenetic editing
US12590288B2 (en) 2017-04-12 2026-03-31 The Broad Institute, Inc. Method of treating an inflammatory disease by administering an agent which binds a surface receptor on a tuft cell that induces an ILC class 2 inflammatory response
WO2026072529A1 (en) 2024-09-24 2026-04-02 University Of Florida Research Foundation, Incorporated Mettl7a for improved embryo competence
US12595478B2 (en) 2016-06-29 2026-04-07 The Broad Institute, Inc. Crispr-Cas systems having destabilization domain
US12600943B2 (en) 2019-02-01 2026-04-14 The University Of Hong Kong Innervated organoid compositions and methods of making same
WO2026080515A2 (en) 2024-10-08 2026-04-16 Regeneron Pharmaceuticals, Inc. Crispr sam biosensor cells and cell lines and methods of use thereof
US12617822B2 (en) 2018-09-18 2026-05-05 Aera Therapeutics, Inc. Arc-based capsids and uses thereof
US12629428B2 (en) 2020-04-14 2026-05-19 Duke University AAV vector-mediated deletion of large mutational hotspot for treatment of Duchenne muscular dystrophy

Families Citing this family (1125)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11859168B2 (en) * 2007-05-29 2024-01-02 Christopher B. REID Electroporation, developmentally-activated cells, pluripotent-like cells, cell reprogramming and regenerative medicine
EP2449112A1 (en) 2009-07-01 2012-05-09 Transposagen Biopharmaceuticals, Inc. Genetically modified rat models for severe combined immunodeficiency (scid)
CN104711218B (zh) 2010-06-11 2018-09-25 瑞泽恩制药公司 由xy es细胞制备能育的xy雌性动物
US11844720B2 (en) 2011-02-04 2023-12-19 Seed Health, Inc. Method and system to reduce the likelihood of dental caries and halitosis
US10842834B2 (en) 2016-01-06 2020-11-24 Joseph E. Kovarik Method and system for reducing the likelihood of developing liver cancer in an individual diagnosed with non-alcoholic fatty liver disease
US10512661B2 (en) 2011-02-04 2019-12-24 Joseph E. Kovarik Method and system for reducing the likelihood of developing liver cancer in an individual diagnosed with non-alcoholic fatty liver disease
US11951139B2 (en) 2015-11-30 2024-04-09 Seed Health, Inc. Method and system for reducing the likelihood of osteoporosis
US12533312B2 (en) 2011-02-04 2026-01-27 Seed Health, Inc. Method and system for preventing sore throat in humans
US10314865B2 (en) 2011-02-04 2019-06-11 Katherine Rose Kovarik Method and system for treating cancer and other age-related diseases by extending the healthspan of a human
US11998479B2 (en) 2011-02-04 2024-06-04 Seed Health, Inc. Method and system for addressing adverse effects on the oral microbiome and restoring gingival health caused by sodium lauryl sulphate exposure
US11191665B2 (en) 2011-02-04 2021-12-07 Joseph E. Kovarik Method and system for reducing the likelihood of a porphyromonas gingivalis infection in a human being
US12279989B2 (en) 2011-02-04 2025-04-22 Seed Health, Inc. Method and system for increasing beneficial bacteria and decreasing pathogenic bacteria in the oral cavity
US11273187B2 (en) 2015-11-30 2022-03-15 Joseph E. Kovarik Method and system for reducing the likelihood of developing depression in an individual
US10583033B2 (en) 2011-02-04 2020-03-10 Katherine Rose Kovarik Method and system for reducing the likelihood of a porphyromonas gingivalis infection in a human being
US11419903B2 (en) 2015-11-30 2022-08-23 Seed Health, Inc. Method and system for reducing the likelihood of osteoporosis
US12257272B2 (en) 2015-12-24 2025-03-25 Seed Health, Inc. Method and system for reducing the likelihood of developing depression in an individual
US9730967B2 (en) 2011-02-04 2017-08-15 Katherine Rose Kovarik Method and system for treating cancer cachexia
US11951140B2 (en) 2011-02-04 2024-04-09 Seed Health, Inc. Modulation of an individual's gut microbiome to address osteoporosis and bone disease
EP2689019A2 (en) 2011-03-23 2014-01-29 Pioneer Hi-Bred International Inc. Methods for producing a complex transgenic trait locus
ES2764105T3 (es) 2011-10-17 2020-06-02 Massachusetts Inst Technology Administración intracelular
EP2790708B1 (en) 2011-12-16 2024-10-23 Targetgene Biotechnologies Ltd. Compositions and methods for modifying a predetermined target nucleic acid sequence
WO2013138351A1 (en) 2012-03-13 2013-09-19 Board Of Trustees Of The University Of Arkansas Separatome-based protein expression and purification platform
US9637739B2 (en) 2012-03-20 2017-05-02 Vilnius University RNA-directed DNA cleavage by the Cas9-crRNA complex
US20150225734A1 (en) * 2012-06-19 2015-08-13 Regents Of The University Of Minnesota Gene targeting in plants using dna viruses
CA2875618C (en) 2012-07-11 2021-04-27 Sangamo Biosciences, Inc. Methods and compositions for the treatment of lysosomal storage diseases
US10648001B2 (en) 2012-07-11 2020-05-12 Sangamo Therapeutics, Inc. Method of treating mucopolysaccharidosis type I or II
JP2015527889A (ja) * 2012-07-25 2015-09-24 ザ ブロード インスティテュート， インコーポレイテッド 誘導可能なｄｎａ結合タンパク質およびゲノム撹乱ツール、ならびにそれらの適用
US10107795B2 (en) * 2012-10-25 2018-10-23 The United States Of America As Represented By The Department Of Veterans Affairs Composition and methods for the prevention and treatment of diet-induced obesity
SG10201912991WA (en) 2012-12-17 2020-03-30 Harvard College Rna-guided human genome engineering
EP3919505B1 (en) 2013-01-16 2023-08-30 Emory University Uses of cas9-nucleic acid complexes
WO2014125668A1 (ja) * 2013-02-14 2014-08-21 国立大学法人大阪大学 内在性dna配列特異的結合分子を用いる特定ゲノム領域の単離方法
US20140235933A1 (en) 2013-02-20 2014-08-21 Regeneron Pharmaceuticals, Inc. Genetic modification of rats
WO2014153118A1 (en) * 2013-03-14 2014-09-25 The Board Of Trustees Of The Leland Stanford Junior University Treatment of diseases and conditions associated with dysregulation of mammalian target of rapamycin complex 1 (mtorc1)
US10760064B2 (en) 2013-03-15 2020-09-01 The General Hospital Corporation RNA-guided targeting of genetic and epigenomic regulatory proteins to specific genomic loci
WO2014204578A1 (en) 2013-06-21 2014-12-24 The General Hospital Corporation Using rna-guided foki nucleases (rfns) to increase specificity for rna-guided genome editing
US20140273235A1 (en) * 2013-03-15 2014-09-18 Regents Of The University Of Minnesota ENGINEERING PLANT GENOMES USING CRISPR/Cas SYSTEMS
US10378027B2 (en) 2013-03-15 2019-08-13 The General Hospital Corporation RNA-guided targeting of genetic and epigenomic regulatory proteins to specific genomic loci
US20140273230A1 (en) * 2013-03-15 2014-09-18 Sigma-Aldrich Co., Llc Crispr-based genome modification and regulation
JP2016522679A (ja) 2013-04-04 2016-08-04 プレジデント アンド フェローズ オブ ハーバード カレッジ ＣＲＩＳＰＲ／Ｃａｓ系を用いたゲノム編集の治療的使用
WO2014172470A2 (en) * 2013-04-16 2014-10-23 Whitehead Institute For Biomedical Research Methods of mutating, modifying or modulating nucleic acid in a cell or nonhuman mammal
WO2014190181A1 (en) 2013-05-22 2014-11-27 Northwestern University Rna-directed dna cleavage and gene editing by cas9 enzyme from neisseria meningitidis
ES3029138T3 (en) * 2013-06-05 2025-06-23 Univ Duke Rna-guided gene editing and gene regulation
US9982277B2 (en) 2013-06-11 2018-05-29 The Regents Of The University Of California Methods and compositions for target DNA modification
JP2016528890A (ja) 2013-07-09 2016-09-23 プレジデント アンド フェローズ オブ ハーバード カレッジ ＣＲＩＳＰＲ／Ｃａｓ系を用いるゲノム編集の治療用の使用
BR112016000571B1 (pt) 2013-07-10 2023-12-26 President And Fellows Of Harvard College Métodos in vitro para modular a expressão e para alterar um ou mais ácidos nucleicos alvo em uma célula simultaneamente com a regulação da expressão de um ou mais ácidos nucleicos alvo em uma célula, bem como célula de levedura ou bactéria compreendendo ácidos nucleicos
JP6482546B2 (ja) 2013-07-19 2019-03-13 ラリクス・バイオサイエンス・リミテッド・ライアビリティ・カンパニーＬａｒｉｘ Ｂｉｏｓｃｉｅｎｃｅ， Ｌｌｃ 二重対立遺伝子ノックアウトを生成するための方法および組成物
US11060083B2 (en) 2013-07-19 2021-07-13 Larix Bioscience Llc Methods and compositions for producing double allele knock outs
US10563225B2 (en) 2013-07-26 2020-02-18 President And Fellows Of Harvard College Genome engineering
SG10201801188XA (en) 2013-08-16 2018-03-28 Massachusetts Inst Technology Selective delivery of material to cells
CA3221516A1 (en) 2013-08-22 2015-02-26 E. I. Du Pont De Nemours And Company Plant genome modification using guide rna/cas endonuclease systems and methods of use
CA2920899C (en) 2013-08-28 2023-02-28 Sangamo Biosciences, Inc. Compositions for linking dna-binding domains and cleavage domains
WO2015033343A1 (en) 2013-09-03 2015-03-12 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Compositions and methods for expressing recombinant polypeptides
WO2015042105A1 (en) 2013-09-17 2015-03-26 Board Of Trustees Of The University Of Arkansas E. coli separatome-based protein expression and purification platform
WO2015048690A1 (en) * 2013-09-27 2015-04-02 The Regents Of The University Of California Optimized small guide rnas and methods of use
CA2926078C (en) 2013-10-17 2021-11-16 Sangamo Biosciences, Inc. Delivery methods and compositions for nuclease-mediated genome engineering in hematopoietic stem cells
CN110713995B (zh) 2013-10-17 2023-08-01 桑格摩生物科学股份有限公司 用于核酸酶介导的基因组工程改造的递送方法和组合物
US10767156B2 (en) 2013-10-24 2020-09-08 Yeda Research And Development Co., Ltd. Polynucleotides encoding BREX system polypeptides and methods of using same
WO2015066119A1 (en) * 2013-10-30 2015-05-07 North Carolina State University Compositions and methods related to a type-ii crispr-cas system in lactobacillus buchneri
WO2015070062A1 (en) * 2013-11-07 2015-05-14 Massachusetts Institute Of Technology Cell-based genomic recorded accumulative memory
US10787684B2 (en) 2013-11-19 2020-09-29 President And Fellows Of Harvard College Large gene excision and insertion
US9074199B1 (en) 2013-11-19 2015-07-07 President And Fellows Of Harvard College Mutant Cas9 proteins
EP3835419A1 (en) * 2013-12-12 2021-06-16 The Regents of The University of California Methods and compositions for modifying a single stranded target nucleic acid
CN106030310B (zh) 2013-12-13 2019-01-04 通用医疗公司 可溶性高分子量(hmw)tau种类及其应用
CA2931684C (en) 2013-12-19 2024-02-20 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
US11980643B2 (en) 2013-12-20 2024-05-14 Seed Health, Inc. Method and system to modify an individual's gut-brain axis to provide neurocognitive protection
US12329783B2 (en) 2013-12-20 2025-06-17 Seed Health, Inc. Method and system to improve the health of a person's skin microbiome
US12246043B2 (en) 2013-12-20 2025-03-11 Seed Health, Inc. Topical application to treat acne vulgaris
US12005085B2 (en) 2013-12-20 2024-06-11 Seed Health, Inc. Probiotic method and composition for maintaining a healthy vaginal microbiome
US11833177B2 (en) 2013-12-20 2023-12-05 Seed Health, Inc. Probiotic to enhance an individual's skin microbiome
US11969445B2 (en) 2013-12-20 2024-04-30 Seed Health, Inc. Probiotic composition and method for controlling excess weight, obesity, NAFLD and NASH
AU2014368892B2 (en) 2013-12-20 2019-06-13 Fred Hutchinson Cancer Center Tagged chimeric effector molecules and receptors thereof
US11998574B2 (en) 2013-12-20 2024-06-04 Seed Health, Inc. Method and system for modulating an individual's skin microbiome
US11839632B2 (en) 2013-12-20 2023-12-12 Seed Health, Inc. Topical application of CRISPR-modified bacteria to treat acne vulgaris
US11826388B2 (en) 2013-12-20 2023-11-28 Seed Health, Inc. Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation
US12318377B2 (en) 2013-12-20 2025-06-03 Seed Health, Inc. Method and system for reducing the likelihood of a porphyromonas gingivalis infection in a human being
WO2015103026A2 (en) 2014-01-03 2015-07-09 The Regents Of The University Of Michigan Treatment of neurological disorders
US9850525B2 (en) * 2014-01-29 2017-12-26 Agilent Technologies, Inc. CAS9-based isothermal method of detection of specific DNA sequence
GB201401707D0 (en) * 2014-01-31 2014-03-19 Sec Dep For Health The Adeno-associated viral vectors
US20180142307A1 (en) * 2014-02-11 2018-05-24 California Institute Of Technology Recording and mapping lineage information and molecular events in individual cells
US10287590B2 (en) * 2014-02-12 2019-05-14 Dna2.0, Inc. Methods for generating libraries with co-varying regions of polynuleotides for genome modification
EP3107999A4 (en) 2014-02-18 2017-10-04 Duke University Compositions for the inactivation of virus replication and methods of making and using the same
EP3971283A1 (en) 2014-02-27 2022-03-23 Monsanto Technology LLC Compositions and methods for site directed genomic modification
EP3115457B1 (en) 2014-03-05 2019-10-02 National University Corporation Kobe University Genomic sequence modification method for specifically converting nucleic acid bases of targeted dna sequence, and molecular complex for use in same
AU2015229299A1 (en) * 2014-03-12 2016-09-22 Precision Biosciences, Inc. Dystrophin gene exon deletion using engineered nucleases
EP3593812A3 (en) 2014-03-15 2020-05-27 Novartis AG Treatment of cancer using chimeric antigen receptor
EP3126498A4 (en) 2014-03-20 2017-08-23 Université Laval Crispr-based methods and products for increasing frataxin levels and uses thereof
IL322264A (en) 2014-04-07 2025-09-01 Novartis Ag Cancer treatment using chimeric antigen receptor (CAR) against CD19
EP3129490A4 (en) 2014-04-08 2017-10-04 North Carolina State University Methods and compositions for rna-directed repression of transcription using crispr-associated genes
KR102595473B1 (ko) * 2014-04-18 2023-10-30 에디타스 메디신, 인코포레이티드 암 면역요법을 위한 crispr-cas-관련 방법, 조성물 및 구성성분
CA2946385A1 (en) * 2014-04-22 2015-10-29 Q-State Biosciences, Inc. Diagnostic methods for neuronal disorders
US20160029604A1 (en) 2014-04-28 2016-02-04 Recombinetics, Inc. Multiplex gene editing
WO2015168404A1 (en) * 2014-04-30 2015-11-05 Massachusetts Institute Of Technology Toehold-gated guide rna for programmable cas9 circuitry with rna input
GB201407852D0 (en) * 2014-05-02 2014-06-18 Iontas Ltd Preparation of libraries od protein variants expressed in eukaryotic cells and use for selecting binding molecules
WO2015175642A2 (en) 2014-05-13 2015-11-19 Sangamo Biosciences, Inc. Methods and compositions for prevention or treatment of a disease
EP3151846A4 (en) 2014-06-05 2017-12-27 Sangamo BioSciences, Inc. Methods and compositions for nuclease design
WO2015191693A2 (en) 2014-06-10 2015-12-17 Massachusetts Institute Of Technology Method for gene editing
EP3154694B1 (en) 2014-06-13 2025-01-29 Children's Medical Center Corporation Products and methods to isolate mitochondria
EP3674408A1 (en) 2014-06-16 2020-07-01 The Johns Hopkins University Compositions and methods for the expression of crispr guide rnas
EP3919621A1 (en) 2014-06-23 2021-12-08 The General Hospital Corporation Genomewide unbiased identification of dsbs evaluated by sequencing (guide-seq)
US20180187172A1 (en) * 2014-07-01 2018-07-05 Board Of Regents, The University Of Texas System Regulated gene expression from viral vectors
WO2016005985A2 (en) 2014-07-09 2016-01-14 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Method for reprogramming cells
CN106687594A (zh) 2014-07-11 2017-05-17 纳幕尔杜邦公司 用于产生对草甘膦除草剂具有抗性的植物的组合物和方法
ES3047792T3 (en) * 2014-07-14 2025-12-04 Univ California Crispr/cas transcriptional modulation
WO2016011203A1 (en) 2014-07-15 2016-01-21 Life Technologies Corporation Compositions with lipid aggregates and methods for efficient delivery of molecules to cells
US11542488B2 (en) 2014-07-21 2023-01-03 Novartis Ag Sortase synthesized chimeric antigen receptors
WO2016014530A1 (en) 2014-07-21 2016-01-28 Novartis Ag Combinations of low, immune enhancing. doses of mtor inhibitors and cars
MY181834A (en) 2014-07-21 2021-01-08 Novartis Ag Treatment of cancer using humanized anti-bcma chimeric antigen receptor
US9777061B2 (en) 2014-07-21 2017-10-03 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
US9757420B2 (en) 2014-07-25 2017-09-12 Sangamo Therapeutics, Inc. Gene editing for HIV gene therapy
US9816074B2 (en) 2014-07-25 2017-11-14 Sangamo Therapeutics, Inc. Methods and compositions for modulating nuclease-mediated genome engineering in hematopoietic stem cells
US9616090B2 (en) 2014-07-30 2017-04-11 Sangamo Biosciences, Inc. Gene correction of SCID-related genes in hematopoietic stem and progenitor cells
US20170209492A1 (en) 2014-07-31 2017-07-27 Novartis Ag Subset-optimized chimeric antigen receptor-containing t-cells
US11299732B2 (en) * 2014-08-07 2022-04-12 The Rockefeller University Compositions and methods for transcription-based CRISPR-Cas DNA editing
WO2016022866A1 (en) * 2014-08-07 2016-02-11 Agilent Technologies, Inc. Cis-blocked guide rna
US10513711B2 (en) 2014-08-13 2019-12-24 Dupont Us Holding, Llc Genetic targeting in non-conventional yeast using an RNA-guided endonuclease
CN107429241B (zh) 2014-08-14 2025-10-24 百奥赛图(北京)医药科技股份有限公司 Dna敲入系统
WO2016025880A1 (en) 2014-08-14 2016-02-18 Novartis Ag Treatment of cancer using gfr alpha-4 chimeric antigen receptor
SG11201700770PA (en) 2014-08-19 2017-03-30 Novartis Ag Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment
US20180320226A1 (en) 2014-08-19 2018-11-08 President And Fellows Of Harvard College RNA-Guided Systems For Probing And Mapping Of Nucleic Acids
US10435685B2 (en) 2014-08-19 2019-10-08 Pacific Biosciences Of California, Inc. Compositions and methods for enrichment of nucleic acids
CA2959070C (en) 2014-08-27 2020-11-10 Caribou Biosciences, Inc. Methods for increasing cas9-mediated engineering efficiency
US10450584B2 (en) 2014-08-28 2019-10-22 North Carolina State University Cas9 proteins and guiding features for DNA targeting and genome editing
BR112017003757A2 (pt) 2014-09-12 2017-12-26 Du Pont ?plantas de milho, partes de planta de milho ou sementes de milho?
EP3842514A1 (en) 2014-09-12 2021-06-30 Whitehead Institute for Biomedical Research Cells expressing apolipoprotein e and uses thereof
IL234638A0 (en) 2014-09-14 2014-12-02 Yeda Res & Dev NMDA receptor antagonists for the treatment of Gaucher disease
HUE055583T2 (hu) 2014-09-16 2021-12-28 Sangamo Therapeutics Inc Eljárások és készítmények nukleáz által közvetített genommódosításhoz és -javításhoz hematopoetikus õssejtekben
ES2891332T3 (es) 2014-09-17 2022-01-27 Novartis Ag Direccionamiento a células citotóxicas con receptores quiméricos para la inmunoterapia adoptiva
US10040048B1 (en) 2014-09-25 2018-08-07 Synthego Corporation Automated modular system and method for production of biopolymers
CN113016623A (zh) 2014-09-26 2021-06-25 谱赛科美国股份有限公司 用于甜菊的单核苷酸多态性(snp)标志物
SG10201902811TA (en) 2014-09-29 2019-04-29 Jackson Lab High efficiency, high throughput generation of genetically modified mammals by electroporation
IL287561B2 (en) 2014-10-01 2024-03-01 Massachusetts Gen Hospital Methods for increasing efficiency of nuclease-induced homology-directed repair
CN107208086A (zh) 2014-10-17 2017-09-26 霍华德休斯医学研究所 基因组探针
GB201418965D0 (enExample) 2014-10-24 2014-12-10 Ospedale San Raffaele And Fond Telethon
US10612042B2 (en) 2014-10-24 2020-04-07 Avectas Limited Delivery across cell plasma membranes
JP6788584B2 (ja) 2014-10-31 2020-11-25 マサチューセッツ インスティテュート オブ テクノロジー Ｃｒｉｓｐｒについての超並列コンビナトリアル遺伝学
KR20170075013A (ko) 2014-10-31 2017-06-30 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 Cart 세포에서 유전자 발현의 변경 및 그의 용도
RU2739794C2 (ru) 2014-10-31 2020-12-28 Массачусетс Инститьют Оф Текнолоджи Доставка биомолекул в клетки иммунной системы
EP3215623A4 (en) 2014-11-06 2018-09-26 President and Fellows of Harvard College Cells lacking b2m surface expression and methods for allogeneic administration of such cells
JP6823593B2 (ja) 2014-11-06 2021-02-03 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーＥ．Ｉ．Ｄｕ Ｐｏｎｔ Ｄｅ Ｎｅｍｏｕｒｓ Ａｎｄ Ｃｏｍｐａｎｙ Ｒｎａ誘導型エンドヌクレアーゼの細胞へのペプチド媒介輸送
EP3218497A1 (en) 2014-11-12 2017-09-20 NMC Inc. Transgenic plants with engineered redox sensitive modulation of photosynthetic antenna complex pigments and methods for making the same
WO2016080097A1 (ja) * 2014-11-17 2016-05-26 国立大学法人東京医科歯科大学 簡便で高効率の遺伝子改変非ヒト哺乳動物の作製方法
KR101833433B1 (ko) 2014-11-25 2018-02-28 한국생명공학연구원 돼지 t 세포 및 b 세포 면역결핍 세포주 생산 및 그의 제조 방법
US20170327834A1 (en) 2014-12-15 2017-11-16 Syngenta Participations Ag Pesticidal microrna carriers and use thereof
US10889834B2 (en) 2014-12-15 2021-01-12 Sangamo Therapeutics, Inc. Methods and compositions for enhancing targeted transgene integration
JP6725513B2 (ja) 2014-12-16 2020-07-22 ダニスコ・ユーエス・インク ヘルパー株媒介型真菌ゲノム改変用の組成物および方法
WO2016100389A1 (en) 2014-12-16 2016-06-23 Synthetic Genomics, Inc. Compositions of and methods for in vitro viral genome engineering
WO2016100951A2 (en) * 2014-12-18 2016-06-23 Integrated Dna Technologies, Inc. Crispr-based compositions and methods of use
US20190054117A1 (en) 2014-12-19 2019-02-21 Novartis Ag Dimerization switches and uses thereof
EP3237624B1 (en) 2014-12-23 2020-01-29 Syngenta Participations AG Methods and compositions for identifying and enriching for cells comprising site specific genomic modifications
CA2972454C (en) 2014-12-31 2024-09-10 Phykion Inc. Compositions and methods for high efficiency in in vivo genome editing
AU2016206870B2 (en) * 2015-01-12 2022-02-17 Massachusetts Institute Of Technology Gene editing through microfluidic delivery
EP3245232B1 (en) * 2015-01-12 2021-04-21 The Regents of The University of California Heterodimeric cas9 and methods of use thereof
WO2016112963A1 (en) 2015-01-13 2016-07-21 Riboxx Gmbh Delivery of biomolecules into cells
US20180073035A1 (en) * 2015-01-19 2018-03-15 Institute Of Genetics And Developmental Biology, Chinese Academy Of Sciences A method for precise modification of plant via transient gene expression
HK1246690A1 (zh) 2015-01-21 2018-09-14 Sangamo Therapeutics, Inc. 用於鉴定高度特异性核酸酶的方法和组合物
ES2945315T3 (es) 2015-01-27 2023-06-30 Inst Genetics & Developmental Biology Cas Método para realizar modificaciones específicas de sitio en la planta completa a través de la expresión transitoria de genes
US11180792B2 (en) 2015-01-28 2021-11-23 The Regents Of The University Of California Methods and compositions for labeling a single-stranded target nucleic acid
EP3798302A1 (fr) 2015-01-29 2021-03-31 Meiogenix Procede pour induire des recombinaisons meiotiques ciblees
US10485196B2 (en) 2015-02-03 2019-11-26 The Institute Of Genetics And Developmental Biology Chinese Academy Of Scinces Rice plants with altered seed phenotype and quality
WO2016124918A1 (en) 2015-02-03 2016-08-11 The Institute Of Genetics And Developmental Biology Plants with increased seed size
US10765699B2 (en) 2015-02-06 2020-09-08 National University Of Singapore Methods for enhancing efficacy of therapeutic immune cells
TW201702380A (zh) * 2015-02-27 2017-01-16 再生元醫藥公司 宿主細胞蛋白質修飾
CA2977271A1 (en) * 2015-03-02 2016-09-09 Synthetic Genomics, Inc. Regulatory elements from labyrinthulomycetes microorganisms
JP6817215B2 (ja) 2015-03-03 2021-01-20 ザ ジェネラル ホスピタル コーポレイション 変更ＰＡＭ特異性を有する遺伝子操作ＣＲＩＳＰＲ−Ｃａｓ９ヌクレアーゼ
WO2016142427A1 (en) 2015-03-10 2016-09-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Method ank kit for reprogramming somatic cells
US10410118B2 (en) 2015-03-13 2019-09-10 Deep Genomics Incorporated System and method for training neural networks
KR102194612B1 (ko) 2015-03-16 2020-12-23 인스티튜트 오브 제네틱스 앤드 디벨롭멘털 바이오롤지, 차이니즈 아카데미 오브 사이언시스 비-유전성 물질을 이용한 식물 게놈의 부위-특이적인 변형 방법
WO2016149547A1 (en) 2015-03-17 2016-09-22 Bio-Rad Laboratories, Inc. Detection of genome editing
WO2016157175A1 (en) 2015-03-27 2016-10-06 Yeda Research And Development Co. Ltd. Methods of treating motor neuron diseases
EP3553178A1 (en) 2015-03-27 2019-10-16 E. I. du Pont de Nemours and Company Soybean u6 small nuclear rna gene promoters and their use in constitutive expression of small rna genes in plants
EP3277805B1 (en) 2015-03-31 2025-05-07 SOHM, Inc. Cas 9 retroviral integrase systems for targeted incorporation of a dna sequence into a genome of a cell
US11214779B2 (en) 2015-04-08 2022-01-04 University of Pittsburgh—of the Commonwealth System of Higher Education Activatable CRISPR/CAS9 for spatial and temporal control of genome editing
GB201506509D0 (en) 2015-04-16 2015-06-03 Univ Wageningen Nuclease-mediated genome editing
EP3286211A1 (en) 2015-04-23 2018-02-28 Novartis AG Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
WO2016176652A2 (en) 2015-04-29 2016-11-03 Fred Hutchinson Cancer Research Center Modified stem cells and uses thereof
US20160346359A1 (en) * 2015-05-01 2016-12-01 Spark Therapeutics, Inc. Adeno-associated Virus-Mediated CRISPR-Cas9 Treatment of Ocular Disease
US10179918B2 (en) 2015-05-07 2019-01-15 Sangamo Therapeutics, Inc. Methods and compositions for increasing transgene activity
CA2988854A1 (en) 2015-05-08 2016-11-17 President And Fellows Of Harvard College Universal donor stem cells and related methods
CA2985816A1 (en) 2015-05-15 2016-11-24 The General Hospital Corporation Antagonistic anti-tumor necrosis factor receptor superfamily antibodies
RU2021132397A (ru) 2015-05-16 2022-02-24 Джензим Корпорейшн Генное редактирование глубоких интронных мутаций
BR112017024757A2 (pt) 2015-05-18 2018-11-13 TCR2 Therapeutics Inc. composições e métodos para reprogramação de tcr utilizando proteínas de fusão
EP3095870A1 (en) 2015-05-19 2016-11-23 Kws Saat Se Methods for the in planta transformation of plants and manufacturing processes and products based and obtainable therefrom
DE102015006335A1 (de) 2015-05-19 2016-11-24 Kws Saat Se Verfahren und Konstrukte zur gezielten Nukleinsäure Editierung in Pflanzen
DE102015014252A1 (de) 2015-11-05 2017-05-11 Kws Saat Se Verfahren und Konstrukte zur gezielten Nukleinsäure Editierung in Pflanzen
EP3297642B1 (en) 2015-05-22 2019-09-11 STCube & Co., Inc. Screening methods for targets for cancer therapy
EP3689139B1 (en) 2015-05-29 2025-01-01 Regeneron Pharmaceuticals, Inc. Rodent cells having a disruption in a c9orf72 locus
US10117911B2 (en) 2015-05-29 2018-11-06 Agenovir Corporation Compositions and methods to treat herpes simplex virus infections
EP3919622A1 (en) 2015-06-01 2021-12-08 Temple University - Of The Commonwealth System of Higher Education Methods and compositions for rna-guided treatment of hiv infection
EP3303585A4 (en) 2015-06-03 2018-10-31 Board of Regents of the University of Nebraska Dna editing using single-stranded dna
EP3303634B1 (en) 2015-06-03 2023-08-30 The Regents of The University of California Cas9 variants and methods of use thereof
EP3302525A2 (en) 2015-06-05 2018-04-11 Novartis AG Methods and compositions for diagnosing, treating, and monitoring treatment of shank3 deficiency associated disorders
US10185803B2 (en) 2015-06-15 2019-01-22 Deep Genomics Incorporated Systems and methods for classifying, prioritizing and interpreting genetic variants and therapies using a deep neural network
JP7051438B2 (ja) 2015-06-15 2022-04-11 ノース カロライナ ステート ユニバーシティ 核酸およびｒｎａに基づく抗菌剤の効率的な送達のための方法および組成物
IL316159A (en) 2015-06-15 2024-12-01 Mpeg La Llc Defined Oligonucleotide Multimers and Methods for Manufacture Thereof
JP2018518182A (ja) 2015-06-17 2018-07-12 ザ ユーエービー リサーチ ファンデーション ゲノム編集のためのｃｒｉｓｐｒ／ｃａｓ９複合体
CA2989858A1 (en) 2015-06-17 2016-12-22 The Uab Research Foundation Crispr/cas9 complex for introducing a functional polypeptide into cells of blood cell lineage
US9790490B2 (en) 2015-06-18 2017-10-17 The Broad Institute Inc. CRISPR enzymes and systems
US10648020B2 (en) 2015-06-18 2020-05-12 The Broad Institute, Inc. CRISPR enzymes and systems
US9957501B2 (en) 2015-06-18 2018-05-01 Sangamo Therapeutics, Inc. Nuclease-mediated regulation of gene expression
EP3313420B1 (en) 2015-06-25 2024-03-13 The Children's Medical Center Corporation Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance
AU2016289530B2 (en) 2015-07-09 2021-05-06 Massachusetts Institute Of Technology Delivery of materials to anucleate cells
CN108024544B (zh) 2015-07-13 2022-04-29 桑格摩生物治疗股份有限公司 用于核酸酶介导的基因组工程化的递送方法及组合物
JP7044373B2 (ja) 2015-07-15 2022-03-30 ラトガース，ザ ステート ユニバーシティ オブ ニュージャージー ヌクレアーゼ非依存的な標的化遺伝子編集プラットフォームおよびその用途
EP3744340A3 (en) 2015-07-16 2021-03-03 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
CA2992799A1 (en) 2015-07-17 2017-01-26 Institute Of Genetics And Developmental Biology Chinese Academy Of Sciences Modified plants
WO2017015101A1 (en) * 2015-07-17 2017-01-26 University Of Washington Methods for maximizing the efficiency of targeted gene correction
DK3329001T3 (da) 2015-07-28 2021-12-20 Danisco Us Inc Genomredigeringssystemer og anvendelsesfremgangsmåder
AU2016301196B2 (en) 2015-08-06 2022-09-08 Dana-Farber Cancer Institute, Inc. Tunable endogenous protein degradation
WO2017024317A2 (en) 2015-08-06 2017-02-09 Dana-Farber Cancer Institute, Inc. Methods to induce targeted protein degradation through bifunctional molecules
US9580727B1 (en) 2015-08-07 2017-02-28 Caribou Biosciences, Inc. Compositions and methods of engineered CRISPR-Cas9 systems using split-nexus Cas9-associated polynucleotides
US11667691B2 (en) 2015-08-07 2023-06-06 Novartis Ag Treatment of cancer using chimeric CD3 receptor proteins
WO2017024407A1 (en) 2015-08-11 2017-02-16 The Royal Institution For The Advancement Of Learning/Mcgill University Peptidic tgf-beta antagonists
JP2018527920A (ja) 2015-08-14 2018-09-27 インスティテュート・オブ・ジェネティクス・アンド・ディヴェロプメンタル・バイオロジー、チャイニーズ・アカデミー・オブ・サイエンシズＩｎｓｔｉｔｕｔｅ ｏｆ Ｇｅｎｅｔｉｃｓ ａｎｄ Ｄｅｖｅｌｏｐｍｅｎｔａｌ Ｂｉｏｌｏｇｙ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ ｏｆ Ｓｃｉｅｎｃｅｓ 部位特異的ヌクレオチド置換によりグリホサート耐性イネを取得するための方法
WO2017031341A1 (en) 2015-08-19 2017-02-23 Children's Research Institute, Children's National Medical Center Compositions and methods for treating graft versus host disease
AU2016316845B2 (en) 2015-08-28 2022-03-10 The General Hospital Corporation Engineered CRISPR-Cas9 nucleases
US9512446B1 (en) 2015-08-28 2016-12-06 The General Hospital Corporation Engineered CRISPR-Cas9 nucleases
US9926546B2 (en) 2015-08-28 2018-03-27 The General Hospital Corporation Engineered CRISPR-Cas9 nucleases
WO2017041051A1 (en) 2015-09-04 2017-03-09 Sqz Biotechnologies Company Intracellular delivery of biomolecules to cells comprising a cell wall
DK3348638T3 (da) 2015-09-09 2023-02-13 Univ Kobe Nat Univ Corp Fremgangsmåde til at konvertere genomsekvens fra gram-positiv bakterie ved specifikt at konvertere nukleinsyrebase i tilsigtet dna-sekvens, og molekylkompleks anvendt dertil
IL241462A0 (en) 2015-09-10 2015-11-30 Yeda Res & Dev Heterologous engineering of betalain pigments in plants
CN108350453A (zh) 2015-09-11 2018-07-31 通用医疗公司 核酸酶dsb的完全查询和测序(find-seq)
CN105132427B (zh) * 2015-09-21 2019-01-08 新疆畜牧科学院生物技术研究所 一种以RNA介导的特异性敲除双基因获得基因编辑绵羊的方法及其专用sgRNA
JP2018529353A (ja) 2015-09-30 2018-10-11 ザ ジェネラル ホスピタル コーポレイション 配列決定法による切断事象の包括的生体外報告（ＣＩＲＣＬＥ−ｓｅｑ）
WO2017059241A1 (en) 2015-10-02 2017-04-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Lentiviral protein delivery system for rna-guided genome editing
EP4108255A1 (en) 2015-10-05 2022-12-28 Precision Biosciences, Inc. Genetically-modified cells comprising a modified human t cell receptor alpha constant region gene
ES2883116T3 (es) 2015-10-05 2021-12-07 Prec Biosciences Inc Meganucleasas diseñadas con secuencias de reconocimiento encontradas en el gen de la región constante alfa del receptor de células T humanas
FI4144844T3 (fi) 2015-10-12 2025-11-24 Dupont Us Holding Llc Suojatut dna-templaatit geenimuokkaukseen ja homologisen rekombinaation lisäämiseen soluissa ja niiden käyttömenetelmät
US10829787B2 (en) * 2015-10-14 2020-11-10 Life Technologies Corporation Ribonucleoprotein transfection agents
AU2016337525B2 (en) 2015-10-16 2022-01-20 The Trustees Of Columbia University In The City Of New York Compositions and methods for inhibition of lineage specific antigens
WO2017066561A2 (en) 2015-10-16 2017-04-20 President And Fellows Of Harvard College Regulatory t cell pd-1 modulation for regulating t cell effector immune responses
WO2017070056A1 (en) * 2015-10-20 2017-04-27 10X Genomics, Inc. Methods and systems for high throughput single cell genetic manipulation
US11371040B2 (en) * 2015-10-22 2022-06-28 Institut National De La Sante Et De La Recherche Medical (Inserm) Endonuclease-barcoding
EP3350327B1 (en) 2015-10-23 2018-09-26 Caribou Biosciences, Inc. Engineered crispr class 2 cross-type nucleic-acid targeting nucleic acids
EP3368157B1 (en) 2015-10-29 2022-06-29 Dana-Farber Cancer Institute, Inc. Methods for identification, assessment, prevention, and treatment of metabolic disorders using pm20d1 and n-lipidated amino acids
WO2017083852A1 (en) 2015-11-13 2017-05-18 MOORE, Tara Methods for the treatment of corneal dystrophies
US20180332790A1 (en) 2015-11-18 2018-11-22 Syngenta Participations Ag Haploid induction compositions and methods for use therefor
US12282014B2 (en) 2015-11-19 2025-04-22 Dana-Farber Cancer Institute, Inc. Methods of identifying compounds that interfere with ERG-driven misguidance of BAF complexes in TMPRSS2-ERG driven prostate cancers
US10639383B2 (en) 2015-11-23 2020-05-05 Sangamo Therapeutics, Inc. Methods and compositions for engineering immunity
WO2017090761A1 (ja) 2015-11-27 2017-06-01 国立大学法人神戸大学 標的化したｄｎａ配列の核酸塩基を特異的に変換する、単子葉植物のゲノム配列の変換方法、及びそれに用いる分子複合体
EP3383411B1 (en) 2015-11-30 2025-07-09 Sana Biotechnology, Inc. Sub-mitochondrial particles for use in treating metabolic conditions
CN105296518A (zh) * 2015-12-01 2016-02-03 中国农业大学 一种用于CRISPR/Cas9技术的同源臂载体构建方法
DK3371310T3 (da) 2015-12-04 2019-08-05 Caribou Biosciences Inc Nucleinsyrekonstruerede targetnucleinsyrer
US11208649B2 (en) 2015-12-07 2021-12-28 Zymergen Inc. HTP genomic engineering platform
US9988624B2 (en) 2015-12-07 2018-06-05 Zymergen Inc. Microbial strain improvement by a HTP genomic engineering platform
CA3007635A1 (en) 2015-12-07 2017-06-15 Zymergen Inc. Promoters from corynebacterium glutamicum
WO2017106251A1 (en) * 2015-12-14 2017-06-22 President And Fellows Of Harvard College Cas discrimination using tuned guide rna
WO2017106569A1 (en) * 2015-12-18 2017-06-22 The Regents Of The University Of California Modified site-directed modifying polypeptides and methods of use thereof
US12110490B2 (en) 2015-12-18 2024-10-08 The Broad Institute, Inc. CRISPR enzymes and systems
AU2016374253B2 (en) 2015-12-18 2021-10-21 Sangamo Therapeutics, Inc. Targeted disruption of the MHC cell receptor
ES2983043T3 (es) 2015-12-18 2024-10-21 Sangamo Therapeutics Inc Alteración dirigida del receptor de células T
WO2017112620A1 (en) 2015-12-22 2017-06-29 North Carolina State University Methods and compositions for delivery of crispr based antimicrobials
EP3394092A1 (en) 2015-12-23 2018-10-31 Fred Hutchinson Cancer Research Center High affinity t cell receptors and uses thereof
US20190010495A1 (en) * 2015-12-28 2019-01-10 Novartis Ag Compositions and methods for the treatment of hemoglobinopathies
AU2016380836A1 (en) * 2015-12-30 2018-07-12 Avectas Limited Vector-free delivery of gene editing proteins and compositions to cells and tissues
NZ743682A (en) 2016-01-04 2020-01-31 Univ Leland Stanford Junior Gene therapy for recessive dystrophic epidermolysis bullosa using genetically corrected autologous keratinocytes
WO2017118985A1 (en) 2016-01-06 2017-07-13 Yeda Research And Development Co. Ltd. Compositions and methods for treating malignant, autoimmune and inflammatory diseases
MX2018008345A (es) 2016-01-11 2018-12-06 Univ Leland Stanford Junior Proteínas quiméricas y métodos de inmunoterapia.
IL304088A (en) 2016-01-11 2023-08-01 Univ Leland Stanford Junior Systems containing chimeric proteins and their uses for controlling gene expression
AU2017208086A1 (en) 2016-01-15 2018-08-09 The Jackson Laboratory Genetically modified non-human mammals by multi-cycle electroporation of Cas9 protein
ES3057779T3 (en) 2016-01-15 2026-03-04 Childrens Medical Ct Corp Therapeutic use of mitochondria and combined mitochondrial agents
US11839195B2 (en) 2016-01-21 2023-12-12 The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) Parthenocarpic tomato plants with loss of function mutation in an AGL6 gene and methods of producing same
WO2017130205A1 (en) 2016-01-31 2017-08-03 Hadasit Medical Research Services And Development Ltd. Autosomal-identical pluripotent stem cell populations having non-identical sex chromosomal composition and uses thereof
CN109069568B (zh) 2016-02-02 2023-07-07 桑格摩生物治疗股份有限公司 用于连接dna结合结构域和切割结构域的组合物
WO2017139309A1 (en) 2016-02-12 2017-08-17 Ceres, Inc. Methods and materials for high throughput testing of mutagenized allele combinations
US20190046497A1 (en) 2016-02-14 2019-02-14 Yeda Research And Development Co., Ltd. Methods of modulating protein exocytosis and uses of same in therapy
EP3417061B1 (en) 2016-02-18 2022-10-26 The Regents of the University of California Methods and compositions for gene editing in stem cells
US10973930B2 (en) 2016-02-18 2021-04-13 The Penn State Research Foundation Generating GABAergic neurons in brains
WO2017147278A1 (en) 2016-02-25 2017-08-31 The Children's Medical Center Corporation Customized class switch of immunoglobulin genes in lymphoma and hybridoma by crispr/cas9 technology
CA3015665C (en) 2016-02-26 2020-09-22 Lanzatech New Zealand Limited Crispr/cas systems for c1-fixing bacteria
WO2017152023A1 (en) 2016-03-04 2017-09-08 Indoor Biotechnologies Inc. Fel d 1 knockouts and associated compositions and methods based on crispr-cas9 genomic editing
WO2017153982A1 (en) 2016-03-06 2017-09-14 Yeda Research And Development Co. Ltd. Method for modulating myelination
WO2017161001A1 (en) 2016-03-15 2017-09-21 Children's Medical Center Corporation Methods and compositions relating to hematopoietic stem cell expansion
WO2017161043A1 (en) 2016-03-16 2017-09-21 The J. David Gladstone Institutes Methods and compositions for treating obesity and/or diabetes and for identifying candidate treatment agents
EP3430035A4 (en) 2016-03-16 2020-02-19 Conagen Inc. PRODUCTION OF PROTEINS IN LABYRINE THULOMYCETES
JP2019512271A (ja) 2016-03-21 2019-05-16 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド Ｔ細胞疲弊状態特異的遺伝子発現調節因子およびその使用
EP3443096B1 (en) 2016-04-15 2023-03-01 Novartis AG Compositions and methods for selective expression of chimeric antigen receptors
ES3039670T3 (en) 2016-04-15 2025-10-23 Memorial Sloan Kettering Cancer Center Transgenic t cell and chimeric antigen receptor t cell compositions and related methods
AU2017253107B2 (en) 2016-04-19 2023-07-20 Massachusetts Institute Of Technology CPF1 complexes with reduced indel activity
SG11201810179RA (en) 2016-04-19 2018-12-28 Broad Inst Inc Novel crispr enzymes and systems
KR101868601B1 (ko) * 2016-04-22 2018-06-18 한양대학교 산학협력단 클라미도모나스 변이주 함유 사료를 이용하여 생산된 계란 및 이의 생산방법
JP2019514377A (ja) 2016-04-26 2019-06-06 マサチューセッツ インスティテュート オブ テクノロジー 拡張可能なリコンビナーゼカスケード
US20170362609A1 (en) 2016-05-02 2017-12-21 Massachusetts Institute Of Technology AMPHIPHILIC NANOPARTICLES FOR CODELIVERY OF WATER-INSOLUBLE SMALL MOLECULES AND RNAi
JP2019519501A (ja) * 2016-05-12 2019-07-11 ブライアン ピー． ハンリーＢｒｉａｎ Ｐ． ＨＡＮＬＥＹ ヒトおよび動物における体細胞の大部分へのｃｒｉｓｐｒおよび他の遺伝子治療薬の安全な送達
EP3463371B1 (en) 2016-05-24 2022-02-23 Indiana University Research & Technology Corporation Ku inhibitors and their use
KR20190032295A (ko) 2016-05-25 2019-03-27 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) 암 치료 방법 및 조성물
LT3604527T (lt) 2016-06-02 2021-06-25 Sigma-Aldrich Co., Llc Programuojamų, dnr surišančių baltymų panaudojimas tiksliniam genomo modifikavimui pagerinti
US12626782B2 (en) 2016-06-15 2026-05-12 Deep Genomics Incorporated Architectures for training neural networks using biological sequences, conservation, and molecular phenotypes
CN109790551A (zh) * 2016-06-16 2019-05-21 奥斯陆大学医院Hf 改进的基因编辑
US11293021B1 (en) 2016-06-23 2022-04-05 Inscripta, Inc. Automated cell processing methods, modules, instruments, and systems
WO2018005445A1 (en) 2016-06-27 2018-01-04 The Broad Institute, Inc. Compositions and methods for detecting and treating diabetes
WO2018005793A1 (en) 2016-06-30 2018-01-04 Zymergen Inc. Methods for generating a glucose permease library and uses thereof
JP2019519242A (ja) 2016-06-30 2019-07-11 ザイマージェン インコーポレイテッド 細菌ヘモグロビンライブラリーを生成するための方法およびその使用
WO2018013720A1 (en) * 2016-07-12 2018-01-18 Washington University Incorporation of internal polya-encoded poly-lysine sequence tags and their variations for the tunable control of protein synthesis in bacterial and eukaryotic cells
SG11201900344YA (en) 2016-07-15 2019-02-27 Novartis Ag Treatment and prevention of cytokine release syndrome using a chimeric antigen receptor in combination with a kinase inhibitor
CN106191061B (zh) * 2016-07-18 2019-06-18 暨南大学 一种特异靶向人ABCG2基因的sgRNA导向序列及其应用
US20190309283A1 (en) * 2016-07-19 2019-10-10 Biodynamics Laboratory, Inc. Method for preparing long-chain single-stranded dna
WO2018026953A1 (en) 2016-08-02 2018-02-08 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
KR101710026B1 (ko) 2016-08-10 2017-02-27 주식회사 무진메디 Cas9 단백질 및 가이드 RNA의 혼성체를 함유하는 나노 리포좀 전달체 조성물
EP3498834A4 (en) 2016-08-10 2020-06-17 Genahead Bio, Inc. METHOD FOR MODIFYING A DESTINATION IN THE GENOM OF EUKARYOTIC CELLS AND METHOD FOR DETECTING THE PRESENCE OR ABSENCE OF A NUCLEIC ACID SEQUENCE TO BE DETECTED AT THE DESTINATION
US20190284581A1 (en) 2016-08-12 2019-09-19 Nexuspiral Inc. Genome editing method
IL247368A0 (en) 2016-08-18 2016-11-30 Yeda Res & Dev Diagnostic and therapeutic uses of exosomes
WO2018034554A1 (ko) 2016-08-19 2018-02-22 주식회사 툴젠 인위적으로 조작된 신생혈관형성 조절 시스템
WO2020225754A1 (en) 2019-05-06 2020-11-12 Mcmullen Tara Crispr gene editing for autosomal dominant diseases
EP3500677A4 (en) 2016-08-20 2020-04-01 Avellino Lab USA, Inc. Single guide rna, crispr/cas9 systems, and methods of use thereof
IL300783B2 (en) 2016-08-24 2026-03-01 Sangamo Therapeutics Inc Engineered nucleases with target-specific zinc fingers
WO2018049009A2 (en) 2016-09-07 2018-03-15 Sangamo Therapeutics, Inc. Modulation of liver genes
US20190242908A1 (en) 2016-09-08 2019-08-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing and treating nephrotic syndrome
IL247752A0 (en) 2016-09-11 2016-11-30 Yeda Res & Dev Compositions and methods for modulating gene expression for site-directed mutagenesis
US10787670B2 (en) 2016-09-15 2020-09-29 Labcyte Inc. High-efficiency transfection of biological cells using sonoporation
ES3033182T3 (en) 2016-09-20 2025-07-31 Dana Farber Cancer Inst Inc Compositions and methods for identification, assessment, prevention, and treatment of aml using usp10 biomarkers and modulators
MX2019003176A (es) 2016-09-23 2019-07-04 Hutchinson Fred Cancer Res Receptores de linfocitos t (tcr) especificos del antigeno menor de histocompatibilidad (h) ah-1 y sus usos.
WO2018064387A1 (en) 2016-09-28 2018-04-05 Novartis Ag Porous membrane-based macromolecule delivery system
EP3519562A4 (en) 2016-09-29 2020-03-25 Nantkwest, Inc. NK-92 HLA CLASS I DEFICIENT CELLS WITH REDUCED IMMUNOGENICITY
JP2019532644A (ja) 2016-09-30 2019-11-14 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Ｒｎａ誘導型核酸修飾酵素及びその使用方法
EP3518667B1 (en) * 2016-09-30 2024-10-30 Regeneron Pharmaceuticals, Inc. Rodents having a hexanucleotide repeat expansion in a c9orf72 locus
AU2017338846B2 (en) 2016-10-04 2020-09-24 Precision Biosciences, Inc. Co-stimulatory domains for use in genetically-modified cells
US10669539B2 (en) 2016-10-06 2020-06-02 Pioneer Biolabs, Llc Methods and compositions for generating CRISPR guide RNA libraries
US11242542B2 (en) 2016-10-07 2022-02-08 Integrated Dna Technologies, Inc. S. pyogenes Cas9 mutant genes and polypeptides encoded by same
MX2019003899A (es) 2016-10-07 2019-08-14 Tcr2 Therapeutics Inc Composiciones y metodos para reprogramacion de receptores de linfocitos t mediante el uso de proteinas de fusion.
CA3039409A1 (en) 2016-10-07 2018-04-12 Integrated Dna Technologies, Inc. S. pyogenes cas9 mutant genes and polypeptides encoded by same
WO2018069232A1 (en) 2016-10-10 2018-04-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the risk of having cardiac hypertrophy
EP3525832A4 (en) 2016-10-14 2020-04-29 The General Hospital Corp. Epigenetically regulated site-specific nucleases
GB201617559D0 (en) 2016-10-17 2016-11-30 University Court Of The University Of Edinburgh The Swine comprising modified cd163 and associated methods
CN110022904B (zh) 2016-10-20 2024-04-19 桑格摩生物治疗股份有限公司 用于治疗法布里病的方法和组合物
WO2018081531A2 (en) 2016-10-28 2018-05-03 Ariad Pharmaceuticals, Inc. Methods for human t-cell activation
CN106637421B (zh) * 2016-10-28 2019-12-27 博雅缉因（北京）生物科技有限公司 双sgRNA文库的构建及其应用于高通量功能性筛选研究的方法
WO2018076335A1 (en) 2016-10-31 2018-05-03 Institute Of Genetics And Developmental Biology, Chinese Academy Of Sciences Compositions and methods for enhancing abiotic stress tolerance
US11020492B2 (en) 2016-10-31 2021-06-01 Sangamo Therapeutics, Inc. Gene correction of SCID-related genes in hematopoietic stem and progenitor cells
US10633454B2 (en) 2016-11-01 2020-04-28 Conagen Inc. Expression of modified glycoproteins and glycopeptides
WO2018144097A1 (en) 2016-11-04 2018-08-09 Akeagen Llc Genetically modified non-human animals and methods for producing heavy chain-only antibodies
CA3042259A1 (en) 2016-11-04 2018-05-11 Flagship Pioneering Innovations V. Inc. Novel plant cells, plants, and seeds
WO2018087391A1 (en) 2016-11-14 2018-05-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for modulating stem cells proliferation or differentiation
EP4520828A3 (en) 2016-11-15 2025-07-09 The Schepens Eye Research Institute, Inc. Compositions and methods for the treatment of aberrant angiogenesis
US11440958B2 (en) 2016-11-22 2022-09-13 National University Of Singapore Blockade of CD7 expression and chimeric antigen receptors for immunotherapy of T-cell malignancies
AU2017363311A1 (en) 2016-11-22 2019-06-13 TCR2 Therapeutics Inc. Compositions and methods for TCR reprogramming using fusion proteins
AU2017364084B2 (en) 2016-11-22 2024-07-04 Integrated Dna Technologies, Inc. CRISPR/Cpf1 systems and methods
US11542508B2 (en) 2016-11-28 2023-01-03 Yeda Research And Development Co. Ltd. Isolated polynucleotides and polypeptides and methods of using same for expressing an expression product of interest
EP3548894B1 (en) 2016-12-02 2021-10-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for diagnosing renal cell carcinoma
US9816093B1 (en) 2016-12-06 2017-11-14 Caribou Biosciences, Inc. Engineered nucleic acid-targeting nucleic acids
CA3046199A1 (en) 2016-12-08 2018-06-14 Case Western Reserve University Methods and compositions for enhancing functional myelin production
US11293022B2 (en) 2016-12-12 2022-04-05 Integrated Dna Technologies, Inc. Genome editing enhancement
US20180179553A1 (en) 2016-12-14 2018-06-28 Ligandal, Inc. Compositions and methods for nucleic acid and/or protein payload delivery
JP2020513754A (ja) 2016-12-21 2020-05-21 ティーシーアール２ セラピューティクス インク． がん治療用に操作されたｔ細胞
CA3047163A1 (en) 2016-12-22 2018-06-28 Monsanto Technology Llc Genome editing-based crop engineering and production of brachytic plants
US11981915B2 (en) 2016-12-22 2024-05-14 Avectas Limited Vector-free intracellular delivery by reversible permeabilization
US11597947B2 (en) 2016-12-29 2023-03-07 Asc Therapeutics Inc. Gene editing method using virus
US20200124615A1 (en) 2016-12-29 2020-04-23 Ukko Inc. Methods for identifying and de-epitoping allergenic polypeptides
US11859219B1 (en) 2016-12-30 2024-01-02 Flagship Pioneering Innovations V, Inc. Methods of altering a target nucleotide sequence with an RNA-guided nuclease and a single guide RNA
JP7219972B2 (ja) 2017-01-05 2023-02-09 ラトガース，ザ ステート ユニバーシティ オブ ニュー ジャージー Ｄｎａ二本鎖切断に非依存的な標的化遺伝子編集プラットフォームおよびその用途
WO2018127585A1 (en) 2017-01-06 2018-07-12 Txcell Monospecific regulatory t cell population with cytotoxicity for b cells
EP3346001A1 (en) 2017-01-06 2018-07-11 TXCell Monospecific regulatory t cell population with cytotoxicity for b cells
EP3565889B1 (en) 2017-01-06 2025-03-26 ImmunityBio, Inc. Genetically modified nk-92 cells with decreased cd96/tigit expression
US11519009B2 (en) 2017-01-09 2022-12-06 University Of Massachusetts Complexes for gene deletion and editing
CN106636204B (zh) * 2017-01-09 2019-08-23 华中农业大学 一种能够稳定遗传的白化大鳞副泥鳅育种方法
FI3565891T3 (fi) 2017-01-09 2023-07-04 Whitehead Inst Biomedical Res Menetelmiä geeniekspression muuttamiseksi häiritsemällä säätelysilmukoita muodostavia transkriptiotekijämultimeerejä
GB201700380D0 (en) 2017-01-10 2017-02-22 Plant Bioscience Ltd Methods of increasing seed yield
US20230190958A1 (en) 2017-01-13 2023-06-22 Jichi Medical University AAV Vector for Disrupting Coagulation Factor-Related Gene on Liver Genome
EP3574005B1 (en) 2017-01-26 2021-12-15 Novartis AG Cd28 compositions and methods for chimeric antigen receptor therapy
SG11201906795SA (en) 2017-01-28 2019-08-27 Inari Agriculture Inc Novel plant cells, plants, and seeds
JP2020506700A (ja) 2017-01-31 2020-03-05 ノバルティス アーゲー 多重特異性を有するキメラｔ細胞受容体タンパク質を用いた癌の治療
IL250479A0 (en) 2017-02-06 2017-03-30 Sorek Rotem Genetically engineered cells expressing a disarm system that confers resistance to phages and methods for their production
WO2018148246A1 (en) 2017-02-07 2018-08-16 Massachusetts Institute Of Technology Methods and compositions for rna-guided genetic circuits
EP3580212A4 (en) 2017-02-08 2021-03-17 Dana Farber Cancer Institute, Inc. REGULATION OF CHEMERIC ANTIGEN RECEPTORS
WO2018146481A1 (en) 2017-02-09 2018-08-16 Fujian Agriculture And Forestry University Expression of a phosphate transporter for improving plant yield
US11471538B2 (en) 2017-02-10 2022-10-18 INSERM (Institut National de la Santéet de la Recherche Medicale) Methods and pharmaceutical compositions for the treatment of cancers associated with activation of the MAPK pathway
CA3049989A1 (en) 2017-02-10 2018-08-16 Zymergen Inc. A modular universal plasmid design strategy for the assembly and editing of multiple dna constructs for multiple hosts
JP7669113B2 (ja) 2017-02-17 2025-04-28 デナリ セラピューティクス インコーポレイテッド トランスフェリン受容体トランスジェニックモデル
EP3585807A1 (en) * 2017-02-22 2020-01-01 CRISPR Therapeutics AG Materials and methods for treatment of early onset parkinson's disease (park1) and other synuclein, alpha (snca) gene related conditions or disorders
US20200048359A1 (en) 2017-02-28 2020-02-13 Novartis Ag Shp inhibitor compositions and uses for chimeric antigen receptor therapy
EP3595645A1 (en) 2017-03-15 2020-01-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Pharmaceutical compositions for the treatment of thrombosis in patients suffering from a myeloproliferative neoplasm
EP3595708A4 (en) 2017-03-15 2020-12-16 Fred Hutchinson Cancer Research Center HIGH AFFINITY MAGE-A1 SPECIFIC TCRS AND THEIR USES
US11771703B2 (en) 2017-03-17 2023-10-03 The Johns Hopkins University Targeted epigenetic therapy against distal regulatory element of TGFβ2 expression
EP3601320A1 (en) 2017-03-24 2020-02-05 Institute Of Genetics And Developmental Biology, Chinese Academy Of Sciences Methods for increasing grain yield
EP3600427A1 (en) 2017-03-24 2020-02-05 INSERM - Institut National de la Santé et de la Recherche Médicale Methods and compositions for treating melanoma
EP3600269A1 (en) 2017-03-24 2020-02-05 INSERM - Institut National de la Santé et de la Recherche Médicale Gfi1 inhibitors for the treatment of hyperglycemia
EP3600353A4 (en) * 2017-03-29 2020-12-23 The Broad Institute, Inc. COMPOSITIONS AND METHODS FOR THE TREATMENT OF GAMMA RECEPTOR ACTIVATED BY PEROXYSOME PROLIFERATORS (PPARG)
WO2018178237A1 (en) 2017-03-30 2018-10-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of mitochondrial genetic diseases
AU2018243383B2 (en) 2017-03-30 2024-12-05 Monsanto Technology Llc Systems and methods for use in identifying multiple genome edits and predicting the aggregate effects of the identified genome edits
US20200032252A1 (en) * 2017-04-06 2020-01-30 Dsm Ip Assets B.V. Self-guiding integration construct (sgic)
AU2018253115B2 (en) 2017-04-12 2022-08-11 Edigene Biotechnology, Inc. Aryl hydrocarbon receptor antagonists and uses thereof
US11458118B2 (en) 2017-04-21 2022-10-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of diseases associated with reduced CFTR function
ES2992912T3 (en) 2017-04-21 2024-12-19 Massachusetts Gen Hospital Variants of cpf1 (cas12a) with altered pam specificity
ES2981244T3 (es) 2017-04-28 2024-10-07 Acuitas Therapeutics Inc Novedosas formulaciones de nanopartículas de lípidos de carbonilo y lípidos para la administración de ácidos nucleicos
US20200055948A1 (en) 2017-04-28 2020-02-20 Novartis Ag Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
US20200179511A1 (en) 2017-04-28 2020-06-11 Novartis Ag Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor
US11655275B2 (en) 2017-05-03 2023-05-23 Sangamo Therapeutics, Inc. Methods and compositions for modification of a cystic fibrosis transmembrane conductance regulator (CFTR) gene
IL252151A0 (en) 2017-05-07 2017-07-31 Fainzilber Michael Treatment of stress disorders
CA3062698A1 (en) 2017-05-08 2018-11-15 Precision Biosciences, Inc. Nucleic acid molecules encoding an engineered antigen receptor and an inhibitory nucleic acid molecule and methods of use thereof
WO2019103857A1 (en) 2017-11-22 2019-05-31 Iovance Biotherapeutics, Inc. Expansion of peripheral blood lymphocytes (pbls) from peripheral blood
JP2020519665A (ja) 2017-05-17 2020-07-02 アンセルム（アンスティテュト ナショナル ド ラ サンテ エ ド ラ ルシェルシュ メディカル） オピオイドによる痛みの処置を改善する為のｆｌｔ３阻害剤
CA3064000A1 (en) 2017-05-24 2018-11-29 Effector Therapeutics, Inc. Methods and compositions for cellular immunotherapy
AU2018273986A1 (en) 2017-05-25 2019-12-12 The General Hospital Corporation Bipartite base editor (BBE) architectures and type-II-C-Cas9 zinc finger editing
US11725214B2 (en) 2017-05-25 2023-08-15 Institute Of Genetics And Developmental Biology Chinese Academy Of Sciences Methods for increasing grain productivity
EP3409104A1 (en) 2017-05-31 2018-12-05 Vilmorin et Cie Tomato plant resistant to tomato yellow leaf curl virus, powdery mildew, and nematodes
WO2020249996A1 (en) 2019-06-14 2020-12-17 Vilmorin & Cie Resistance in plants of solanum lycopersicum to the tobamovirus tomato brown rugose fruit virus
EP3409106A1 (en) 2017-06-01 2018-12-05 Vilmorin et Cie Tolerance in plants of solanum lycopersicum to the tobamovirus tomato brown rugose fruit virus (tbrfv)
US11879128B2 (en) 2017-06-05 2024-01-23 Consejo Superior De Investigaciones Científicas (Csic)—Delegación Andalucía Targeting of gluten by genome editing
KR20200026878A (ko) 2017-06-06 2020-03-11 지머젠 인코포레이티드 균류 균주를 개량하기 위한 htp 게놈 공학 플랫폼
US11820822B2 (en) 2017-06-06 2023-11-21 Dana-Farber Cancer Institute, Inc. Methods for sensitizing cancer cells to T cell-mediated killing by modulating molecular pathways
KR20200026874A (ko) 2017-06-06 2020-03-11 지머젠 인코포레이티드 대장균 개량을 위한 htp 게놈 공학 플랫폼
US20210079100A1 (en) 2017-06-08 2021-03-18 Inserm (Institute National De La Sante Et De La Recherche Medicale) Methods and compositions for treating hyperpigmentation disorders
EP3635119A4 (en) 2017-06-09 2021-04-14 Vilmorin & Cie COMPOSITIONS AND PROCEDURES FOR GENO EDITING
IL271275B1 (en) 2017-06-13 2026-04-01 Flagship Pioneering Innovations V Inc Preparations containing croons and their uses
JP7402503B2 (ja) 2017-06-14 2023-12-21 テクニスチェ ユニベルシタト ドレスデン デザイナーｄｎａ組換え酵素を利用したゲノムを遺伝的に改変するための方法及び手段
US11512287B2 (en) 2017-06-16 2022-11-29 Sangamo Therapeutics, Inc. Targeted disruption of T cell and/or HLA receptors
JP7388798B2 (ja) 2017-06-20 2023-11-29 アンスティテュート キュリー Ｓｕｖ３９ｈ１を欠損する免疫細胞
WO2018237170A1 (en) 2017-06-21 2018-12-27 Bertram Timothy A BIOACTIVE IMMUNO-PRIVILEGE RENAL CELLS FOR THE TREATMENT OF RENAL DISEASE
AU2018289077B2 (en) 2017-06-23 2022-03-10 Inscripta, Inc. Nucleic acid-guided nucleases
JP2020529834A (ja) 2017-06-30 2020-10-15 プレシジョン バイオサイエンシズ，インク． Ｔ細胞受容体アルファ遺伝子の改変されたイントロンを含む遺伝子改変ｔ細胞
HUE058668T2 (hu) 2017-06-30 2022-09-28 Inscripta Inc Automatizált sejtkezelési eljárások, modulok, berendezések és rendszerek
EP3652209A2 (en) 2017-07-11 2020-05-20 Compass Therapeutics LLC Agonist antibodies that bind human cd137 and uses thereof
WO2019011118A1 (zh) 2017-07-14 2019-01-17 苏州克睿基因生物科技有限公司 一种基因编辑系统及基因编辑的方法
US20200149042A1 (en) * 2017-07-14 2020-05-14 William N. Haining Modulating biomarkers to increase tumor immunity and improve the efficacy of cancer immunotherapy
US20190316101A1 (en) 2017-07-18 2019-10-17 Howard Hughes Medical Institute Methods and compositions for genetically manipulating genes and cells
WO2019016310A1 (en) 2017-07-20 2019-01-24 INSERM (Institut National de la Santé et de la Recherche Médicale) METHODS AND COMPOSITIONS FOR TREATING CANCERS
IL253642A0 (en) 2017-07-24 2017-09-28 Seger Rony Combined treatment for cancer
WO2019020593A1 (en) 2017-07-25 2019-01-31 INSERM (Institut National de la Santé et de la Recherche Médicale) METHODS AND PHARMACEUTICAL COMPOSITIONS FOR MODULATION OF MONOCYTOPOISIS
WO2019023291A2 (en) 2017-07-25 2019-01-31 Dana-Farber Cancer Institute, Inc. COMPOSITIONS AND METHODS FOR PRODUCTION AND DECODING OF GUIDE RNA LIBRARIES AND USES THEREOF
CN120989074A (zh) 2017-07-31 2025-11-21 映像生物有限公司 眼部疾病的细胞模型及用于眼部疾病的疗法
US11897920B2 (en) 2017-08-04 2024-02-13 Peking University Tale RVD specifically recognizing DNA base modified by methylation and application thereof
CA3071683A1 (en) 2017-08-08 2019-02-14 Sangamo Therapeutics, Inc. Chimeric antigen receptor mediated cell targeting
WO2019028686A1 (zh) 2017-08-08 2019-02-14 北京大学 基因敲除方法
US12398191B2 (en) 2017-08-11 2025-08-26 Fred Hutchinson Cancer Center BRAF-specific TCRs and uses thereof
CN111263810A (zh) * 2017-08-22 2020-06-09 纳匹基因公司 使用多核苷酸指导的核酸内切酶的细胞器基因组修饰
CA3073448A1 (en) 2017-08-23 2019-02-28 The General Hospital Corporation Engineered crispr-cas9 nucleases with altered pam specificity
WO2019038771A1 (en) 2017-08-23 2019-02-28 Technion Research & Development Foundation Limited COMPOSITIONS AND METHODS FOR ENHANCING ALCOHOL TOLERANCE IN YEAST
JP2020534024A (ja) 2017-08-24 2020-11-26 ボード オブ リージェンツ オブ ザ ユニバーシティ オブ ネブラスカ インサイチュ生殖細胞系列ゲノムエンジニアリングのための方法および組成物
WO2019038417A1 (en) 2017-08-25 2019-02-28 Institute Of Genetics And Developmental Biology, Chinese Academy Of Sciences METHODS FOR INCREASING GRAIN YIELD
US10738327B2 (en) 2017-08-28 2020-08-11 Inscripta, Inc. Electroporation cuvettes for automation
WO2019046791A1 (en) 2017-09-01 2019-03-07 The Johns Hopkins University TARGETED EPIGENETIC THERAPY FOR AERIAL CONDITION OF AERTICAL HERITATION
CN107446859B (zh) * 2017-09-02 2020-12-18 河南省农业科学院畜牧兽医研究所 一株鸡毒支原体及其应用
WO2019050948A1 (en) 2017-09-05 2019-03-14 Regeneron Pharmaceuticals, Inc. ADMINISTRATION OF A GENE EDITION SYSTEM HAVING ONLY ONE RETROVIRAL PARTICLE AND METHODS OF GENERATING AND USING
CA3071661A1 (en) 2017-09-06 2019-03-14 Fred Hutchinson Cancer Research Center Strep-tag specific chimeric receptors and uses thereof
WO2019051135A1 (en) 2017-09-06 2019-03-14 Fred Hutchinson Cancer Research Center METHODS FOR IMPROVING ADOPTIVE CELL THERAPY
US20190076814A1 (en) 2017-09-11 2019-03-14 Synthego Corporation Biopolymer synthesis system and method
US20200262879A1 (en) 2017-09-11 2020-08-20 Insideoutbio, Inc. Methods and compositions to enhance the immunogenicity of tumors
WO2019055862A1 (en) 2017-09-14 2019-03-21 Fred Hutchinson Cancer Research Center HIGH AFFINITY T CELL RECEPTORS AND USES THEREOF
ES2983336T3 (es) 2017-09-18 2024-10-22 Futuragene Israel Ltd Control de la expresión de polipéptidos DELLA en tejidos específicos
CN109517796A (zh) 2017-09-18 2019-03-26 博雅辑因（北京）生物科技有限公司 一种基因编辑t细胞及其用途
WO2019056099A1 (en) 2017-09-19 2019-03-28 The University Of British Columbia ANTI-HLA-A2 ANTIBODIES AND METHODS OF USE
WO2019057649A1 (en) 2017-09-19 2019-03-28 INSERM (Institut National de la Santé et de la Recherche Médicale) METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA
CA3075956A1 (en) 2017-09-19 2019-03-28 The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) Genome-edited birds
JP7330174B2 (ja) 2017-09-20 2023-08-21 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル オートファジーをモジュレーションするための方法及び医薬組成物
JP7317023B2 (ja) 2017-09-20 2023-07-28 ザ・ユニバーシティ・オブ・ブリティッシュ・コロンビア 新規抗ｈｌａ－ａ２抗体、およびその使用
WO2019060759A1 (en) 2017-09-21 2019-03-28 Dana-Farber Cancer Institute, Inc. ISOLATION, PRESERVATION, COMPOSITIONS AND USES OF PLANT EXTRACTS JUSTICIA
KR101896847B1 (ko) 2017-09-22 2018-09-07 한국생명공학연구원 DNA 절단 활성이 불활성화된 Cpf1을 포함하는 유전자 발현 억제용 조성물 및 그 용도
BR112020005803A2 (pt) 2017-09-25 2020-12-01 Agrospheres, Inc. composições e métodos para produção e administração moduláveis de produtos biológicos
US11603536B2 (en) * 2017-09-29 2023-03-14 Inari Agriculture Technology, Inc. Methods for efficient maize genome editing
WO2019068022A1 (en) 2017-09-30 2019-04-04 Inscripta, Inc. CONTINUOUS FLOW ELECTROPORATION INSTRUMENTATION
CA3076020A1 (en) 2017-10-02 2019-04-11 Syngenta Participations Ag Engineered pesticidal proteins and methods of controlling plant pests
US20200239544A1 (en) 2017-10-03 2020-07-30 Precision Biosciences, Inc. Modified epidermal growth factor receptor peptides for use in genetically-modified cells
US20200291383A1 (en) * 2017-10-06 2020-09-17 Oregon Health & Science University Compositions and methods for editing rna
WO2019075197A1 (en) 2017-10-11 2019-04-18 The General Hospital Corporation METHODS OF DETECTION OF INDIVIDUAL SITE-SPECIFIC PARASITE GENOMIC DEAMINATION BY BASE EDITING TECHNOLOGIES
US10709085B2 (en) 2017-10-13 2020-07-14 Bejo Zaden Bv Lettuce variety ‘80020-0911-007’
EP3697435A1 (en) 2017-10-20 2020-08-26 Fred Hutchinson Cancer Research Center Compositions and methods of immunotherapy targeting tigit and/or cd112r or comprising cd226 overexpression
WO2019081428A1 (en) 2017-10-23 2019-05-02 INSERM (Institut National de la Santé et de la Recherche Médicale) COMPOUNDS FOR THE TREATMENT OF CMV RELATED DISEASES
US11701391B2 (en) 2017-10-24 2023-07-18 Dalia ELANI Methods of treating an ischemic disease
CN109722414A (zh) 2017-10-27 2019-05-07 博雅辑因（北京）生物科技有限公司 一种高效制备成熟红细胞的方法以及用于制备成熟红细胞的培养基
WO2019089798A1 (en) 2017-10-31 2019-05-09 Novartis Ag Anti-car compositions and methods
US11718679B2 (en) 2017-10-31 2023-08-08 Compass Therapeutics Llc CD137 antibodies and PD-1 antagonists and uses thereof
JP7412341B2 (ja) 2017-10-31 2024-01-12 エディジーン バイオテクノロジー インコーポレイテッド 造血幹細胞および前駆細胞の増幅のための組成物および方法
US20190343885A1 (en) 2017-10-31 2019-11-14 Magenta Therapeutics Inc. Compositions and methods for hematopoietic stem and progenitor cell transplant therapy
US20200299658A1 (en) 2017-11-01 2020-09-24 Precision Biosciences, Inc. Engineered nucleases that target human and canine factor viii genes as a treatment for hemophilia a
WO2019084958A1 (en) 2017-11-06 2019-05-09 Shenzhen Cell Inspire Biotechnology Co., Ltd. Novel human induced pluripotent stem cell lines for modeling alzheimer's disease and usage thereof
BR112020008568A2 (pt) 2017-11-09 2020-10-06 Sangamo Therapeutics, Inc. modificação genética de gene de proteína contendo sh2 indutível por citoquina (cish)
IL255664A0 (en) 2017-11-14 2017-12-31 Shachar Idit Hematopoietic stem cells with enhanced properties
WO2019099560A1 (en) 2017-11-14 2019-05-23 The Schepens Eye Research Institute, Inc. Runx1 inhibition for treatment of proliferative vitreoretinopathy and conditions associated with epithelial to mesenchymal transition
WO2019099823A1 (en) * 2017-11-17 2019-05-23 Stc.Unm Therapy for myotonic dystrophy type 1 via genome editing of the dmpk gene
CN111601883B (zh) 2017-11-17 2024-06-21 艾欧凡斯生物治疗公司 由细针抽吸物和小活检物扩增til
EP3713961A2 (en) 2017-11-20 2020-09-30 Compass Therapeutics LLC Cd137 antibodies and tumor antigen-targeting antibodies and uses thereof
AU2018371212B2 (en) 2017-11-24 2025-04-17 Assistance Publique - Hôpitaux De Paris Methods and compositions for treating cancers
WO2019101995A1 (en) 2017-11-27 2019-05-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for cardiac regeneration
SG11202004980RA (en) 2017-11-28 2020-06-29 Mirimus Inc METHODS OF GENETIC MEDIATED ENGINEERING OF RNAi MODELS
WO2019109047A1 (en) 2017-12-01 2019-06-06 Fred Hutchinson Cancer Research Center Binding proteins specific for 5t4 and uses thereof
GB201720351D0 (en) 2017-12-06 2018-01-17 Iontas Ltd Selecting for developability in drug discovery
CN111712262A (zh) 2017-12-06 2020-09-25 美真达治疗公司 用于动员造血干细胞和祖细胞的给药方案
CA3082956A1 (en) 2017-12-08 2019-06-13 Synthetic Genomics, Inc. Improving algal lipid productivity via genetic modification of a tpr domain containing protein
CN111344402A (zh) 2017-12-14 2020-06-26 Ezy生物科技有限公司 受试者特异性肿瘤抑制细胞及其用途
WO2019118463A1 (en) 2017-12-15 2019-06-20 Danisco Us Inc Cas9 variants and methods of use
WO2019126709A1 (en) 2017-12-22 2019-06-27 The Broad Institute, Inc. Cas12b systems, methods, and compositions for targeted dna base editing
CN107868123B (zh) 2017-12-25 2020-05-12 中国农业科学院作物科学研究所 一种同时提高植物产量和抗性的基因及其应用
WO2019133881A1 (en) 2017-12-29 2019-07-04 Rubius Therapeutics, Inc. Gene editing and targeted transcriptional modulation for enginerering erythroid cells
AU2019205262A1 (en) 2018-01-03 2020-07-23 Magenta Therapeutics Inc. Compositions and methods for the expansion of hematopoietic stem and progenitor cells and treatment of inherited metabolic disorders
EP3735590A1 (en) 2018-01-04 2020-11-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma resistant
WO2019140278A1 (en) 2018-01-11 2019-07-18 Fred Hutchinson Cancer Research Center Immunotherapy targeting core binding factor antigens
EP3743096A1 (en) 2018-01-25 2020-12-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonists of il-33 for use in methods for preventing ischemia reperfusion injury in an organ
WO2019147743A1 (en) 2018-01-26 2019-08-01 Massachusetts Institute Of Technology Structure-guided chemical modification of guide rna and its applications
US11802288B1 (en) * 2018-01-29 2023-10-31 Inari Agriculture Technology, Inc. Methods for efficient soybean genome editing
IL257225A (en) 2018-01-29 2018-04-09 Yeda Res & Dev Treatment of sarcoma
US11220694B1 (en) 2018-01-29 2022-01-11 Inari Agriculture, Inc. Rice cells and rice plants
US11926835B1 (en) * 2018-01-29 2024-03-12 Inari Agriculture Technology, Inc. Methods for efficient tomato genome editing
US11497752B2 (en) 2018-01-30 2022-11-15 Foghorn Therapeutics Inc. Compounds and uses thereof
WO2019153067A1 (en) * 2018-02-06 2019-08-15 Valorbec, Société en commandite Microfluidic devices, systems, infrastructures, uses thereof and methods for genetic engineering using same
WO2019157326A1 (en) 2018-02-08 2019-08-15 Zymergen Inc. Genome editing using crispr in corynebacterium
EP3751990A1 (en) 2018-02-14 2020-12-23 Institute Of Genetics And Developmental Biology Chinese Academy of Sciences Methods of increasing nutrient use efficiency
EP3752134B1 (en) 2018-02-16 2024-12-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating vitiligo
EP3755792A4 (en) 2018-02-23 2021-12-08 Pioneer Hi-Bred International, Inc. NEW CAS9 ORTHOLOGIST
EP3759130A1 (en) 2018-02-26 2021-01-06 Fred Hutchinson Cancer Research Center Compositions and methods for cellular immunotherapy
US20190284553A1 (en) 2018-03-15 2019-09-19 KSQ Therapeutics, Inc. Gene-regulating compositions and methods for improved immunotherapy
WO2019190874A1 (en) 2018-03-29 2019-10-03 Inscripta, Inc. Automated control of cell growth rates for induction and transformation
WO2019193375A1 (en) 2018-04-04 2019-10-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fzd7 inhibitors for the treatment of retinal neovascularization
IT201800004253A1 (it) 2018-04-05 2019-10-05 Composizioni e metodi per il trattamento della tachicardia ventricolare polimorfa catecolaminergica dominante ereditaria.
US12103972B2 (en) 2018-04-06 2024-10-01 Dana-Farber Cancer Institute, Inc. KIR3DL3 as an HHLA2 receptor, anti-HHLA2 antibodies, and uses thereof
CN116536272A (zh) 2018-04-06 2023-08-04 儿童医疗中心有限公司 用于体细胞重新编程和调整印记的组合物和方法
JP7304888B2 (ja) 2018-04-12 2023-07-07 プレシジョン バイオサイエンシズ，インク． ヒトｔ細胞受容体アルファ定常領域遺伝子に特異性を有する最適化された操作されたヌクレアーゼ
WO2019200004A1 (en) 2018-04-13 2019-10-17 Inscripta, Inc. Automated cell processing instruments comprising reagent cartridges
SG11202010116PA (en) 2018-04-13 2020-11-27 Sangamo Therapeutics France Chimeric antigen receptor specific for interleukin-23 receptor
EP3781585A4 (en) 2018-04-17 2022-01-26 The General Hospital Corporation SENSITIVE IN VITRO TESTS FOR SUBSTRATE PREFERENCES AND SITE FOR NUCLEIC ACID BINDERS, MODIFIERS AND CLEAVAGE AGENTS
GB2587970B (en) 2018-04-19 2023-02-08 Univ California Compositions and methods for gene editing
US10858761B2 (en) 2018-04-24 2020-12-08 Inscripta, Inc. Nucleic acid-guided editing of exogenous polynucleotides in heterologous cells
US10526598B2 (en) 2018-04-24 2020-01-07 Inscripta, Inc. Methods for identifying T-cell receptor antigens
US10508273B2 (en) 2018-04-24 2019-12-17 Inscripta, Inc. Methods for identifying selective binding pairs
US20190330643A1 (en) * 2018-04-25 2019-10-31 The Catholic University Of America Engineering of bacteriophages by genome editing using the crispr-cas9 system
CN108707621B (zh) 2018-04-26 2021-02-12 中国农业科学院作物科学研究所 一种CRISPR/Cpf1系统介导的以RNA转录本为修复模板的同源重组方法
EP3784351A1 (en) 2018-04-27 2021-03-03 Novartis AG Car t cell therapies with enhanced efficacy
EP3784254A1 (en) 2018-04-27 2021-03-03 Iovance Biotherapeutics, Inc. Closed process for expansion and gene editing of tumor infiltrating lymphocytes and uses of same in immunotherapy
WO2019210216A2 (en) * 2018-04-27 2019-10-31 Seattle Children's Hospital D/B/A Seattle Children's Research Institute Talen-based and crispr/cas-based gene editing for bruton's tyrosine kinase
JP7568511B2 (ja) 2018-04-27 2024-10-16 ジーンエディット インコーポレイテッド カチオン性ポリマーおよびその生体分子送達のための使用
CN112218945A (zh) 2018-05-08 2021-01-12 国立大学法人大阪大学 纯合细胞的制作方法
EP3794130A4 (en) 2018-05-16 2022-07-27 Synthego Corporation METHODS AND SYSTEMS FOR DESIGNING AND USING GUIDE RNA
US11690921B2 (en) 2018-05-18 2023-07-04 Sangamo Therapeutics, Inc. Delivery of target specific nucleases
EP3784776A4 (en) 2018-05-23 2022-01-26 National University of Singapore Blockade of cd2 surface expression and expression of chimeric antigen receptors for immunotherapy of t-cell malignancies
GB201808424D0 (en) 2018-05-23 2018-07-11 Lucite Int Uk Ltd Methods for producing BMA and MMA using genetically modified microorganisms
WO2019229722A1 (en) 2018-06-01 2019-12-05 Avectas Limited Cell engineering platform
US11866719B1 (en) 2018-06-04 2024-01-09 Inari Agriculture Technology, Inc. Heterologous integration of regulatory elements to alter gene expression in wheat cells and wheat plants
KR20210018437A (ko) 2018-06-07 2021-02-17 더 브리검 앤드 우먼즈 하스피털, 인크. 조혈 줄기 세포를 생산하기 위한 방법
US20220403001A1 (en) 2018-06-12 2022-12-22 Obsidian Therapeutics, Inc. Pde5 derived regulatory constructs and methods of use in immunotherapy
AU2019284911B2 (en) 2018-06-13 2026-04-09 Novartis Ag BCMA chimeric antigen receptors and uses thereof
WO2019237386A1 (zh) * 2018-06-16 2019-12-19 深圳市博奥康生物科技有限公司 一种敲除人ct1.1基因的方法
EP3813871A4 (en) 2018-06-29 2022-10-12 Icahn School of Medicine at Mount Sinai SPHINGOLIPID METABOLIZING PROTEINS ENCODING FOR ANC80
AU2019292919A1 (en) 2018-06-30 2021-03-11 Inscripta, Inc. Instruments, modules, and methods for improved detection of edited sequences in live cells
US20210292381A1 (en) 2018-07-04 2021-09-23 Ukko Inc. Methods of de-epitoping wheat proteins and use of same for the treatment of celiac disease
CN112823011B (zh) 2018-07-09 2026-05-08 加利福尼亚大学董事会 基于t细胞的免疫疗法的基因靶标
US20210261957A1 (en) * 2018-07-10 2021-08-26 Alia Therapeutics S.R.L. Vesicles for traceless delivery of guide rna molecules and/or guide rna molecule/rna-guided nuclease complex(es) and a production method thereof
JP2021530212A (ja) 2018-07-13 2021-11-11 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニアThe Regents Of The University Of California レトロトランスポゾンベースの送達媒体及びその使用方法
WO2020018142A1 (en) * 2018-07-16 2020-01-23 Arbor Biotechnologies, Inc. Novel crispr dna targeting enzymes and systems
WO2020018918A1 (en) 2018-07-19 2020-01-23 The Board Of Trustees Of The University Of Illinois Methods for exon skipping and gene knockout using base editors
WO2020018964A1 (en) 2018-07-20 2020-01-23 Fred Hutchinson Cancer Research Center Compositions and methods for controlled expression of antigen-specific receptors
WO2020028686A1 (en) * 2018-08-01 2020-02-06 New York University Targeting piezo1 for treatment of cancer and infectious diseases
CN112703011A (zh) 2018-08-06 2021-04-23 国家医疗保健研究所 用于治疗癌症的方法和组合物
EP3607819A1 (en) 2018-08-10 2020-02-12 Vilmorin et Cie Resistance to xanthomonas campestris pv. campestris (xcc) in cauliflower
US20210292389A1 (en) 2018-08-10 2021-09-23 Sangamo Therapeutics France New car constructs comprising tnfr2 domains
US11142740B2 (en) 2018-08-14 2021-10-12 Inscripta, Inc. Detection of nuclease edited sequences in automated modules and instruments
US10752874B2 (en) 2018-08-14 2020-08-25 Inscripta, Inc. Instruments, modules, and methods for improved detection of edited sequences in live cells
US10532324B1 (en) 2018-08-14 2020-01-14 Inscripta, Inc. Instruments, modules, and methods for improved detection of edited sequences in live cells
EP3821020A4 (en) 2018-08-15 2022-05-04 Zymergen Inc. APPLICATIONS OF CRISPRI IN HIGH-PERFORMANCE METABOLIC ENGINEERING
US12460244B2 (en) 2018-08-20 2025-11-04 The Broad Institute, Inc. Inhibitors of RNA-guided nuclease activity and uses thereof
KR20210049119A (ko) 2018-08-22 2021-05-04 프레드 헛친슨 켄서 리서치 센터 Kras 또는 her2 항원을 표적으로 하는 면역요법
EP3841205A4 (en) 2018-08-22 2022-08-17 The Regents of The University of California Variant type v crispr/cas effector polypeptides and methods of use thereof
EP3841204A4 (en) 2018-08-23 2022-05-18 Sangamo Therapeutics, Inc. CHANGED TARGET SPECIFIC BASE EDITORS
WO2020047164A1 (en) 2018-08-28 2020-03-05 Vor Biopharma, Inc Genetically engineered hematopoietic stem cells and uses thereof
BR112021003830A2 (pt) 2018-08-28 2021-07-20 Fred Hutchinson Cancer Research Center métodos e composições para terapia celular t adotiva incorporando sinalização notch induzida
US11965154B2 (en) 2018-08-30 2024-04-23 Inscripta, Inc. Detection of nuclease edited sequences in automated modules and instruments
US12534743B2 (en) 2018-08-31 2026-01-27 Inari Agriculture Technology, Inc. Compositions, systems, and methods for genome editing
US11459551B1 (en) 2018-08-31 2022-10-04 Inari Agriculture Technology, Inc. Compositions, systems, and methods for genome editing
US12545910B2 (en) 2018-08-31 2026-02-10 Inari Agriculture Technology, Inc. Compositions, systems, and methods for genome editing
WO2020048942A1 (en) 2018-09-04 2020-03-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for enhancing cytotoxic t lymphocyte-dependent immune responses
KR20210071976A (ko) 2018-09-04 2021-06-16 마젠타 테라퓨틱스 인코포레이티드 아릴 하이드로카본 수용체 길항제 및 사용 방법
WO2020051283A1 (en) * 2018-09-05 2020-03-12 The Regents Of The University Of California Generation of heritably gene-edited plants without tissue culture
JP7444858B2 (ja) 2018-09-05 2024-03-06 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル 喘息及びアレルギー性疾患を処置するための方法及び組成物
US12215377B2 (en) 2018-09-07 2025-02-04 The J. David Gladstone Institute, a testamentary trust established under the Will of J. David Gladstone HIV or HCV detection with CRISPR-CAS13A
EP3849545A1 (en) 2018-09-10 2021-07-21 Institut National de la Santé et de la Recherche Médicale (INSERM) Methods for the treatment of neurofibromatosis
AU2019344927A1 (en) 2018-09-18 2021-04-01 Sangamo Therapeutics, Inc. Programmed cell death 1 (PD1) specific nucleases
WO2020061391A1 (en) * 2018-09-20 2020-03-26 The Trustees Of Columbia University In The City Of New York Methods for inhibiting tumor cells using inhibitors of foxo3a antagonists
IL281615B2 (en) 2018-09-21 2026-01-01 Acuitas Therapeutics Inc Systems and methods for producing lipid nanoparticles and liposomes
CA3113676A1 (en) 2018-09-21 2020-03-26 President And Fellows Of Harvard College Methods and compositions for treating diabetes, and methods for enriching mrna coding for secreted proteins
US20240165232A1 (en) 2018-09-24 2024-05-23 Fred Hutchinson Cancer Research Center Chimeric receptor proteins and uses thereof
WO2020064702A1 (en) 2018-09-25 2020-04-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of antagonists of th17 cytokines for the treatment of bronchial remodeling in patients suffering from allergic asthma
GB201815672D0 (en) 2018-09-26 2018-11-07 Innes John Centre Methods for altering starch granule size profile
CA3114405A1 (en) * 2018-09-28 2020-04-02 Board Of Trustees Of Southern Illinois University Anti-crispr nucleic acid inhibitors of crispr-cas effector enzymes
WO2020070062A1 (en) 2018-10-01 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of tim-3 inhibitors for the treatment of exacerbations in patients suffering from severe asthma
WO2020072250A1 (en) 2018-10-01 2020-04-09 North Carolina State University Recombinant type i crispr-cas system and uses thereof for genome modification and alteration of expression
WO2020072253A1 (en) 2018-10-01 2020-04-09 North Carolina State University Recombinant type i crispr-cas system and uses thereof for screening for variant cells
US12264330B2 (en) 2018-10-01 2025-04-01 North Carolina State University Recombinant type I CRISPR-Cas system and uses thereof for killing target cells
US10711267B2 (en) 2018-10-01 2020-07-14 North Carolina State University Recombinant type I CRISPR-Cas system
JP7288915B2 (ja) 2018-10-04 2023-06-08 株式会社カネカ 植物のゲノム編集に用いられるｄｎａ構築物
WO2020074937A1 (en) 2018-10-09 2020-04-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of alpha-v-integrin (cd51) inhibitors for the treatment of cardiac fibrosis
US11851663B2 (en) 2018-10-14 2023-12-26 Snipr Biome Aps Single-vector type I vectors
WO2020081588A1 (en) 2018-10-17 2020-04-23 Dana-Farber Cancer Institute, Inc. Swi/snf family chromatin remodeling complexes and uses thereof
US12583816B2 (en) 2018-10-18 2026-03-24 Acuitas Therapeutics, Inc. Lipids for lipid nanoparticle delivery of active agents
BR112021007301A2 (pt) 2018-10-18 2021-07-27 Intellia Therapeutics, Inc. composições e métodos para expressar fator ix
SG11202103733SA (en) * 2018-10-18 2021-05-28 Intellia Therapeutics Inc Compositions and methods for transgene expression from an albumin locus
WO2020079162A1 (en) 2018-10-18 2020-04-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for inducing full ablation of hematopoiesis
US11214781B2 (en) 2018-10-22 2022-01-04 Inscripta, Inc. Engineered enzyme
EP3870697A4 (en) 2018-10-22 2022-11-09 Inscripta, Inc. GMO ENZYMES
WO2020086742A1 (en) 2018-10-24 2020-04-30 Obsidian Therapeutics, Inc. Er tunable protein regulation
US12116458B2 (en) 2018-10-24 2024-10-15 Genedit Inc. Cationic polymer with alkyl side chains and use for biomolecule delivery
US11407995B1 (en) 2018-10-26 2022-08-09 Inari Agriculture Technology, Inc. RNA-guided nucleases and DNA binding proteins
IL262658A (en) 2018-10-28 2020-04-30 Memorial Sloan Kettering Cancer Center Prevention of age related clonal hematopoiesis and diseases associated therewith
SG11202104409YA (en) 2018-10-31 2021-05-28 Zymergen Inc Multiplexed deterministic assembly of dna libraries
WO2020093025A1 (en) * 2018-11-01 2020-05-07 Synthego Corporation Methods for knock-out of a target sequence through introduction of a premature stop codon
US11434477B1 (en) 2018-11-02 2022-09-06 Inari Agriculture Technology, Inc. RNA-guided nucleases and DNA binding proteins
US20210403519A1 (en) 2018-11-02 2021-12-30 Insideoutbio, Inc. Methods and compositions to induce or suppress immune responses through the use of membrane bound complement split products
MX2021004819A (es) 2018-11-02 2021-06-08 Annexon Inc Composiciones y metodos para tratar lesiones cerebrales.
TW202039831A (zh) 2018-11-05 2020-11-01 美商艾歐凡斯生物治療公司 對抗ｐｄ－１抗體呈現難治性之非小細胞肺癌（ｎｓｃｌｃ）病患之治療
TW202039829A (zh) 2018-11-05 2020-11-01 美商艾歐凡斯生物治療公司 改善之腫瘤反應性ｔ細胞的選擇
CR20210295A (es) 2018-11-05 2021-07-09 Iovance Biotherapeutics Inc Procesos para la producción de linfocitos infiltrantes de tumor y usos de estos en inmunoterapia
CA3118493A1 (en) 2018-11-05 2020-05-14 Iovance Biotherapeutics, Inc. Expansion of tils utilizing akt pathway inhibitors
IL282875B2 (en) 2018-11-08 2026-05-01 Sutro Biopharma Inc E. coli strains with oxygenated cytoplasm
EP3877517A4 (en) 2018-11-09 2022-09-07 Inari Agriculture, Inc. RNA-DRIVEN NUCLEASES AND DNA-BINDING PROTEINS
KR20210102231A (ko) 2018-11-09 2021-08-19 프레드 헛친슨 켄서 리서치 센터 메소텔린에 특이적인 t 세포 수용체 및 면역요법에서의 그의 용도
WO2020102387A1 (en) 2018-11-13 2020-05-22 Compass Therapeutics Llc Multispecific binding constructs against checkpoint molecules and uses thereof
EP3653708A1 (en) 2018-11-14 2020-05-20 Evonik Operations GmbH Isomaltulose production
WO2020102659A1 (en) 2018-11-15 2020-05-22 The Broad Institute, Inc. G-to-t base editors and uses thereof
US12227548B2 (en) 2018-11-19 2025-02-18 Dana-Farber Cancer Institute, Inc. Use of IRE1α-XBP1 signaling pathway biomarkers for modulating immune responses
CN113271943A (zh) 2018-11-26 2021-08-17 比奥基内生物科学协会合作研究中心 用于诊断和/或治疗急性或慢性肝、肾或肺病的方法
RU2712497C1 (ru) * 2018-11-26 2020-01-29 Автономная некоммерческая образовательная организация высшего образования Сколковский институт науки и технологий Средство разрезания ДНК на основе Cas9 белка из биотехнологически значимой бактерии Clostridium cellulolyticum
US11166996B2 (en) 2018-12-12 2021-11-09 Flagship Pioneering Innovations V, Inc. Anellovirus compositions and methods of use
EP3893898B1 (en) 2018-12-13 2024-04-03 Versiti Blood Research Institute Foundation, Inc. Method of treating autoimmune and inflammatory diseases using b cells
CN113166744B (zh) 2018-12-14 2025-02-07 先锋国际良种公司 用于基因组编辑的新颖crispr-cas系统
WO2020131547A1 (en) 2018-12-19 2020-06-25 Iovance Biotherapeutics, Inc. Methods of expanding tumor infiltrating lymphocytes using engineered cytokine receptor pairs and uses thereof
WO2020128163A1 (en) 2018-12-20 2020-06-25 Itä-Suomen Yliopisto Synthetic microrna mimics
US20220090047A1 (en) 2018-12-21 2022-03-24 Precision Biosciences, Inc. Genetic modification of the hydroxyacid oxidase 1 gene for treatment of primary hyperoxaluria
WO2020136216A1 (en) 2018-12-27 2020-07-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of identifying subjects having or at risk of having a coagulation related disorder
WO2020141199A1 (en) 2019-01-03 2020-07-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for enhancing cd8+ t cell-dependent immune responses in subjects suffering from cancer
JP7523449B2 (ja) 2019-01-11 2024-07-26 アクイタス セラピューティクス インコーポレイテッド 活性剤の脂質ナノ粒子送達のための脂質
AU2020208190B2 (en) 2019-01-15 2022-07-28 Seminis Vegetable Seeds, Inc. Green bean plants with improved disease resistance
JP2022522265A (ja) 2019-01-16 2022-04-15 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル エリスロフェロンの変異体及びその使用
CN113557036A (zh) 2019-01-18 2021-10-26 奥泽生物疗法公司 基因编辑以改善关节功能
US12188081B2 (en) 2019-01-24 2025-01-07 The Translational Genomics Research Institute Bioinformatics methods of in silico validation and selection of circRNAs
WO2020160100A1 (en) 2019-01-29 2020-08-06 Foghorn Therapeutics Inc. Compounds and uses thereof
WO2020160196A1 (en) 2019-01-29 2020-08-06 Foghorn Therapeutics Inc. Compounds and uses thereof
US20220117911A1 (en) 2019-02-04 2022-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating blood-brain barrier
EP3921417A4 (en) 2019-02-04 2022-11-09 The General Hospital Corporation VARIANTS OF ADENINE DNA BASES WITH REDUCED OFF-TARGET RNA EDIT
WO2020163379A1 (en) * 2019-02-05 2020-08-13 Emendobio Inc. Crispr compositions and methods for promoting gene editing of ribosomal protein s19 (rps19) gene
US11857641B2 (en) 2019-02-06 2024-01-02 Sangamo Therapeutics, Inc. Method for the treatment of mucopolysaccharidosis type I
WO2020163856A1 (en) 2019-02-10 2020-08-13 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Modified mitochondrion and methods of use thereof
WO2020169472A2 (en) 2019-02-18 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of inducing phenotypic changes in macrophages
GB2596461B (en) 2019-02-20 2023-09-27 Fred Hutchinson Cancer Center Binding proteins specific for RAS neoantigens and uses thereof
KR20210136050A (ko) 2019-03-01 2021-11-16 이오반스 바이오테라퓨틱스, 인크. 액상 종양으로부터의 종양 침윤 림프구의 확장 및 그의 치료 용도
US12215382B2 (en) 2019-03-01 2025-02-04 The General Hospital Corporation Liver protective MARC variants and uses thereof
EA202192430A1 (ru) 2019-03-05 2022-02-11 Те Стейт Оф Израэл, Министри Оф Эгрикалчер Энд Рурал Дивелопмент, Эгрикалчарал Рисёрч Органайзейшн (Аро) (Волкани Сентер) Птицы с отредактированным геномом
EP4219700A1 (en) 2019-03-07 2023-08-02 The Regents of the University of California Crispr-cas effector polypeptides and methods of use thereof
EP3935179A4 (en) 2019-03-07 2022-11-23 The Trustees of Columbia University in the City of New York RNA-GUIDED DNA INTEGRATION USING TN7-LIKE TRANSPOSONS
US11053515B2 (en) 2019-03-08 2021-07-06 Zymergen Inc. Pooled genome editing in microbes
KR20210149251A (ko) 2019-03-08 2021-12-08 옵시디안 테라퓨틱스, 인크. 조율가능한 조절을 위한 인간 탄산 무수화효소 2 조성물 및 방법
CA3129871A1 (en) 2019-03-08 2020-09-17 Zymergen Inc. Iterative genome editing in microbes
WO2020185796A1 (en) 2019-03-11 2020-09-17 Fred Hutchinson Cancer Research Center High avidity wt1 t cell receptors and uses thereof
US20220145333A1 (en) 2019-03-11 2022-05-12 Sorrento Therapeutics, Inc. Improved process for integration of dna constructs using rna-guided endonucleases
US11001831B2 (en) 2019-03-25 2021-05-11 Inscripta, Inc. Simultaneous multiplex genome editing in yeast
CN113631713A (zh) 2019-03-25 2021-11-09 因思科瑞普特公司 酵母中的同时多重基因组编辑
WO2020193740A1 (en) 2019-03-28 2020-10-01 INSERM (Institut National de la Santé et de la Recherche Médicale) New strategy for treating pancreatic cancer
WO2020201073A1 (en) 2019-03-29 2020-10-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of keloid, hypertrophic scars and/or hyperpigmentation disorders
US20220175848A1 (en) 2019-04-01 2022-06-09 The Broad Institute, Inc. Methods and compositions for cell therapy
US20200316116A1 (en) 2019-04-02 2020-10-08 Sangamo Therapeutics, Inc. Method for the treatment of beta-thalassemia
US20220177978A1 (en) 2019-04-02 2022-06-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting and preventing cancer in patients having premalignant lesions
WO2020206248A1 (en) 2019-04-03 2020-10-08 Precision Biosciences, Inc. Genetically-modified immune cells comprising a microrna-adapted shrna (shrnamir)
EP3947436A4 (en) 2019-04-05 2022-12-28 Rootpath Genomics, Inc. COMPOSITIONS AND METHODS FOR ASSEMBLING T LYMPHOCYTE RECEPTOR GENE
CA3136113A1 (en) 2019-04-05 2020-10-08 Danisco Us Inc. Methods for polynucleotide integration into the genome of bacillus using dual circular recombinant dna constructs and compositions thereof
US20220204994A1 (en) 2019-04-05 2022-06-30 Precision Biosciences, Inc. Methods of preparing populations of genetically-modified immune cells
JP2022526982A (ja) 2019-04-05 2022-05-27 ダニスコ・ユーエス・インク 線状組換えＤＮＡコンストラクトを使用してバチルス（Ｂａｃｉｌｌｕｓ）のゲノムにドナーＤＮＡ配列を組み込むための方法及びその組成物
WO2020208082A1 (en) 2019-04-09 2020-10-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Method for treating cmv related diseases
WO2020219776A1 (en) 2019-04-23 2020-10-29 Genedit Inc. Cationic polymer with alkyl side chains
EP3959320A1 (en) 2019-04-24 2022-03-02 Novartis AG Compositions and methods for selective protein degradation
WO2020221796A1 (en) 2019-04-30 2020-11-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
PE20220003A1 (es) 2019-04-30 2022-01-05 Edigene Inc Metodo para la prediccion de eficacia del tratamiento de hemoglobinopatia
US11162079B2 (en) 2019-05-10 2021-11-02 The Regents Of The University Of California Blood type O Rh-hypo-immunogenic pluripotent cells
WO2020232029A1 (en) 2019-05-13 2020-11-19 Iovance Biotherapeutics, Inc. Methods and compositions for selecting tumor infiltrating lymphocytes and uses of the same in immunotherapy
US12116583B2 (en) 2019-05-14 2024-10-15 Yield10 Bioscience, Inc. Modified plants comprising a polynucleotide comprising a non-cognate promoter operably linked to a coding sequence that encodes a transcription factor
WO2020232319A1 (en) 2019-05-15 2020-11-19 Insideoutbio, Inc. Modular therapeutics for the treatment of inflammatory diseases and cancer
WO2020236645A1 (en) * 2019-05-17 2020-11-26 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for homology directed repair
JP2022533713A (ja) 2019-05-21 2022-07-25 サンガモ セラピューティクス， インコーポレイテッド 調節性ｔ細胞における制御された導入遺伝子発現
CN113924367B (zh) 2019-05-23 2024-07-23 南京农业大学 提高水稻籽粒产量的方法
WO2020239623A1 (en) 2019-05-24 2020-12-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of ngal inhibitors for the treating chronic wound
JP7805789B2 (ja) 2019-05-28 2026-01-26 ジーンエディット インコーポレイテッド 生体分子送達のための複数の機能化側鎖を含むポリマー
MX2021014528A (es) 2019-05-29 2022-01-06 Monsanto Technology Llc Metodos y composiciones para generar alelos dominantes usando edicion del genoma.
WO2020245210A1 (en) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) A neuropilin antagonist in combination with a p38alpha-kinase inhibitor for the treatment of cancer
US12523663B2 (en) 2019-06-04 2026-01-13 Inserm (Institut National De La Santé Et De La Rescherche Médicale) Use of CD9 as a biomarker and as a biotarget in glomerulonephritis or glomerulosclerosis
WO2020244759A1 (en) 2019-06-05 2020-12-10 Klemm & Sohn Gmbh & Co. Kg New plants having a white foliage phenotype
US10837021B1 (en) 2019-06-06 2020-11-17 Inscripta, Inc. Curing for recursive nucleic acid-guided cell editing
WO2020249769A1 (en) 2019-06-14 2020-12-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating ocular diseases related to mitochondrial dna maintenance
US10907125B2 (en) 2019-06-20 2021-02-02 Inscripta, Inc. Flow through electroporation modules and instrumentation
WO2020257395A1 (en) 2019-06-21 2020-12-24 Inscripta, Inc. Genome-wide rationally-designed mutations leading to enhanced lysine production in e. coli
WO2020254850A1 (en) 2019-06-21 2020-12-24 Vilmorin & Cie Improvement of quality and permanence of green color of peppers at maturity and over-maturity
AU2020308448B2 (en) 2019-06-24 2026-04-30 Promega Corporation Modified polyamine polymers for delivery of biomolecules into cells
CN120665955A (zh) 2019-06-25 2025-09-19 伊纳瑞农业技术有限公司 改善的同源依赖修复基因组编辑
US10927385B2 (en) 2019-06-25 2021-02-23 Inscripta, Inc. Increased nucleic-acid guided cell editing in yeast
EP3993786A1 (en) 2019-07-02 2022-05-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the prophylactic treatment of cancer in patients suffering from pancreatitis
WO2021001431A1 (en) 2019-07-02 2021-01-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of pi3ka-selective inhibitors for treating metastatic disease in patients suffering from pancreatic cancer
US12552844B2 (en) 2019-07-04 2026-02-17 Ukko Inc. De-epitoped alpha gliadin and use of same for the management of celiac disease and gluten sensitivity
US10557149B1 (en) 2019-07-15 2020-02-11 Vigene Biosciences, Inc. Recombinantly-modified adeno-associated virus helper vectors and their use to improve the packaging efficiency of recombinantly-modified adeno-associated virus
US10801042B1 (en) 2019-07-15 2020-10-13 Vigene Biosciences, Inc. Use of ion concentrations to increase the packaging efficiency of recombinant adeno-associated virus
US10653731B1 (en) 2019-07-15 2020-05-19 Vigene Biosciences Inc. Recombinantly-modified adeno-associated virus (rAAV) having improved packaging efficiency
IL268111A (en) 2019-07-16 2021-01-31 Fainzilber Michael Methods of treating pain
WO2021009299A1 (en) 2019-07-17 2021-01-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Bcl-xl:fkbp12 fusion proteins suitable for screening agents capable of slowing down the aging process
US11746354B2 (en) 2019-07-19 2023-09-05 Inari Agriculture Technology, Inc. Homology dependent repair genome editing
US20220251572A1 (en) 2019-07-23 2022-08-11 Mnemo Therapeutics Immune cells defective for suv39h1
US20220249426A1 (en) 2019-07-24 2022-08-11 Inserm (Institut National De La Santé Et De La Recherch Médicale) Inhibitors of the sting pathway for the treatment of hidradenitis suppurativa
WO2021016608A1 (en) 2019-07-25 2021-01-28 Precision Biosciences, Inc. Compositions and methods for sequential stacking of nucleic acid sequences into a genomic locus
WO2021019272A1 (en) 2019-07-31 2021-02-04 Vilmorin & Cie Tolerance to tolcndv in cucumber
EP4007584A1 (en) 2019-08-02 2022-06-08 Institut National de la Santé et de la Recherche Médicale (INSERM) Neutralizing granzyme b for providing cardioprotection in a subject who experienced a myocardial infarction
WO2021026294A1 (en) 2019-08-06 2021-02-11 Children's Medical Center Corporation Methods and compositions for reconstituting microglia
WO2021028359A1 (en) 2019-08-09 2021-02-18 Sangamo Therapeutics France Controlled expression of chimeric antigen receptors in t cells
AU2020333851A1 (en) 2019-08-20 2022-03-31 Precision Biosciences, Inc. Lymphodepletion dosing regimens for cellular immunotherapies
AU2020334064A1 (en) 2019-08-20 2022-03-03 Fred Hutchinson Cancer Center T-cell immunotherapy specific for WT-1
WO2021035170A1 (en) 2019-08-21 2021-02-25 Precision Biosciences, Inc. Compositions and methods for tcr reprogramming using fusion proteins
WO2021043278A1 (zh) 2019-09-04 2021-03-11 博雅辑因（北京）生物科技有限公司 基于脱靶评估评价基因编辑治疗的方法
WO2021044027A1 (en) 2019-09-05 2021-03-11 Institute Of Genetics And Developmental Biology Chinese Academy Of Sciences Methods of improving seed size and quality
US20220340975A1 (en) 2019-09-05 2022-10-27 INSERM (Institute National de la Santé et de la Recherche Médicale) Method of treatment and pronostic of acute myeloid leukemia
WO2021046451A1 (en) 2019-09-06 2021-03-11 Obsidian Therapeutics, Inc. Compositions and methods for dhfr tunable protein regulation
GB201913060D0 (en) 2019-09-10 2019-10-23 Innes John Centre Methods of increasing biotic stress resistance in plants
WO2021047775A1 (en) 2019-09-12 2021-03-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of inhibitors of tgfb/activinb signaling pathway for the treatment of patients suffering from medulloblastoma group 3
AU2020352552A1 (en) 2019-09-23 2022-03-17 Omega Therapeutics, Inc. Compositions and methods for modulating hepatocyte nuclear factor 4-alpha (HNF4α) gene expression
CN114391040A (zh) 2019-09-23 2022-04-22 欧米茄治疗公司 用于调节载脂蛋白b(apob)基因表达的组合物和方法
US11542513B2 (en) 2019-09-26 2023-01-03 Seminis Vegetable Seeds, Inc. Lettuce plants having resistance to Nasonovia ribisnigri biotype Nr:1
WO2021063968A1 (en) 2019-09-30 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Method and composition for diagnosing chronic obstructive pulmonary disease
GB201914137D0 (en) 2019-10-01 2019-11-13 Univ Leeds Innovations Ltd Modified Plants
WO2021064180A1 (en) 2019-10-03 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating macrophages polarization
CN115103910A (zh) 2019-10-03 2022-09-23 工匠开发实验室公司 具有工程化的双引导核酸的crispr系统
WO2021072031A1 (en) 2019-10-11 2021-04-15 Insideoutbio, Inc. Methods and compositions for the manufacture and use of circular dna encoded therapeutics for genetic disorders and other diseases
WO2021072244A1 (en) 2019-10-11 2021-04-15 Beth Israel Deaconess Medical Center, Inc. Anti-tn antibodies and uses thereof
EP3808766A1 (en) 2019-10-15 2021-04-21 Sangamo Therapeutics France Chimeric antigen receptor specific for interleukin-23 receptor
CA3153902A1 (en) 2019-10-16 2021-04-22 Pardis SABETI Engineered muscle targeting compositions
WO2021078359A1 (en) 2019-10-21 2021-04-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of inhibitors of cubilin for the treatment of chronic kidney diseases
WO2021081468A1 (en) * 2019-10-25 2021-04-29 The Johns Hokins University A crispr-cas9 platform with an intrinsic off-switch and enhanced specificity
WO2021081378A1 (en) 2019-10-25 2021-04-29 Iovance Biotherapeutics, Inc. Gene editing of tumor infiltrating lymphocytes and uses of same in immunotherapy
US20240122938A1 (en) 2019-10-29 2024-04-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating uveal melanoma
WO2021087305A1 (en) 2019-10-30 2021-05-06 Precision Biosciences, Inc. Cd20 chimeric antigen receptors and methods of use for immunotherapy
IL270306A (en) 2019-10-30 2021-05-31 Yeda Res & Dev Prevention and treatment of pre-myeloid and myeloid malignancies
WO2021087406A1 (en) 2019-11-01 2021-05-06 Magenta Therapeutics, Inc. Dosing regimens for the mobilization of hematopoietic stem and progentor cells
GB201916020D0 (en) 2019-11-04 2019-12-18 Univ Of Essex Enterprise Limited Crispr-mediated identification of biotinylated proteins and chromatin regions
AR120470A1 (es) * 2019-11-13 2022-02-16 Crispr Therapeutics Ag Métodos para fabricar células t car
AU2020382219A1 (en) * 2019-11-13 2022-05-12 Crispr Therapeutics Ag Manufacturing process for making T cells expressing chimeric antigen receptors
WO2021094805A1 (en) 2019-11-14 2021-05-20 Vilmorin & Cie Resistance to acidovorax valerianellae in corn salad
WO2021102059A1 (en) 2019-11-19 2021-05-27 Inscripta, Inc. Methods for increasing observed editing in bacteria
WO2021099600A1 (en) 2019-11-22 2021-05-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibitors of adrenomedullin for the treatment of acute myeloid leukemia by eradicating leukemic stem cells
WO2021102084A1 (en) 2019-11-22 2021-05-27 President And Fellows Of Harvard College Ionic liquids for drug delivery
US20230357796A1 (en) 2019-11-27 2023-11-09 Danmarks Tekniske Universitet Constructs, compositions and methods thereof having improved genome editing efficiency and specificity
US12241839B2 (en) 2019-11-27 2025-03-04 Promega Corporation Multipartite luciferase peptides and polypeptides
WO2021105368A1 (en) 2019-11-27 2021-06-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of neuropilin antagonists for the treatment of endometriosis
EP4069285A1 (en) 2019-12-06 2022-10-12 Precision BioSciences, Inc. Methods for cancer immunotherapy, using lymphodepletion regimens and cd19, cd20 or bcma allogeneic car t cells
BR112022011372A2 (pt) 2019-12-10 2022-08-23 Univ Indiana Trustees Inibidores de interação de proteína a de replicação (rpa)-dna
KR20250033331A (ko) 2019-12-10 2025-03-07 인스크립타 인코포레이티드 신규 mad 뉴클레아제
WO2021118990A1 (en) 2019-12-11 2021-06-17 Iovance Biotherapeutics, Inc. Processes for the production of tumor infiltrating lymphocytes (tils) and methods of using the same
US10704033B1 (en) 2019-12-13 2020-07-07 Inscripta, Inc. Nucleic acid-guided nucleases
WO2021118927A1 (en) 2019-12-13 2021-06-17 Insideoutbio, Inc. Methods and compositions for targeted delivery of nucleic acid therapeutics
EP4074821A4 (en) 2019-12-13 2024-01-17 Chugai Seiyaku Kabushiki Kaisha System for detecting extracellular purinergic receptor ligand and nonhuman animal having same transferred thereinto
CA3157127A1 (en) 2019-12-18 2021-06-24 Aamir MIR Cascade/dcas3 complementation assays for in vivo detection of nucleic acid-guided nuclease edited cells
GB201918902D0 (en) 2019-12-19 2020-02-05 Genome Res Ltd Cell differentiation
EP4706689A2 (en) 2019-12-19 2026-03-11 Entrada Therapeutics, Inc. Compositions for delivery of antisense compounds
IL271656A (en) 2019-12-22 2021-06-30 Yeda Res & Dev System and methods for identifying cells that have undergone genome editing
US11060141B1 (en) 2019-12-23 2021-07-13 Stilla Technologies Multiplex drop-off digital polymerase chain reaction methods
US20230026352A1 (en) 2019-12-26 2023-01-26 Figene, Llc Suppression of interleukin-17 production and inhibition of th17 cell generation by fibroblasts and products thereof
CN114867850A (zh) 2019-12-30 2022-08-05 博雅缉因（北京）生物科技有限公司 一种纯化ucart细胞的方法与应用
JP2023508731A (ja) * 2019-12-30 2023-03-03 ライフエディット セラピューティクス，インコーポレイティド Ｒｎａ誘導ヌクレアーゼ、その活性断片および多様体、ならびに使用方法
US20230059884A1 (en) 2019-12-30 2023-02-23 Edigene Biotechnology Inc. Universal car-t targeting t-cell lymphoma cell and preparation method therefor and use thereof
US11859172B2 (en) 2020-01-02 2024-01-02 The Trustees Of Columbia University In The City Of New York Programmable and portable CRISPR-Cas transcriptional activation in bacteria
US10689669B1 (en) 2020-01-11 2020-06-23 Inscripta, Inc. Automated multi-module cell processing methods, instruments, and systems
CN116234906A (zh) 2020-01-13 2023-06-06 萨那生物技术股份有限公司 血型抗原的修饰
EP4090770A1 (en) 2020-01-17 2022-11-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2021151085A2 (en) 2020-01-24 2021-07-29 The General Hospital Corporation Crispr-cas enzymes with enhanced on-target activity
WO2021151073A2 (en) 2020-01-24 2021-07-29 The General Hospital Corporation Unconstrained genome targeting with near-pamless engineered crispr-cas9 variants
KR20220133257A (ko) 2020-01-27 2022-10-04 인스크립타 인코포레이티드 전기천공 모듈 및 기구
BR112022015004A2 (pt) 2020-01-29 2022-09-20 Foghorn Therapeutics Inc Composto, composição farmacêutica, métodos para diminuir a atividade de um complexo baf, induzir apoptose, reduzir o crescimento tumoral, suprimir a progressão e a colonização metastática do câncer e reduzir o nível e/ou a atividade de brg1 e/ou brm em um câncer e métodos de tratamento e de inibição de brm e brg1
WO2021152587A1 (en) 2020-01-30 2021-08-05 Yeda Research And Development Co. Ltd. Treating acute liver disease with tlr-mik inhibitors
CN115135142A (zh) 2020-02-07 2022-09-30 中国科学院遗传与发育生物学研究所 控制籽粒大小和粒重的方法
CN115485300A (zh) 2020-02-26 2022-12-16 索伦托药业有限公司 具有通用掩蔽部分的可活化的抗原结合蛋白
WO2021183720A1 (en) 2020-03-11 2021-09-16 Omega Therapeutics, Inc. Compositions and methods for modulating forkhead box p3 (foxp3) gene expression
AU2021237790A1 (en) 2020-03-20 2022-10-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Chimeric antigen receptor specific for human CD45RC and uses thereof
US20210290757A1 (en) 2020-03-23 2021-09-23 Avectas Limited Engineering of dendritic cells for generation of vaccines against sars-cov-2
US20240099210A1 (en) 2020-03-26 2024-03-28 National Agriculture And Food Research Organization Method for producing temperature-sensitive male sterile plant
CN115697044A (zh) 2020-03-31 2023-02-03 艾洛生物系统有限公司 西瓜和其他葫芦科中内源罗汉果苷途径基因的调控
WO2021204877A2 (en) 2020-04-08 2021-10-14 Astrazeneca Ab Compositions and methods for improved site-specific modification
WO2021204878A1 (en) 2020-04-08 2021-10-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of cdon inhibitors for the treatment of endothelial dysfunction
NL2025344B1 (en) 2020-04-14 2021-10-26 Academisch Ziekenhuis Leiden Methods for induction of endogenous tandem duplication events
WO2021210976A1 (en) 2020-04-14 2021-10-21 ACADEMISCH ZIEKENHUIS LEIDEN (h.o.d.n. LUMC) Methods for induction of endogenous tandem duplication events
US20250263752A1 (en) 2020-04-21 2025-08-21 Aspen Neuroscience, Inc. Gene editing of gba1 in stem cells and method of use of cells differentiated therefrom
US20230165909A1 (en) 2020-04-21 2023-06-01 Aspen Neuroscience, Inc. Gene editing of lrrk2 in stem cells and method of use of cells differentiated therefrom
WO2021217082A1 (en) 2020-04-23 2021-10-28 Genedit Inc. Polymer with cationic and hydrophobic side chains
US20210332388A1 (en) 2020-04-24 2021-10-28 Inscripta, Inc. Compositions, methods, modules and instruments for automated nucleic acid-guided nuclease editing in mammalian cells
WO2021217083A1 (en) 2020-04-24 2021-10-28 Sorrento Therapeutics, Inc. Memory dimeric antigen receptors
MX2022013493A (es) 2020-04-27 2023-02-22 Magenta Therapeutics Inc Metodos y composiciones para transducir celulas madre y progenitoras hematopoyeticas in vivo.
US12351850B2 (en) 2020-04-30 2025-07-08 Sutro Biopharma, Inc. Methods of producing full-length antibodies using E. coli
GB202006463D0 (en) 2020-05-01 2020-06-17 Innes John Centre Metabolic engineering of plants enriched in L-DOPA
CA3176826A1 (en) 2020-05-04 2021-11-11 Iovance Biotherapeutics, Inc. Processes for production of tumor infiltrating lymphocytes and uses of the same in immunotherapy
EP4146797A1 (en) 2020-05-06 2023-03-15 Orchard Therapeutics (Europe) Limited Treatment for neurodegenerative diseases
WO2021224401A1 (en) 2020-05-07 2021-11-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for determining a reference range of β-galactose exposure platelet
WO2021231259A1 (en) 2020-05-11 2021-11-18 Precision Biosciences, Inc. Self-limiting viral vectors encoding nucleases
US11787841B2 (en) 2020-05-19 2023-10-17 Inscripta, Inc. Rationally-designed mutations to the thrA gene for enhanced lysine production in E. coli
US12383555B2 (en) 2020-05-20 2025-08-12 Foghorn Therapeutics Inc. Methods of treating cancers
CN121884957A (zh) 2020-05-22 2026-04-17 因斯特罗公司 使用机器学习模型预测疾病结果
GB202007943D0 (en) 2020-05-27 2020-07-08 Snipr Biome Aps Products & methods
WO2021245435A1 (en) 2020-06-03 2021-12-09 Vilmorin & Cie Melon plants resistant to scab disease, aphids and powdery mildew
EP4162039A4 (en) * 2020-06-04 2024-12-11 Emendobio Inc. NEW OMNI-59,61,67,76,79,80,81 AND 82 CRISPR NUCLEASES
WO2021245224A1 (en) 2020-06-05 2021-12-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for treating ocular diseases
BR112022024738A2 (pt) 2020-06-05 2023-03-07 Vilmorin & Cie Planta, célula de planta, cultura de tecidos de células, parte de planta, semente, uso de uma planta, métodos para detectar e/ou selecionar plantas, conferir resistência ao tobrfv, melhorar o rendimento de tomateiros e reduzir a perda na produção de tomate e usos de um marcador
EP4161552A1 (en) 2020-06-05 2023-04-12 The Broad Institute, Inc. Compositions and methods for treating neoplasia
US20230193356A1 (en) 2020-06-08 2023-06-22 The Broad Institute, Inc. Single cell combinatorial indexing from amplified nucleic acids
CN116096862A (zh) 2020-06-11 2023-05-09 诺华股份有限公司 Zbtb32抑制剂及其用途
US20230218608A1 (en) 2020-06-18 2023-07-13 INSERM (Institut National de la Santé et de la Recherche Médicale) New strategy for treating pancreatic cancer
WO2022008597A1 (en) 2020-07-08 2022-01-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of infectious diseases
AU2021204717A1 (en) 2020-07-15 2022-02-03 Seminis Vegetable Seeds, Inc. Green Bean Plants with Improved Disease Resistance
JP7798855B2 (ja) 2020-07-16 2026-01-14 アクイタス セラピューティクス インコーポレイテッド 脂質ナノ粒子に使用するためのカチオン性脂質
US20230159949A1 (en) 2020-07-22 2023-05-25 The Broad Institute, Inc. Engineered muscle targeting compositions
CN116096864A (zh) 2020-07-30 2023-05-09 居里研究所 Socs1缺陷的免疫细胞
EP4189071A1 (en) 2020-08-03 2023-06-07 Institut National de la Santé et de la Recherche Médicale (INSERM) Population of treg cells functionally committed to exert a regulatory activity and their use for adoptive therapy
US20260028412A1 (en) 2020-08-10 2026-01-29 Precision Biosciences, Inc. Antibodies and fragments specific for b-cell maturation antigen and uses thereof
CN116096378A (zh) 2020-08-10 2023-05-09 诺华股份有限公司 视网膜变性疾病的治疗
US20230304047A1 (en) 2020-08-11 2023-09-28 University Of Oslo Improved gene editing
EP4097486A4 (en) 2020-08-20 2023-09-06 A2 Biotherapeutics, Inc. COMPOSITIONS AND METHODS OF TREATMENT OF POSITIVE CANCERS AT CEACAM
WO2022040454A1 (en) 2020-08-20 2022-02-24 A2 Biotherapeutics, Inc. Compositions and methods for treating mesothelin positive cancers
EP4058474B1 (en) 2020-08-20 2024-05-08 A2 Biotherapeutics, Inc. Compositions and methods for treating egfr positive cancers
EP4501951A3 (en) 2020-08-25 2025-04-30 Kite Pharma, Inc. T cells with improved functionality
EP4211235A2 (en) 2020-09-11 2023-07-19 Lifeedit Therapeutics, Inc. Dna modifying enzymes and active fragments and variants thereof and methods of use
WO2022060749A1 (en) 2020-09-15 2022-03-24 Inscripta, Inc. Crispr editing to embed nucleic acid landing pads into genomes of live cells
EP4214311A2 (en) 2020-09-18 2023-07-26 Artisan Development Labs, Inc. Constructs and uses thereof for efficient and specific genome editing
WO2022066973A1 (en) 2020-09-24 2022-03-31 Fred Hutchinson Cancer Research Center Immunotherapy targeting pbk or oip5 antigens
CN116724053A (zh) 2020-09-24 2023-09-08 弗雷德哈钦森癌症中心 靶向sox2抗原的免疫治疗
JP7830442B2 (ja) 2020-10-02 2026-03-16 ビルモラン エ コンパニー 貯蔵寿命が延長されたメロン
WO2022074646A1 (en) 2020-10-05 2022-04-14 Protalix Ltd. Dicer-like knock-out plant cells
EP4226160A1 (en) 2020-10-05 2023-08-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Gdf3 as biomarker and biotarget in post-ischemic cardiac remodeling
WO2022076606A1 (en) 2020-10-06 2022-04-14 Iovance Biotherapeutics, Inc. Treatment of nsclc patients with tumor infiltrating lymphocyte therapies
TW202222841A (zh) 2020-10-06 2022-06-16 福瑞德哈金森腫瘤研究中心 用於治療表現mage-a1之疾病的組成物及方法
EP4225330A1 (en) 2020-10-06 2023-08-16 Iovance Biotherapeutics, Inc. Treatment of nsclc patients with tumor infiltrating lymphocyte therapies
WO2022076547A1 (en) 2020-10-07 2022-04-14 Precision Biosciences, Inc. Lipid nanoparticle compositions
EP4228637A1 (en) 2020-10-15 2023-08-23 Yeda Research and Development Co. Ltd Method of treating myeloid malignancies
US20240060079A1 (en) 2020-10-23 2024-02-22 Elo Life Systems Methods for producing vanilla plants with improved flavor and agronomic production
AU2021366741A1 (en) 2020-10-23 2023-05-11 Rootpath Genomics, Inc. Compositions and methods for t-cell receptor identification
WO2022084531A1 (en) 2020-10-23 2022-04-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating glioma
US11332744B1 (en) 2020-10-26 2022-05-17 Arsenal Biosciences, Inc. Safe harbor loci
RU2762831C1 (ru) * 2020-10-26 2021-12-23 Федеральное государственное бюджетное научное учреждение "Всероссийский научно-исследовательский институт сельскохозяйственной биотехнологии" (ФГБНУ ВНИИСБ) Молекула рнк-проводника для геномного редактирования протомоторной области гена vrn-a1 однодольных зерновых с применением системы crispr/cas9
RU2749307C1 (ru) * 2020-10-30 2021-06-08 Федеральное государственное бюджетное научное учреждение "Всероссийский научно-исследовательский институт сельскохозяйственной биотехнологии" (ФГБНУ ВНИИСБ) Новая компактная нуклеаза CAS9 II типа из Anoxybacillus flavithermus
US11512297B2 (en) 2020-11-09 2022-11-29 Inscripta, Inc. Affinity tag for recombination protein recruitment
MX2023005609A (es) 2020-11-13 2023-05-29 Novartis Ag Terapias de combinacion con celulas que expresan receptores quimericos para el antigeno (car).
EP4244391A1 (en) 2020-11-16 2023-09-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
WO2022115498A1 (en) 2020-11-26 2022-06-02 Ukko Inc. Modified high molecular weight glutenin subunit and uses thereof
US20240000970A1 (en) * 2020-12-01 2024-01-04 Emendobio Inc. Differential knockout of a heterozygous allele of lrrk2
EP4255172A1 (en) 2020-12-03 2023-10-11 Vilmorin & Cie Tomato plants resistant to tobrfv, tmv, tomv and tommv and corresponding resistance genes
WO2022132836A2 (en) 2020-12-14 2022-06-23 Fred Hutchinson Cancer Research Center Compositions and methods for cellular immunotherapy
CA3202483A1 (en) 2020-12-17 2022-06-23 Maria Fardis Treatment with tumor infiltrating lymphocyte therapies in combination with ctla-4 and pd-1 inhibitors
IL279559A (en) 2020-12-17 2022-07-01 Yeda Res & Dev Controlling ubiquitination of mlkl for treatment of disease
US20240123067A1 (en) 2020-12-17 2024-04-18 Iovance Biotherapeutics, Inc. Treatment of cancers with tumor infiltrating lymphocyte therapies
WO2022130388A2 (en) 2020-12-18 2022-06-23 Yeda Research And Development Co. Ltd. Compositions for use in the treatment of chd2 haploinsufficiency and methods of identifying same
US20240254500A1 (en) 2020-12-18 2024-08-01 Rothamsted Research Limited Increasing the accumulation of epa and dha in recombinant camelina
US20250304988A1 (en) 2020-12-23 2025-10-02 Institute Of Genetics And Developmental Biology Chinese Academy Of Sciences Methods of controlling grain size
KR20230124682A (ko) 2020-12-23 2023-08-25 플래그쉽 파이어니어링 이노베이션스 브이, 인크. Rna를 봉입하는 아넬로바이러스 캡시드의 시험관 내어셈블리
CA3204158A1 (en) 2021-01-04 2022-07-07 Juhan Kim Mad nucleases
US11332742B1 (en) 2021-01-07 2022-05-17 Inscripta, Inc. Mad nucleases
EP4284823A1 (en) 2021-01-28 2023-12-06 Precision BioSciences, Inc. Modulation of tgf beta signaling in genetically-modified eukaryotic cells
WO2022165260A1 (en) 2021-01-29 2022-08-04 Iovance Biotherapeutics, Inc. Methods of making modified tumor infiltrating lymphocytes and their use in adoptive cell therapy
AU2022213019A1 (en) 2021-02-01 2023-08-10 Avectas Limited Delivery platform
US11884924B2 (en) 2021-02-16 2024-01-30 Inscripta, Inc. Dual strand nucleic acid-guided nickase editing
WO2022177979A1 (en) 2021-02-16 2022-08-25 A2 Biotherapeutics, Inc. Compositions and methods for treating her2 positive cancers
EP4298212A4 (en) 2021-02-25 2026-04-15 Celyntra Therapeutics Sa Compositions and methods for targeting, editing, or modifying genes
WO2022187278A1 (en) * 2021-03-01 2022-09-09 The Johns Hopkins University Nucleic acid detection and analysis systems
DE112022001365T5 (de) 2021-03-05 2024-02-15 The Board Of Trustees Of The Leland Stanford Junior University In vivo dna zusammenbau und analyse
JP2024509268A (ja) 2021-03-09 2024-02-29 フォグホーン セラピューティクス インコーポレイテッド 結晶形、それらを含有する組成物、及びそれらの使用方法
KR20240010451A (ko) * 2021-03-11 2024-01-23 에멘도바이오 인코포레이티드 C3 세이프 하버 부위에서의 넉인 전략
EP4308694A1 (en) 2021-03-16 2024-01-24 Magenta Therapeutics, Inc. Dosing regimens for hematopoietic stem cell mobilization for stem cell transplants in multiple myeloma patients
WO2022194908A1 (en) 2021-03-17 2022-09-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
JP2024510505A (ja) 2021-03-19 2024-03-07 アイオバンス バイオセラピューティクス，インコーポレイテッド Ｃｄ３９／ｃｄ６９選択に関連した腫瘍浸潤リンパ球（ｔｉｌ）拡張及びｔｉｌにおける遺伝子ノックアウトのための方法
CN117295817A (zh) 2021-03-22 2023-12-26 生命编辑制药股份有限公司 Dna修饰酶及其活性片段和变体以及使用方法
WO2022204564A2 (en) 2021-03-25 2022-09-29 Iovance Biotherapeutics, Inc. Methods and compositions for t-cell coculture potency assays and use with cell therapy products
US20250243244A1 (en) 2021-03-31 2025-07-31 Entrada Therapeutics, Inc. Cyclic cell penetrating peptides
WO2022208489A1 (en) 2021-04-02 2022-10-06 Vilmorin & Cie Semi-determinate or determinate growth habit trait in cucurbita
JP2024513087A (ja) 2021-04-07 2024-03-21 アストラゼネカ・アクチエボラーグ 部位特異的改変のための組成物及び方法
WO2022214681A1 (en) 2021-04-09 2022-10-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of anaplastic large cell lymphoma
KR20240037185A (ko) 2021-04-19 2024-03-21 이오반스 바이오테라퓨틱스, 인크. 키메라 공동자극 수용체, 케모카인 수용체, 및 세포 면역치료에서의 이의 용도
WO2022225978A1 (en) 2021-04-21 2022-10-27 The Regents Of The University Of California Use of a split dcas fusion protein system for epigenetic editing
WO2022226316A1 (en) 2021-04-22 2022-10-27 Precision Biosciences, Inc. Compositions and methods for generating male sterile plants
EP4326903A1 (en) 2021-04-23 2024-02-28 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and compositions for treating cell senescence accumulation related disease
CA3217862A1 (en) 2021-05-05 2022-11-10 Radius Pharmaceuticals, Inc. Animal model having homologous recombination of mouse pth1 receptor
US20220356264A1 (en) * 2021-05-06 2022-11-10 New York University Inhibition of atf7ip and setdb1 for cancer treatment
WO2022240721A1 (en) 2021-05-10 2022-11-17 Entrada Therapeutics, Inc. Compositions and methods for modulating interferon regulatory factor-5 (irf-5) activity
EP4337261A2 (en) 2021-05-10 2024-03-20 Entrada Therapeutics, Inc. Compositions and methods for modulating mrna splicing
US20240316006A1 (en) 2021-05-10 2024-09-26 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Pharmaceutical compositions for treating neurological conditions
AU2022271873A1 (en) 2021-05-10 2024-01-04 Entrada Therapeutics, Inc. Compositions and methods for intracellular therapeutics
US20220372486A1 (en) * 2021-05-11 2022-11-24 Yekaterina Galat Methods of cancer treatment by inhibition of vasculogenesis and gli1
US20240352456A1 (en) 2021-05-13 2024-10-24 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Compositions and methods for treating sickle cell diseases
JP2024519029A (ja) 2021-05-17 2024-05-08 アイオバンス バイオセラピューティクス，インコーポレイテッド Ｐｄ－１遺伝子編集された腫瘍浸潤リンパ球及び免疫療法におけるその使用
EP4419672A2 (en) 2021-06-01 2024-08-28 Artisan Development Labs, Inc. Compositions and methods for targeting, editing, or modifying genes
EP4352131A1 (en) 2021-06-11 2024-04-17 Genedit Inc. Biodegradable polymer comprising side chains with polyamine and polyalkylene oxide groups
IL309333A (en) 2021-06-13 2024-02-01 Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd A method for reprogramming cells
US20240252549A1 (en) * 2021-06-16 2024-08-01 The Regents Of The University Of Michigan Compositions and methods to transfect, test, and treat skin cells
EP4370676A2 (en) 2021-06-18 2024-05-22 Artisan Development Labs, Inc. Compositions and methods for targeting, editing or modifying human genes
GEAP202416440A (en) 2021-06-23 2024-04-25 Entrada Therapeutics Inc Antisense compounds and methods for targeting cug repeats
FR3124522B1 (fr) 2021-06-25 2025-02-28 Cherbonneau Francois Composition et méthode permettant l’édition génomique
WO2023283359A2 (en) 2021-07-07 2023-01-12 Omega Therapeutics, Inc. Compositions and methods for modulating secreted frizzled receptor protein 1 (sfrp1) gene expression
US20250250319A1 (en) 2021-07-15 2025-08-07 Fred Hutchinson Cancer Center Chimeric transmembrane polypeptides comprising a tgf beta receptor extracellular domain, a transmembrane domain and an interleukin receptor 2 intracellular signalling domain and its use in therapy
JP2024526898A (ja) 2021-07-22 2024-07-19 アイオバンス バイオセラピューティクス，インコーポレイテッド 固形腫瘍断片の凍結保存のための方法
WO2023009716A1 (en) 2021-07-28 2023-02-02 Iovance Biotherapeutics, Inc. Treatment of cancer patients with tumor infiltrating lymphocyte therapies in combination with kras inhibitors
EP4130028A1 (en) 2021-08-03 2023-02-08 Rhazes Therapeutics Ltd Engineered tcr complex and methods of using same
CA3226947A1 (en) 2021-08-03 2023-02-09 Muhammad YASSIN Engineered tcr complex and methods of using same
MX2024001624A (es) 2021-08-06 2024-04-30 Vilmorin & Cie Resistencia a leveillula taurica en el pimiento.
AU2022324708A1 (en) 2021-08-06 2024-02-15 Kws Vegetables B.V. Durable downy mildew resistance in spinach
EP4396357A1 (en) 2021-09-02 2024-07-10 SESVanderHave NV Methods and compositions for ppo herbicide tolerance
JP7125727B1 (ja) 2021-09-07 2022-08-25 国立大学法人千葉大学 核酸配列改変用組成物および核酸配列の標的部位を改変する方法
GB202113075D0 (en) 2021-09-14 2021-10-27 Innes John Centre Methods of improving vitamin d levels in plants
JP2024536851A (ja) 2021-09-27 2024-10-08 モンサント テクノロジー エルエルシー 単子葉植物種子から切除された胚外植片を形質転換するための組成物及び方法
EP4596697A3 (en) 2021-09-28 2025-08-27 Acrigen Biosciences Compositions and methods for nucleic acid modifications
GB202113933D0 (en) 2021-09-29 2021-11-10 Genome Res Ltd Methods for gene editing
EP4408996A2 (en) 2021-09-30 2024-08-07 Astrazeneca AB Use of inhibitors to increase efficiency of crispr/cas insertions
WO2023060186A1 (en) 2021-10-07 2023-04-13 Hepatx Corporation Methods of tracking donor cells in a recipient
IL311885A (en) 2021-10-08 2024-06-01 Harvard College Ionic liquids for drug delivery
WO2023062636A1 (en) 2021-10-14 2023-04-20 Weedout Ltd. Methods of weed control
WO2023064872A1 (en) 2021-10-14 2023-04-20 Precision Biosciences, Inc. Combinations of anti-bcma car t cells and gamma secretase inhibitors
US20240408235A1 (en) 2021-10-19 2024-12-12 Precision Biosciences, Inc. Gene editing methods for treating alpha-1 antitrypsin (aat) deficiency
CA3235824A1 (en) 2021-10-27 2023-05-04 Frederick G. Vogt Systems and methods for coordinating manufacturing of cells for patient-specific immunotherapy
WO2023077148A1 (en) 2021-11-01 2023-05-04 Tome Biosciences, Inc. Single construct platform for simultaneous delivery of gene editing machinery and nucleic acid cargo
US20240426823A1 (en) 2021-11-03 2024-12-26 Institut National de la Santé et de la Recherche Médicale Methods and compositions for treating triple negative breast cancer (tnbc)
EP4426832A1 (en) 2021-11-03 2024-09-11 The J. David Gladstone Institutes, A Testamentary Trust Established under The Will of J. David Gladstone Precise genome editing using retrons
US20250032618A1 (en) 2021-11-10 2025-01-30 Iovance Biotherapeutics, Inc. Methods of expansion treatment utilizing cd8 tumor infiltrating lymphocytes
EP4430206A1 (en) 2021-11-10 2024-09-18 Encodia, Inc. Methods for barcoding macromolecules in individual cells
US20250009800A1 (en) 2021-11-16 2025-01-09 Precision Biosciences, Inc. Methods for cancer immunotherapy
US12402582B2 (en) 2021-12-09 2025-09-02 Bejo Zaden B.V. Shallot plant named ‘Innovator’
US20230193310A1 (en) 2021-12-10 2023-06-22 Seminis Vegetabe Seeds, Inc. Lettuce plants having resistance to downy mildew
GB202118058D0 (en) 2021-12-14 2022-01-26 Univ Warwick Methods to increase yields in crops
US20230279442A1 (en) 2021-12-15 2023-09-07 Versitech Limited Engineered cas9-nucleases and method of use thereof
CA3242402A1 (en) 2021-12-16 2023-06-22 Acuitas Therapeutics, Inc. Lipids for use in lipid nanoparticle formulations
WO2023111173A1 (en) 2021-12-16 2023-06-22 INSERM (Institut National de la Santé et de la Recherche Médicale) An ezh2 degrader or inhibitor for use in the treatment of resistant acute myeloid leukemia
WO2023115041A1 (en) 2021-12-17 2023-06-22 Sana Biotechnology, Inc. Modified paramyxoviridae attachment glycoproteins
CN114107253B (zh) * 2021-12-17 2024-03-15 复旦大学附属华山医院 一种利用工程细胞进行基因编辑的系统及方法
US20250059239A1 (en) 2021-12-17 2025-02-20 Sana Biotechnology, Inc. Modified paramyxoviridae fusion glycoproteins
BE1030047B1 (nl) 2021-12-17 2023-07-17 Anheuser Busch Inbev Sa Werkwijzen voor het voorkomen van remming van de smaakproductie in gist
WO2023122805A1 (en) 2021-12-20 2023-06-29 Vestaron Corporation Sorbitol driven selection pressure method
WO2023118165A1 (en) 2021-12-21 2023-06-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
EP4452335A1 (en) 2021-12-22 2024-10-30 Tome Biosciences, Inc. Co-delivery of a gene editor construct and a donor template
KR20240133725A (ko) 2021-12-23 2024-09-04 유니버시티 오브 매사추세츠 취약 x 관련 장애의 치료용 치료제
EP4456910A1 (en) 2021-12-28 2024-11-06 Mnemo Therapeutics Immune cells with inactivated suv39h1 and modified tcr
WO2023133595A2 (en) 2022-01-10 2023-07-13 Sana Biotechnology, Inc. Methods of ex vivo dosing and administration of lipid particles or viral vectors and related systems and uses
WO2023141602A2 (en) 2022-01-21 2023-07-27 Renagade Therapeutics Management Inc. Engineered retrons and methods of use
WO2023144235A1 (en) 2022-01-27 2023-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for monitoring and treating warburg effect in patients with pi3k-related disorders
WO2023147488A1 (en) 2022-01-28 2023-08-03 Iovance Biotherapeutics, Inc. Cytokine associated tumor infiltrating lymphocytes compositions and methods
EP4472646A1 (en) 2022-02-01 2024-12-11 Sana Biotechnology, Inc. Cd3-targeted lentiviral vectors and uses thereof
WO2023150647A1 (en) 2022-02-02 2023-08-10 Sana Biotechnology, Inc. Methods of repeat dosing and administration of lipid particles or viral vectors and related systems and uses
US20250137008A1 (en) 2022-02-08 2025-05-01 University Of Glasgow Modified ion channels
EP4479541A1 (en) 2022-02-15 2024-12-25 Futuragene Israel Ltd. A bacillus thuringiensis pesticidal protein (bt pp) combination useful for plant protection
WO2023158732A1 (en) 2022-02-16 2023-08-24 Dana-Farber Cancer Institute, Inc. Methods for decreasing pathologic alpha-synuclein using agents that modulate fndc5 or biologically active fragments thereof
EP4479143A1 (en) 2022-02-18 2024-12-25 Institut National de la Santé et de la Recherche Médicale (INSERM) Use of tcr-deficient car-tregs in combination with anti-tcr complex monoclonal antibodies for inducing durable tolerance
EP4486881A1 (en) 2022-03-01 2025-01-08 Celyntra Therapeutics SA Composition and methods for transgene insertion
EP4493681A4 (en) 2022-03-17 2026-04-08 Keshihua Nanjing Biotechnology Co Ltd Tumor-Infiltrating Synthetic Lymphocytes (TILS)
EP4256950A1 (en) 2022-04-06 2023-10-11 Vilmorin et Cie Tolerance to cgmmv in cucumber
CA3247638A1 (en) 2022-04-06 2023-10-12 Maria Fardis TREATMENT OF PATIENTS WITH NON-SMALL CELL LUNG CARCINOMA (NSCLC) WITH TUMOR-INFILTRATING LYMPHOCYTE THERAPIES
WO2023201369A1 (en) 2022-04-15 2023-10-19 Iovance Biotherapeutics, Inc. Til expansion processes using specific cytokine combinations and/or akti treatment
WO2023205744A1 (en) 2022-04-20 2023-10-26 Tome Biosciences, Inc. Programmable gene insertion compositions
WO2023215725A1 (en) 2022-05-02 2023-11-09 Fred Hutchinson Cancer Center Compositions and methods for cellular immunotherapy
WO2023215831A1 (en) 2022-05-04 2023-11-09 Tome Biosciences, Inc. Guide rna compositions for programmable gene insertion
WO2023215498A2 (en) 2022-05-05 2023-11-09 Modernatx, Inc. Compositions and methods for cd28 antagonism
EP4522210A1 (en) 2022-05-09 2025-03-19 Synteny Therapeutics, Inc. Erythroparvovirus with a modified genome for gene therapy
WO2023220035A1 (en) 2022-05-09 2023-11-16 Synteny Therapeutics, Inc. Erythroparvovirus compositions and methods for gene therapy
WO2023219933A1 (en) 2022-05-09 2023-11-16 Entrada Therapeutics, Inc. Compositions and methods for delivery of nucleic acid therapeutics
EP4522203A1 (en) 2022-05-09 2025-03-19 Synteny Therapeutics, Inc. Erythroparvovirus with a modified capsid for gene therapy
US20250281537A1 (en) 2022-05-10 2025-09-11 Iovance Biotherapeutics, Inc. Treatment of cancer patients with tumor infiltrating lymphocyte therapies in combination with an il-15r agonist
EP4279085A1 (en) 2022-05-20 2023-11-22 Mnemo Therapeutics Compositions and methods for treating a refractory or relapsed cancer or a chronic infectious disease
WO2023225670A2 (en) 2022-05-20 2023-11-23 Tome Biosciences, Inc. Ex vivo programmable gene insertion
US20250308637A1 (en) 2022-05-20 2025-10-02 Celyntra Therapeutics Sa Systems and methods for assessing risk of genome editing events
CN119563038A (zh) 2022-05-25 2025-03-04 旗舰创业创新七公司 用于调节免疫应答的组合物和方法
JP2025517967A (ja) 2022-05-25 2025-06-12 フラッグシップ パイオニアリング イノベーションズ セブン，エルエルシー サイトカインを調節するための組成物及び方法
EP4532768A2 (en) 2022-05-25 2025-04-09 Flagship Pioneering Innovations VII, LLC Compositions and methods for modulating circulating factors
WO2023230570A2 (en) 2022-05-25 2023-11-30 Flagship Pioneering Innovations Vii, Llc Compositions and methods for modulating genetic drivers
CA3254044A1 (en) 2022-05-25 2023-11-30 Flagship Pioneering Innovations Vii, Llc COMPOSITIONS AND MODULATION METHODS OF TUMOR SUPPRESSANTS AND ONCOGENS
IL317532A (en) 2022-06-10 2025-02-01 Umoja Biopharma Inc Engineered stem cells and their uses
US20230404003A1 (en) 2022-06-21 2023-12-21 Seminis Vegetable Seeds, Inc. Novel qtls conferring resistance to cucumber mosaic virus
WO2024005863A1 (en) 2022-06-30 2024-01-04 Inari Agriculture Technology, Inc. Compositions, systems, and methods for genome editing
WO2024005864A1 (en) 2022-06-30 2024-01-04 Inari Agriculture Technology, Inc. Compositions, systems, and methods for genome editing
GB2621813A (en) 2022-06-30 2024-02-28 Univ Newcastle Preventing disease recurrence in Mitochondrial replacement therapy
EP4299733A1 (en) 2022-06-30 2024-01-03 Inari Agriculture Technology, Inc. Compositions, systems, and methods for genome editing
EP4299739A1 (en) 2022-06-30 2024-01-03 Inari Agriculture Technology, Inc. Compositions, systems, and methods for genome editing
CA3261194A1 (en) 2022-07-05 2024-01-11 John Innes Centre METHODS FOR INCREASING THE IRON CONTENT IN PLANTS
JP2025521677A (ja) 2022-07-06 2025-07-10 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル 増殖性糸球体腎炎を処置するための方法
CN120344660A (zh) 2022-07-18 2025-07-18 雷纳嘉德医疗管理公司 基因编辑组分、系统和使用方法
WO2024020587A2 (en) 2022-07-22 2024-01-25 Tome Biosciences, Inc. Pleiopluripotent stem cell programmable gene insertion
WO2024026406A2 (en) 2022-07-29 2024-02-01 Vestaron Corporation Next Generation ACTX Peptides
LU502613B1 (en) 2022-08-01 2024-02-01 Plant Bioscience Ltd Methods of altering the starch granule profile in plants
US20260060969A1 (en) 2022-08-04 2026-03-05 Institut National de la Santé et de la Recherche Médicale Methods for the treatment of lymphoproliferative disorders
US20260055426A1 (en) 2022-08-19 2026-02-26 Generation Bio Co. CLEAVABLE CLOSED-ENDED DNA (ceDNA) AND METHODS OF USE THEREOF
US20260055146A1 (en) 2022-08-24 2026-02-26 Sana Biotechnology, Inc. Delivery of heterologous proteins
WO2024044723A1 (en) 2022-08-25 2024-02-29 Renagade Therapeutics Management Inc. Engineered retrons and methods of use
EP4577650A1 (en) 2022-08-25 2025-07-02 Life Edit Therapeutics, Inc. Chemical modification of guide rnas with locked nucleic acid for rna guided nuclease-mediated gene editing
EP4580658A1 (en) 2022-08-31 2025-07-09 Institut National de la Santé et de la Recherche Médicale Method to generate more efficient car-t cells
CA3265262A1 (en) 2022-09-01 2024-03-07 SESVanderHave NV PROCESSES AND COMPOSITIONS FOR HERBICIDE TOLERANCE PPO
WO2024050544A2 (en) 2022-09-01 2024-03-07 J.R. Simplot Company Enhanced targeted knock-in frequency in host genomes through crispr exonuclease processing
EP4583905A1 (en) 2022-09-06 2025-07-16 Institut National de la Santé et de la Recherche Médicale Novel dual split car-t cells for the treatment of cd38-positive hematological malignancies
WO2024056659A1 (en) 2022-09-13 2024-03-21 Institut National de la Santé et de la Recherche Médicale Method for treating prostate cancer and other epithelial cancers
TW202417626A (zh) 2022-09-13 2024-05-01 美商亞森諾生物科學公司 具有共表現的ｔｇｆｂｒ ｓｈｒｎａ之免疫細胞
WO2024056902A2 (en) 2022-09-16 2024-03-21 Christopher Shaw Compositions and methods for treating neurological diseases
CN119968464A (zh) 2022-09-16 2025-05-09 阿森纳生物科学公司 具有组合基因扰动的免疫细胞
WO2024064838A1 (en) 2022-09-21 2024-03-28 Sana Biotechnology, Inc. Lipid particles comprising variant paramyxovirus attachment glycoproteins and uses thereof
WO2024062138A1 (en) 2022-09-23 2024-03-28 Mnemo Therapeutics Immune cells comprising a modified suv39h1 gene
GB202214410D0 (en) 2022-09-30 2022-11-16 Ivy Farm Tech Limited genetically modified cells
WO2024081820A1 (en) 2022-10-13 2024-04-18 Sana Biotechnology, Inc. Viral particles targeting hematopoietic stem cells
WO2024084034A1 (en) 2022-10-21 2024-04-25 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of osteoarthritis
WO2024097639A1 (en) 2022-10-31 2024-05-10 Modernatx, Inc. Hsa-binding antibodies and binding proteins and uses thereof
EP4612277A1 (en) 2022-11-04 2025-09-10 Iovance Biotherapeutics, Inc. Methods for tumor infiltrating lymphocyte (til) expansion related to cd39/cd103 selection
AU2023374241A1 (en) 2022-11-04 2025-06-12 Life Edit Therapeutics, Inc. Evolved adenine deaminases and rna-guided nuclease fusion proteins with internal insertion sites and methods of use
WO2024098024A1 (en) 2022-11-04 2024-05-10 Iovance Biotherapeutics, Inc. Expansion of tumor infiltrating lymphocytes from liquid tumors and therapeutic uses thereof
WO2024102434A1 (en) 2022-11-10 2024-05-16 Senda Biosciences, Inc. Rna compositions comprising lipid nanoparticles or lipid reconstructed natural messenger packs
WO2024107670A1 (en) 2022-11-16 2024-05-23 Regeneron Pharmaceuticals, Inc. Chimeric proteins comprising membrane bound il-12 with protease cleavable linkers
KR20250122544A (ko) 2022-11-21 2025-08-13 이오반스 바이오테라퓨틱스, 인크. 종양 침윤 림프구의 확장을 위한 2차원 공정 및 이를 통한 요법
WO2024118836A1 (en) 2022-11-30 2024-06-06 Iovance Biotherapeutics, Inc. Processes for production of tumor infiltrating lymphocytes with shortened rep step
US12152238B2 (en) * 2022-11-30 2024-11-26 Eberhard-Karls-Universität Tübingen Universitätsklinikum Gene editing system for editing the arylsulfatase A (ARSA) gene
WO2024118881A1 (en) 2022-12-01 2024-06-06 Genencor International Bv Iterative muliplex genome engineering in microbial cells using a bidirectional selection marker system
EP4627076A1 (en) 2022-12-01 2025-10-08 Danisco Us Inc Iterative multiplex genome engineering in microbial cells using a recombinant self-excisable selection marker system
WO2024118882A1 (en) 2022-12-01 2024-06-06 Genencor International Bv Iterative multiplex genome engineering in microbial cells using a selection marker swapping system
WO2024118866A1 (en) 2022-12-01 2024-06-06 Modernatx, Inc. Gpc3-specific antibodies, binding domains, and related proteins and uses thereof
WO2024119157A1 (en) 2022-12-02 2024-06-06 Sana Biotechnology, Inc. Lipid particles with cofusogens and methods of producing and using the same
AU2023392154A1 (en) 2022-12-14 2025-06-26 King's College London Compositions and methods for treating neurological diseases
JP2026504733A (ja) 2022-12-16 2026-02-09 ライフ エディット セラピューティクス，インコーポレイティド Ｔｒａｃ遺伝子を標的とするガイドｒｎａおよび使用方法
WO2024127369A1 (en) 2022-12-16 2024-06-20 LifeEDIT Therapeutics, Inc. Guide rnas that target foxp3 gene and methods of use
WO2024133723A1 (en) 2022-12-22 2024-06-27 Institut National de la Santé et de la Recherche Médicale Methods for decreasing therapeutic acquired resistance to chemotherapy and/or radiotherapy
WO2024138194A1 (en) 2022-12-22 2024-06-27 Tome Biosciences, Inc. Platforms, compositions, and methods for in vivo programmable gene insertion
WO2024141599A1 (en) 2022-12-29 2024-07-04 Vilmorin & Cie Tomato plants resistant to resistance-breaking tswv strains and corresponding resistance genes
GB202219829D0 (en) 2022-12-29 2023-02-15 Ivy Farm Tech Limited Genetically manipulated cells
WO2024148206A1 (en) 2023-01-06 2024-07-11 Bristol-Myers Squibb Company Methods and systems for engineering cells and for target validation
AU2024207718A1 (en) * 2023-01-10 2025-07-17 Robigo, Inc. Plant microbes and uses thereof
CN120936625A (zh) 2023-01-12 2025-11-11 新加坡国立大学 用于t细胞和nk细胞恶性肿瘤的免疫疗法的cd8表达阻断和嵌合抗原受体
EP4658061A1 (en) 2023-02-01 2025-12-10 United Beet Seeds Beet yellows virus resistance
WO2024161022A2 (en) 2023-02-03 2024-08-08 King's College London Compositions and methods for treating neurological diseases
WO2024180095A1 (en) 2023-02-27 2024-09-06 John Innes Centre Methods of enhancing production of metabolites in bacteria
JP2026507228A (ja) 2023-03-03 2026-02-27 アーセナル バイオサイエンシズ インコーポレイテッド Ｐｓｍａ及びｃａ９を標的とするシステム
WO2024189098A1 (en) 2023-03-13 2024-09-19 Iomx Therapeutics Ag Platform technology for the identification of modulators of immune effector cell function
AU2024237292A1 (en) 2023-03-13 2025-10-16 Arsenal Biosciences, Inc. Synthetic pathway activators
US12383615B2 (en) 2023-03-23 2025-08-12 Carbon Biosciences, Inc. Protoparvovirus compositions comprising a protoparvovirus variant VP1 capsid polypeptide and related methods
US12225874B2 (en) 2023-03-27 2025-02-18 Redsea Science And Technology Inc. Tomato plant designated ‘X22-31’
EP4689155A1 (en) 2023-03-29 2026-02-11 Astrazeneca AB Use of inhibitors to increase efficiency of crispr/cas insertions
WO2024208896A1 (en) 2023-04-03 2024-10-10 Plant Bioscience Limited Methods for altering starch granule size profile
WO2024211287A1 (en) 2023-04-03 2024-10-10 Seagen Inc. Production cell lines with targeted integration sites
EP4689127A1 (en) 2023-04-03 2026-02-11 Sutro Biopharma, Inc. Rf1 ko e. coli strains
WO2024216116A1 (en) 2023-04-14 2024-10-17 Precision Biosciences, Inc. Muscle-specific expression cassettes
KR20260010765A (ko) 2023-04-14 2026-01-21 프리시젼 바이오사이언시스 인코포레이티드 근육-특이적 발현 카세트
MX2024004405A (es) 2023-04-14 2024-11-08 Seminis Vegetable Seeds Inc Métodos y composiciones de resistencia a peronospora en la espinaca
WO2024220560A1 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Engineered protein g fusogens and related lipid particles and methods thereof
WO2024220598A2 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Lentiviral vectors with two or more genomes
WO2024220574A1 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Universal protein g fusogens and adapter systems thereof and related lipid particles and uses
CN121443140A (zh) 2023-04-21 2026-01-30 非营利性组织佛兰芒综合大学生物技术研究所 用于作物产量提升的等位基因组合
WO2024226499A1 (en) 2023-04-24 2024-10-31 The Broad Institute, Inc. Compositions and methods for modifying fertility
EP4701654A2 (en) 2023-04-25 2026-03-04 Arsenal Biosciences, Inc. Novel receptors for transcription regulation
WO2024226822A2 (en) * 2023-04-26 2024-10-31 Spotlight Therapeutics Cd11a tage compositions and uses thereof
WO2024223900A1 (en) 2023-04-28 2024-10-31 Vilmorin & Cie Genetic determinants conferring improved tobrfv resistance
WO2024234006A1 (en) 2023-05-11 2024-11-14 Tome Biosciences, Inc. Systems, compositions, and methods for targeting liver sinusodial endothelial cells (lsecs)
WO2024236336A1 (en) 2023-05-17 2024-11-21 Institut National de la Santé et de la Recherche Médicale Lipc variant in the treatment of hypercholesterolemia and atherosclerotic cardiovascular disease
AU2024274792A1 (en) 2023-05-23 2025-10-23 Sana Biotechnology, Inc. Tandem fusogens and related lipid particles
WO2024243438A2 (en) 2023-05-23 2024-11-28 Omega Therapeutics, Inc. Compositions and methods for reducing cxcl9, cxcl10, and cxcl11 gene expression
WO2024245951A1 (en) 2023-05-26 2024-12-05 Institut National de la Santé et de la Recherche Médicale Combination of slc8a1 inhibitor and mitochondria-targeted antioxidant for treating melanoma
EP4719423A1 (en) 2023-05-30 2026-04-08 Institut National de la Santé et de la Recherche Médicale Method and pharmaceutical composition for use in the treatment of focal cortical dysplasia
EP4722372A2 (en) 2023-05-30 2026-04-08 Hapiseeds Pesquisa e Desenvolvimento Ltda. Plants with agronomic characteristics improved by suppression of aip10/abap1 regulatory network genes
US12484501B2 (en) 2023-06-05 2025-12-02 Bejo Zaden B.V. Garlic variety ‘BGS 352’
CN121399270A (zh) 2023-06-14 2026-01-23 阿森纳生物科学公司 非病毒细胞工程化
WO2024256635A1 (en) 2023-06-15 2024-12-19 Institut National de la Santé et de la Recherche Médicale Dpm1 inhibitor for treating cancer
WO2024261302A1 (en) 2023-06-22 2024-12-26 Institut National de la Santé et de la Recherche Médicale Nlrp3 inhibitors, pak1/2 inhibitors and/or caspase 1 inhibitors for use in the treatment of rac2 monogenic disorders
EP4734755A1 (en) 2023-06-28 2026-05-06 Vilmorin & Cie Pepper resistance to meloidogyne enterolobii
CN117044681B (zh) * 2023-07-11 2026-01-09 吉林大学 一种cop1基因不表达的异种移植供体猪及其制备方法
WO2025017156A1 (en) 2023-07-18 2025-01-23 University Of Glasgow Ion channels with improved properties
WO2025021702A1 (en) 2023-07-21 2025-01-30 Alia Therapeutics S.R.L. Cas9 orthologue nuclease and uses thereof
CN121548346A (zh) 2023-07-24 2026-02-17 维尔莫林公司 甜瓜对cysdv的抗性
WO2025021839A1 (en) 2023-07-25 2025-01-30 Institut National de la Santé et de la Recherche Médicale Method to treat metabolic disorders
US20250092426A1 (en) 2023-07-25 2025-03-20 Flagship Pioneering Innovations Vii, Llc Cas endonucleases and related methods
WO2025030048A2 (en) 2023-08-03 2025-02-06 J.R. Simplot Company Fusarium wilt resistance genes
WO2025032112A1 (en) 2023-08-08 2025-02-13 Institut National de la Santé et de la Recherche Médicale Methods for the treatment of type 2-mediated diseases
WO2025049959A2 (en) 2023-09-01 2025-03-06 Renagade Therapeutics Management Inc. Gene editing systems, compositions, and methods for treatment of vexas syndrome
WO2025050069A1 (en) 2023-09-01 2025-03-06 Tome Biosciences, Inc. Programmable gene insertion using engineered integration enzymes
WO2025054202A1 (en) 2023-09-05 2025-03-13 Sana Biotechnology, Inc. Method of screening a sample comprising a transgene with a unique barcode
EP4520334A1 (en) 2023-09-07 2025-03-12 Mnemo Therapeutics Methods and compositions for improving immune response
WO2025052001A1 (en) 2023-09-07 2025-03-13 Mnemo Therapeutics Methods and compositions for improving immune response
WO2025054540A1 (en) 2023-09-08 2025-03-13 Iovance Biotherapeutics, Inc. Methods of gene-editing using programmable nucleases
WO2025059533A1 (en) 2023-09-13 2025-03-20 The Broad Institute, Inc. Crispr enzymes and systems
CN119614679A (zh) * 2023-09-14 2025-03-14 厦门大学 一款通用型核酸检测平台
WO2025064408A1 (en) 2023-09-18 2025-03-27 The Broad Institute, Inc. Compositions and methods for treating cardiovascular disease
GB202314578D0 (en) 2023-09-22 2023-11-08 Univ Manchester Methods of producing homoplasmic modified plants or parts thereof
WO2025072331A1 (en) 2023-09-26 2025-04-03 Flagship Pioneering Innovations Vii, Llc Cas nucleases and related methods
EP4554371A4 (en) 2023-10-03 2026-04-22 Inari Agriculture Tech Inc GRNA VIRAL ADMINISTRATION IN GRAFTS
WO2025078978A1 (en) 2023-10-09 2025-04-17 Avectas Limited Transfection of cells via reversible permeabilization
WO2025078851A1 (en) 2023-10-11 2025-04-17 Institut National De La Sante Et De La Recherche Medicale (Inserm) Methods of treating cognitive deficit
AU2024357861A1 (en) 2023-10-12 2026-04-23 Renagade Therapeutics Management Inc. Nickase-retron template-based precision editing system and methods of use
WO2025081123A1 (en) 2023-10-12 2025-04-17 Fred Hutchinson Cancer Center Methods and compositions for improving t cell immunotherapy
WO2025078632A1 (en) 2023-10-12 2025-04-17 Institut National de la Santé et de la Recherche Médicale Methods of prognosis and treatment of patients suffering from cancer
WO2025091009A2 (en) 2023-10-27 2025-05-01 Sutro Biopharma, Inc. Overexpression of lysozyme in t7 rna polymerase-expressing host cells
WO2025101484A1 (en) 2023-11-06 2025-05-15 Iovance Biotherapeutics, Inc. Treatment of endometrial cancers with tumor infiltrating lymphocyte therapies
WO2025101820A1 (en) 2023-11-08 2025-05-15 Fred Hutchinson Cancer Center Compositions and methods for cellular immunotherapy
TW202523695A (zh) 2023-11-22 2025-06-16 美商旗艦先鋒創新有限責任（Ｖｉｉ）公司 用於治療非酒精性脂肪性肝病之方法及組成物
WO2025117877A2 (en) 2023-12-01 2025-06-05 Flagship Pioneering Innovations Vii, Llc Cas nucleases and related methods
WO2025129084A1 (en) 2023-12-13 2025-06-19 Umoja Biopharma, Inc. Engineered induced stem cell derived myeloid cells and methods of differentiating and using same
WO2025126153A2 (en) 2023-12-14 2025-06-19 Aviadobio Ltd. Compositions and methods for treating sod1-mediated neurological diseases
WO2025128981A1 (en) 2023-12-14 2025-06-19 Sohm, Inc. Compositions and methods for genome editing
WO2025132479A1 (en) 2023-12-18 2025-06-26 Institut National de la Santé et de la Recherche Médicale Flt3 inhibitor for modulating macrophages polarization
WO2025149984A2 (en) 2024-01-12 2025-07-17 Avectas Limited Delivery platform with flow-through system (fts)
WO2025149983A2 (en) 2024-01-12 2025-07-17 Avectas Limited Delivery platform with integrated non-viral transfection and cell processing
WO2025151838A1 (en) 2024-01-12 2025-07-17 Sana Biotechnology, Inc. Safety switches to control in vitro and in vivo proliferation of cell therapy products
WO2025155753A2 (en) 2024-01-17 2025-07-24 Renagade Therapeutics Management Inc. Improved gene editing system, guides, and methods
WO2025153608A1 (en) 2024-01-18 2025-07-24 Institut National de la Santé et de la Recherche Médicale Wip1 inhibitor for the treatment of glomerular disease
WO2025162980A1 (en) 2024-01-30 2025-08-07 Institut National de la Santé et de la Recherche Médicale Methods for the treatment of breast cancer using a jnk-1 inhibitor
WO2025163107A1 (en) 2024-02-01 2025-08-07 Institut Gustave Roussy Immune cells defective for znf217 and uses thereof
WO2025168705A1 (en) 2024-02-08 2025-08-14 Vib Vzw Means and methods for the production of saponins with endosomal escape-enhancing properties
WO2025174765A1 (en) 2024-02-12 2025-08-21 Renagade Therapeutics Management Inc. Lipid nanoparticles comprising coding rna molecules for use in gene editing and as vaccines and therapeutic agents
WO2025184529A1 (en) 2024-03-01 2025-09-04 Sana Biotechnology, Inc. Viral particles with fusogen display and related compositions and methods
WO2025186284A1 (en) 2024-03-05 2025-09-12 Vilmorin & Cie Increased yield in cucumber
WO2025191018A1 (en) 2024-03-13 2025-09-18 Institut National de la Santé et de la Recherche Médicale Mrgpre binding agent for use in the treatment of inflammatory and pain disorders
WO2025194019A1 (en) 2024-03-14 2025-09-18 Flagship Pioneering Innovations Vii, Llc Methods for treating liver fibrosis and non-alcoholic fatty liver disease
WO2025199346A1 (en) 2024-03-20 2025-09-25 Arsenal Biosciences, Inc. Antigen binding proteins that bind tmprss4 and methods of use thereof
WO2025199338A1 (en) 2024-03-20 2025-09-25 Arsenal Biosciences, Inc. Systems targeting slc34a2 and tmprss4 and methods of use thereof
WO2025210123A1 (en) 2024-04-03 2025-10-09 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical composition for treating cancers
WO2025215354A1 (en) 2024-04-08 2025-10-16 Ivy Farm Technologies Limited Method of culturing an animal cell
US20250332260A1 (en) 2024-04-10 2025-10-30 Garuda Therapeutics, Inc. Immune compatible cells for allogeneic cell therapies to cover global, ethnic, or disease-specific populations
EP4677108A1 (en) 2024-04-22 2026-01-14 Basecamp Research Ltd Method and compositions for detecting off-target editing
WO2025224182A2 (en) 2024-04-23 2025-10-30 Basecamp Research Ltd Single construct platform for simultaneous delivery of gene editing machinery and nucleic acid cargo
WO2025224297A1 (en) 2024-04-26 2025-10-30 Institut National de la Santé et de la Recherche Médicale Antibodies having specificity to tgfbi and uses thereof
EP4643858A1 (en) 2024-04-29 2025-11-05 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical composition for the treatment of uterine disease
WO2025228998A1 (en) 2024-04-30 2025-11-06 Institut National de la Santé et de la Recherche Médicale Use of hdac4 inhibitors for the treatment of melanoma
WO2025240947A1 (en) 2024-05-17 2025-11-20 University Of Massachusetts Therapeutic treatment for fragile x-associated disorder
WO2025245188A2 (en) 2024-05-21 2025-11-27 Flagship Pioneering Innovations Vii, Llc Methods of treating liver steatosis and non-alcoholic fatty liver disease
WO2025245169A1 (en) 2024-05-21 2025-11-27 Fred Hutchinson Cancer Center Immunotherapy cells equipped with a collagen-targeting payload
WO2025247829A1 (en) 2024-05-27 2025-12-04 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical composition for treating prostate cancer
WO2025247951A1 (en) 2024-05-28 2025-12-04 Institut Gustave Roussy Fyn kinase inhibitors, combinations and uses thereof
WO2025248102A1 (en) 2024-05-31 2025-12-04 Institut National de la Santé et de la Recherche Médicale Tbk1 inhibitor for use in the treatment of vitiligo
WO2025257151A1 (en) 2024-06-10 2025-12-18 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical composition for treating ciliopathies
WO2025259554A1 (en) 2024-06-13 2025-12-18 J.R. Simplot Company Engineering remontant flowering in rosaceae
WO2026002934A1 (en) 2024-06-25 2026-01-02 Institut National de la Santé et de la Recherche Médicale Combination of a slc16a1 inhibitor and a smad3 inhibitor for treating cancer
WO2026003754A1 (en) 2024-06-25 2026-01-02 Life Edit Therapeutics, Inc. Novel reverse transcriptases and uses thereof
WO2026006542A2 (en) 2024-06-26 2026-01-02 Yale University Compositions and methods for crispr/cas9 based reactivation of human angelman syndrome
WO2026009227A1 (en) 2024-07-04 2026-01-08 Yeda Research And Development Co. Ltd. Compositions for downregulating zeb2 in macrophages and uses thereof
WO2026012976A1 (en) 2024-07-08 2026-01-15 Institut National de la Santé et de la Recherche Médicale Use of inhibitor of gasdermind for treatment of rac2 monogenic disorders
WO2026013071A1 (en) 2024-07-09 2026-01-15 Institut National de la Santé et de la Recherche Médicale Setdb1 inhibitor for use in the treatment of uveal melanoma
WO2026017833A1 (en) 2024-07-17 2026-01-22 Vilmorin & Cie Tswv-resistant pepper
WO2026020120A1 (en) 2024-07-19 2026-01-22 University Of Massachusetts Increasing cas9 genome editing fidelity through attenuation of guide rna watson-crick base pairing potential
GB202411278D0 (en) 2024-07-31 2024-09-11 Uea Enterprises Ltd Methods of altering plant stress response
WO2026036000A1 (en) 2024-08-08 2026-02-12 Invaio Sciences, Inc. Nature-derived lipid particles for use in agriculture
WO2026038057A1 (en) 2024-08-16 2026-02-19 Genome Research Limited Improved methods for gene editing
WO2026057679A1 (en) 2024-09-11 2026-03-19 Institut National de la Santé et de la Recherche Médicale Inhibitor of rab30 for use in a method of treatment of metabolic dysfunction-associated steatotic liver disease (masld)
US20260071285A1 (en) 2024-09-11 2026-03-12 Seminis Vegetable Seeds, Inc. Novel qtls conferring resistance to cucurbit aphid-borne yellow virus
WO2026083309A1 (en) 2024-10-17 2026-04-23 Astrazeneca Ab Use of inhibitors or modulators of artemis in gene editing
WO2026085495A1 (en) 2024-10-18 2026-04-23 Generation Bio Co. Synthetic partially single-stranded nucleic acid compositions and uses and methods therefor
WO2026083328A1 (en) 2024-10-18 2026-04-23 Precision Biosciences, Inc. Base editing nucleotide sequences using homology directed repair
WO2026083329A1 (en) 2024-10-18 2026-04-23 Precision Biosciences, Inc. Methods of nuclease-initiated homology directed repair and replacement and compositions and uses thereof
WO2026096383A1 (en) 2024-10-28 2026-05-07 The Broad Institute, Inc. Compositions and methods for inducing phagocytosis
CN121483365B (zh) * 2026-01-09 2026-04-10 之江实验室 基于局部几何结构与机器学习的Cas蛋白酶PAM分析方法

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186183A (en) 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4217344A (en) 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4261975A (en) 1979-09-19 1981-04-14 Merck & Co., Inc. Viral liposome particle
US4485054A (en) 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
EP0264166A1 (en) 1986-04-09 1988-04-20 Genzyme Corporation Transgenic animals secreting desired proteins into milk
US4774085A (en) 1985-07-09 1988-09-27 501 Board of Regents, Univ. of Texas Pharmaceutical administration systems containing a mixture of immunomodulators
US4797368A (en) 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US4873316A (en) 1987-06-23 1989-10-10 Biogen, Inc. Isolation of exogenous recombinant proteins from the milk of transgenic mammals
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4946787A (en) 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US5049386A (en) 1985-01-07 1991-09-17 Syntex (U.S.A.) Inc. N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor
WO1991016024A1 (en) 1990-04-19 1991-10-31 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
WO1991017424A1 (en) 1990-05-03 1991-11-14 Vical, Inc. Intracellular delivery of biologically active substances by means of self-assembling lipid complexes
US5173414A (en) 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
WO1993024641A2 (en) 1992-06-02 1993-12-09 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Adeno-associated virus with inverted terminal repeat sequences as promoter
US6479808B1 (en) 1999-07-07 2002-11-12 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Method and systems for collecting data from multiple fields of view
US20030087817A1 (en) 1999-01-12 2003-05-08 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US6603061B1 (en) 1999-07-29 2003-08-05 Monsanto Company Agrobacterium-mediated plant transformation method
US20090100536A1 (en) 2001-12-04 2009-04-16 Monsanto Company Transgenic plants with enhanced agronomic traits
US7868149B2 (en) 1999-07-20 2011-01-11 Monsanto Technology Llc Plant genome sequence and uses thereof
US20110059502A1 (en) 2009-09-07 2011-03-10 Chalasani Sreekanth H Multiple domain proteins
US9405700B2 (en) 2010-11-04 2016-08-02 Sonics, Inc. Methods and apparatus for virtualization in an integrated circuit

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3454818B1 (ja) * 2001-03-16 2003-10-06 直哉 小林 肝臓細胞の増殖方法、該方法により得られる肝臓細胞、およびその用途
US20050220796A1 (en) 2004-03-31 2005-10-06 Dynan William S Compositions and methods for modulating DNA repair
WO2007014275A2 (en) * 2005-07-26 2007-02-01 Sangamo Biosciences, Inc. Targeted integration and expression of exogenous nucleic acid sequences
PT2126130E (pt) * 2007-03-02 2015-08-03 Dupont Nutrition Biosci Aps Culturas com resistência melhorada a fagos
WO2010011961A2 (en) 2008-07-25 2010-01-28 University Of Georgia Research Foundation, Inc. Prokaryotic rnai-like system and methods of use
US20100076057A1 (en) 2008-09-23 2010-03-25 Northwestern University TARGET DNA INTERFERENCE WITH crRNA
US9404098B2 (en) 2008-11-06 2016-08-02 University Of Georgia Research Foundation, Inc. Method for cleaving a target RNA using a Cas6 polypeptide
AU2009322964B2 (en) * 2008-12-04 2014-10-09 Sangamo Therapeutics, Inc. Genome editing in rats using zinc-finger nucleases
US10087431B2 (en) 2010-03-10 2018-10-02 The Regents Of The University Of California Methods of generating nucleic acid fragments
EA024121B9 (ru) 2010-05-10 2017-01-30 Дзе Реджентс Ов Дзе Юниверсити Ов Калифорния Композиции эндорибонуклеаз и способы их использования
EP3156062A1 (en) * 2010-05-17 2017-04-19 Sangamo BioSciences, Inc. Novel dna-binding proteins and uses thereof
WO2012164656A1 (ja) 2011-05-30 2012-12-06 トヨタ自動車株式会社 高強度ポリプロピレン繊維及びその製造方法
WO2012164565A1 (en) 2011-06-01 2012-12-06 Yeda Research And Development Co. Ltd. Compositions and methods for downregulating prokaryotic genes
GB201122458D0 (en) 2011-12-30 2012-02-08 Univ Wageningen Modified cascade ribonucleoproteins and uses thereof
US9637739B2 (en) * 2012-03-20 2017-05-02 Vilnius University RNA-directed DNA cleavage by the Cas9-crRNA complex
WO2013141680A1 (en) 2012-03-20 2013-09-26 Vilnius University RNA-DIRECTED DNA CLEAVAGE BY THE Cas9-crRNA COMPLEX
LT3401400T (lt) 2012-05-25 2019-06-10 The Regents Of The University Of California Būdai ir kompozicijos, skirtos rnr molekulės nukreipiamai tikslinės dnr modifikacijai ir rnr molekulės nukreipiamam transkripcijos moduliavimui
PL4397760T3 (pl) * 2012-10-23 2026-03-30 Toolgen Incorporated Kompozycja do rozszczepiania docelowego dna zawierająca prowadzące rna specyficzne dla docelowego dna i kwas nukleinowy kodujący białko cas lub białko cas oraz jej zastosowanie
EP3135765A1 (en) * 2012-12-06 2017-03-01 Sigma-Aldrich Co. LLC Crispr-based genome modification and regulation
WO2014093479A1 (en) 2012-12-11 2014-06-19 Montana State University Crispr (clustered regularly interspaced short palindromic repeats) rna-guided control of gene regulation
IL239317B (en) 2012-12-12 2022-07-01 Broad Inst Inc Providing, engineering and optimizing systems, methods and compositions for sequence manipulation and therapeutic applications
ES2576126T3 (es) 2012-12-12 2016-07-05 The Broad Institute, Inc. Modificación por tecnología genética y optimización de sistemas, métodos y composiciones enzimáticas mejorados para la manipulación de secuencias
WO2014093701A1 (en) 2012-12-12 2014-06-19 The Broad Institute, Inc. Functional genomics using crispr-cas systems, compositions, methods, knock out libraries and applications thereof
EP3434776A1 (en) 2012-12-12 2019-01-30 The Broad Institute, Inc. Methods, models, systems, and apparatus for identifying target sequences for cas enzymes or crispr-cas systems for target sequences and conveying results thereof
CN114634950A (zh) 2012-12-12 2022-06-17 布罗德研究所有限公司 用于序列操纵的crispr-cas组分系统、方法以及组合物
US8697359B1 (en) 2012-12-12 2014-04-15 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
EP2931898B1 (en) 2012-12-12 2016-03-09 The Broad Institute, Inc. Engineering and optimization of systems, methods and compositions for sequence manipulation with functional domains
JP2016504026A (ja) 2012-12-12 2016-02-12 ザ・ブロード・インスティテュート・インコーポレイテッド 配列操作のための系、方法および最適化ガイド組成物のエンジニアリング
US20140310830A1 (en) 2012-12-12 2014-10-16 Feng Zhang CRISPR-Cas Nickase Systems, Methods And Compositions For Sequence Manipulation in Eukaryotes
EP2896697B1 (en) 2012-12-12 2015-09-02 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
SG10201912991WA (en) 2012-12-17 2020-03-30 Harvard College Rna-guided human genome engineering
JP6244391B2 (ja) * 2016-03-17 2017-12-06 本田技研工業株式会社 車両

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4217344A (en) 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4186183A (en) 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4261975A (en) 1979-09-19 1981-04-14 Merck & Co., Inc. Viral liposome particle
US4485054A (en) 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US5049386A (en) 1985-01-07 1991-09-17 Syntex (U.S.A.) Inc. N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4946787A (en) 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4797368A (en) 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US4774085A (en) 1985-07-09 1988-09-27 501 Board of Regents, Univ. of Texas Pharmaceutical administration systems containing a mixture of immunomodulators
EP0264166A1 (en) 1986-04-09 1988-04-20 Genzyme Corporation Transgenic animals secreting desired proteins into milk
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US4873316A (en) 1987-06-23 1989-10-10 Biogen, Inc. Isolation of exogenous recombinant proteins from the milk of transgenic mammals
WO1991016024A1 (en) 1990-04-19 1991-10-31 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
WO1991017424A1 (en) 1990-05-03 1991-11-14 Vical, Inc. Intracellular delivery of biologically active substances by means of self-assembling lipid complexes
US5173414A (en) 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
WO1993024641A2 (en) 1992-06-02 1993-12-09 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Adeno-associated virus with inverted terminal repeat sequences as promoter
US20030087817A1 (en) 1999-01-12 2003-05-08 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
US6479808B1 (en) 1999-07-07 2002-11-12 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Method and systems for collecting data from multiple fields of view
US7868149B2 (en) 1999-07-20 2011-01-11 Monsanto Technology Llc Plant genome sequence and uses thereof
US6603061B1 (en) 1999-07-29 2003-08-05 Monsanto Company Agrobacterium-mediated plant transformation method
US20090100536A1 (en) 2001-12-04 2009-04-16 Monsanto Company Transgenic plants with enhanced agronomic traits
US20110059502A1 (en) 2009-09-07 2011-03-10 Chalasani Sreekanth H Multiple domain proteins
US9405700B2 (en) 2010-11-04 2016-08-02 Sonics, Inc. Methods and apparatus for virtualization in an integrated circuit

Non-Patent Citations (127)

* Cited by examiner, † Cited by third party
Title
"ANIMAL CELL CULTURE", 1987
"ANTIBODIES, A LABORATORY MANUAL", 1988
"CURRENT PROTOCOLS IN MOLECULAR BIOLOGY", 1987
"Genetic Diseases of the Eye", 2012, OXFORD UNIVERSITY PRESS
"Genetics of Epilepsy and Genetic Epilepsies", 2009, MARIANI FOUNDATION PAEDIATRIC NEUROLOGY, pages: 20
"METHODS IN ENZYMOLOGY", ACADEMIC PRESS, INC.
"PCR 2: A PRACTICAL APPROACH", 1995
A.R. GRUBER ET AL., CELL, vol. 106, no. 1, 2008, pages 23 - 24
AHMAD ET AL., CANCER RES, vol. 52, 1992, pages 4817 - 4820
AMRANN ET AL., GENE, vol. 69, 1988, pages 301 - 315
ANDERSON, SCIENCE, vol. 256, 1992, pages 808 - 813
BAC, T.; SCHNEEWIND, O.: "Allelic replacement in Staphylococcus aureus with inducible counter-selection", PLASMID, vol. 55, 2006, pages 58 - 63
BALDAN ET AL., J., vol. 6, 1987, pages 229 - 234
BANEIJI ET AL., CELL, vol. 33, 1983, pages 729 - 740
BARRANGOU R. ET AL.: "CRISPR provides acquired resistance against viruses in prokaryotes", SCIENCE, vol. 315, no. 5819, 23 March 2007 (2007-03-23), pages 1709 - 12
BARRANGOU, R: "RNA-mediated programmable DNA cleavage", NAT. BIOTECHNOL., vol. 30, 2012, pages 836 - 838
BEHR ET AL., BIOCONJUGATE CHEM, vol. 5, 1994, pages 382 - 389
BIKARD, D.; HATOUM-ASLAN, A.; MUCIDA, D.; MARRAFFINI, I,.A.: "CRISPR interference can prevent natural transformation and virulence acquisition during in vivo bacterial infection", CELL HOST MICROBE, vol. 12, 2012, pages 177 - 186
BLAESE ET AL., CANCEL GENE THER., vol. 2, 1995, pages 291 - 297
BOGDANOVE, A.J.; VOYTAS, D.F.: "TAL effectors: customizable proteins for DNA targeting", SCIENCE, vol. 333, 2011, pages 1843 - 1846
BOSHART ET AL., CELL, vol. 41, 1985, pages 521 - 530
BROUNS, S.: "J. Molecular biology. A Swiss army knife of immunity", SCIENCE, vol. 337, 2012, pages 808 - 809
BROUNS, S.J. ET AL.: "Small CRISPR RNAs guide antiviral defense in prokaryotes", SCIENCE, vol. 321, 2008, pages 960 - 964
BUCHSCHER ET AL., J. VIROL., vol. 66, 1992, pages 2731 - 2719
BYRNE; RUDDLE, PROC. NATL. ACAD. SCI. USA., vol. 86, 1989, pages 5473 - 5477
CALAME; EATON, ADV. IMMUNOL., vol. 43, 1988, pages 235 - 275
CAMPES; TILGHMAN, GENES DEV., vol. 3, 1989, pages 537 - 546
CARROLL, D.: "A CRISPR Approach to Gene Targeting", MOL. THER., vol. 20, 2012, pages 1658 - 1660
CARTE, J.; WANG, R.; LI, H.; TERNS, P.M.; TERNS, M.P.: "Cas6 is an endoribonuclease that generates guide RNAs for invader defense in prokaryotes", GENES DEV., vol. 22, 2008, pages 3489 - 3496
CONG, L. ET AL.: "Multiplex Genome Engineering Using CRISPR/Cas Systems", SCIENCE, 2013
COSTANTINO, N.; COURT, D.L.: "Enhanced levels of lambda Red-mediated recombinants in mismatch repair mutants", PROC. NATL. ACAD. SCI. U.S.A., vol. 100, 2003, pages 15748 - 15753
CRYSTAL, SCIENCE, vol. 270, 1995, pages 404 - 410
DELTCHEVA, E. ET AL.: "CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III", NATURE, vol. 471, 2011, pages 602 - 607
DEVEAU, H. ET AL.: "Phage response to CRISPR-encoded resistance in Streptococcus thermophilus", J. BACTERIOL., vol. 190, 2008, pages 1390 - 1400
DEVEAU, H.; GARNEAU, J.E.; MOINEAU, S.: "CRISPR/Cas system and its role in phage- bacteria interactions", ANNU. REV. MICROBIOL., vol. 64, 2010, pages 475 - 493
DILLON, TIBTECH, vol. 11, 1993, pages 167 - 175
EDGAR, R.; QIMRON, IJ.: "The Escherichia coli CRISPR system protects from lambda lysogenization, lysogens, and prophage induction", J. BACTERIOL., vol. 192, 2010, pages 6291 - 6294
EDLUND ET AL., SCIENCE, vol. 230, 1985, pages 912 - 916
FISCHER, S. ET AL.: "An archaeal immune system can detect multiple Protospacer Adjacent Motifs (PAMs) to target invader DNA", J. BIOL. CHEM., vol. 287, 2012, pages 33351 - 33363
GAO ET AL., GENE THERAPY, vol. 2, 1995, pages 710 - 722
GARNEAU J. E. ET AL.: "The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA", NATURE, vol. 468, 4 November 2010 (2010-11-04), pages 67 - 71
GASIUNAS, G.; BARRANGOU, R.; HORVATH, P.; SIKSNYS, V.: "Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria", PROC. NATL. ACAD. SCI. U.S.A., 2012
GIBSON, D.G. ET AL.: "Enzymatic assembly of DNA molecules up to several hundred kilobases", NAT METHODS, vol. 6, 2009, pages 343 - 345
GOEDDEL: "GENE EXPRESSION TECHNOLOGY METHODS IN ENZYMOLOGY", vol. 185, 1990, ACADEMIC PRESS
GOEDDEL: "GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY", vol. 185, 1990, ACADEMIC PRESS
GROENEN ET AL., MOL. MICROBIOL., vol. 10, 1993, pages 1057 - 1065
GUDBERGSDOTTIR, S ET AL.: "Dynamic properties of the Sulfolobus CRISPR/Cas and CRISPR/Cmr systems when challenged with vector-borne viral. and plasmid genes and protospacers", MOL. MICROBIOL., vol. 79, 2011, pages 35 - 49
HADDADA; DOERFLER; BOHM ET AL.: "urrent ropics in Microbiology and Immunology", 1995
HATOUM-ASLAN, A.; MANIV, I.; MARRAFFINI, L.A.: "Mature clustered, regularly interspaced, short palindromic repeats RNA (crRNA) length is measured by a ruler mechanism anchored at the precursor processing site", PROC. NATL. AC?D. SCI. U.S.A., vol. 108, 2011, pages 21218 - 21222
HAURWITZ, R.E.; JINEK, M.; WIEDENHEFT, B.; ZHOU, K.; DOUDNA, J.A.: "Sequence- and structure-specific RNA processing by a CRISPR endonuclease", SCIENCE, vol. 329, 2010, pages 1355 - 1358
HAVARSTEIN, L.S.; COOMARASWAMY, G.; MORRISON, D.A: "An unmodified heptadecapeptide pheromone induces competence for genetic transformation in Streptococcus pneumoniae", PROC. NATL. ACAD. SCI. U.S.A., vol. 92, 1995, pages 11140 - 11144
HOE ET AL., EMERG. INFECT. DIS., vol. 5, 1999, pages 254 - 263
HORINOUCHI, S.; WEISBLUM, B.: "Nucleotide sequence and functional map of pC194, a plasmid that specifies inducible chloramphenicol resistance", J. BACTERIOL., vol. 150, 1982, pages 815 - 825
HORMONAT; MUZYCZKA, PNAS, vol. 81, 1984, pages 6466 - 6470
HORTON, R.M: "In Vitro Recombination and Mutagenesis of DNA : SOEing Together Tailor-Made Genes", METHODS MOL. BIOL., vol. 15, 1993, pages 251 - 261
HORVATH, P.; BARRANGOU, R.: "CRISPR/Cas, the immune system of bacteria and archaea", SCIENCE, vol. 327, 2010, pages 167 - 170
HOSAKA, T. ET AL.: "The novel mutation K87E in ribosomal protein S12 enhances protein synthesis activity during the late growth phase in Escherichia coli", MOL. GENET. GENOMICS, vol. 271, 2004, pages 317 - 324
HOSKINS, J. ET AL.: "Genome of the bacterium Streptococcus pneumoniae strain R6", J. BACTERIOL., vol. 183, 2001, pages 5709 - 5717
HUSMANN, L.K.; SCOTT, J.R.; LINDAHL, G.; STENBERG, L.: "Expression of the Arp protein, a member of the M protein family, is not sufficient to inhibit phagocytosis of Streptococcus pyogenes", INFECTION AND IMMUNITY, vol. 63, 1995, pages 345 - 348
ISHINO ET AL., J. BACTERIOL., vol. 169, 1987, pages 5429 - 5433
ISHINO Y.: "Nucleotide sequence of the iap gene. responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product", J BACTERIOL., vol. 169, no. 12, December 1987 (1987-12-01), pages 5429 - 33
JANSEN ET AL., MOL. MICROBIOL., vol. 43, 2002, pages 1565 - 1575
JANSEN R. ET AL.: "Identification of genes that are associated with DNA repeats in prokaryotes", MOLECULAR MICROBIOLOGY, vol. 43, no. 6, 2002, pages 1565 - 1575
JANSSEN ET AL., OMICS J. INTEG. BIOL., vol. 6, 2002, pages 23 - 33
JINEK, M. ET AL.: "A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity", SCIENCE, vol. 337, 2012, pages 816 - 821
JOHANN ET AL., 1. VIROL., vol. 66, 1992, pages 1635 - 1640
KAUFMAN ET AL., EMBO J., vol. 6, 1987, pages 187 - 195
KESSEL; GRUSS, SCIENCE, vol. 249, 1990, pages 374 - 379
KOTIN, HUMAN GENE THERAPY, vol. 5, 1994, pages 793 - 801
KREMER; PERRICAUDET, BRITISH MEDICAL BULLETIN, vol. 51, no. 1, 1995, pages 31 - 44
KUIJAN; HERSKOWITZ, CELL, vol. 30, 1982, pages 933 - 943
LUCKLOW; SUMMERS, VIROLOGY, vol. 170, 1989, pages 31 - 39
MAKAROVA, K.S.; ARAVIND, L.; WOLF, Y.I; KOONIN, E.V.: "Unification of Cas protein families and a simple scenario for the origin and evolution of CRISPR-Cas systems", BIOL. DIRECT, vol. 6, 2011, pages 38
MALI, P. ET AL.: "RNA-Guided Human Genome Engineering via Cas9", SCIENCE IN PRESS, 2013
MARRAFFINI, L.A.; DEDENT, A.C.; SCHNEEWIND, O.: "Sortases and the art of anchoring proteins to the envelopes of gram-positive bacteria", MICROBIOL. MOL. BIOL. REV., vol. 70, 2006, pages 192 - 221
MARRAFFINI, L.A.; SONTHEIMER, E.J.: "Self versus non-self discrimination during CRISPR RNA-directed immunity", NATURE, vol. 463, 2010, pages 568 - 571
MASEPOHL ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1307, 1996, pages 26 - 30
MCLVOR EI; POLAK U; NAPIERALA M., RNA BIOL., vol. 7, no. 5, September 2010 (2010-09-01), pages 551 - 8
MILLER ET AL., J. VIROL., vol. 65, 1991, pages 2220 - 2224
MILLER, NATURE, vol. 357, 1992, pages 455 - 460
MITANI; CASKEY, TIBTECH, vol. 11, 1993, pages 162 - 166
MOJICA ET AL., MOL. MICROBIOL., vol. 36, 2000, pages 244 - 246
MOJICA ET AL., MOL.. MICROBIOL., vol. 17, 1995, pages 85 - 93
MOJICA F. J. M ET AL.: "Biological significance of a family of regularly spaced repeats in the genomes of Archaea, Bacteria and mitochondria", MOLECULAR MICROBIOLOGY, vol. 36, no. 1, 2000, pages 244 - 246
MOL CELL. BIOL., vol. 8, no. 1, 1988, pages 466 - 472
MORRELL ET AL.: "Crop genomics advances and applications", NAT REV GENET., vol. 13, no. 2, 29 December 2011 (2011-12-29), pages 85 - 96
MOTAMEDI, M.R.; SZIGETY, S.K.; ROSENBERG, S.M.: "Double-strand-break repair recombination in Escherichia coli: physical evidence for a DNA replication mechanism in vivo", GENES DEV., vol. 13, 1999, pages 2889 - 2903
MUZYCZKA, J. CLIN. INVEST, vol. 94, 1994, pages 1351
NABEL; FELGNER, TIBTECH, vol. 11, 1993, pages 211 - 217
NAKATA ET AL., J. BACTERIOL., vol. 171, 1989, pages 3553 - 3556
PA CARR; GM CHURCH, NATURE BIOTECHNOLOGY, vol. 27, no. 12, 2009, pages 1151 - 62
PMKERT ET AL., GENES DEV., vol. 1, 1987, pages 268 - 277
PODBIELSKI, A.; SPELLERBERG, B.; WOISCHNIK. M.; POHL, B.; LUTTICKEN, R.: "Novel series of plasmid vectors for gene inactivation and expression analysis in group A streptococci (GAS", GENE, vol. 177, 1996, pages 137 - 147
PROC. NATL ACAD SCI. USA., vol. 78, no. 3, 1981, pages 1527 - 31
QUEEN; BALTIMORE, CELL, vol. 33, 1983, pages 741 - 748
REMY ET AL., BIOCONJUGATE CHEM., vol. 5, 1994, pages 647 - 654
ROBERT D. WELLS; TETSUO ASHIZAWA: "Genetic Instabilities and Neurological Diseases", 13 October 2011, ACADEMIC PRESS
SAMBROOK ET AL.: "MOLECULAR CLONING A LABORATORY MANUAL", 1989, COLD SPRING HARBOR LABORATORY COLD SPIRING HARBOR LABORATORY PRESS
SAMBROOK; FRITSCH; MANIATIS: "MOLECULAR CLONING: A LABORATORY MANUAL", 1989
SAMULSKI ET AL., J. VIROL., vol. 63, 1989, pages 03822 - 3828
SAPRANAUSKAS, R. ET AL.: "The Streptococcus thermophilus CRISPR/Cas system provides immunity in Escherichia coli", NUCLEIC ACIDS RES., 2011
SCHULTZ ET AL., GENE, vol. 54, 1987, pages 113 - 123
SEED, NATURE, vol. 329, 1987, pages 840
SEMENOVA, E. ET AL.: "Interference by clustered regularly interspaced short palindromic repeat (CRISPR) RNA is governed by a seed sequence", PROC. NATL. ACAD. SCI. U.S.A., 2011
SHARAN, S.K.; THOMASON, L.C.; KUZNETSOV, S.G.; COURT, D.L.: "Recombineering: a homologous recombination-based method of genetic engineering", NAT. PROTOC., vol. 4, 2009, pages 206 - 223
SMITH ET AL., MOL. CELL BIOL., vol. 3, 1983, pages 2156 - 2165
SMITH; JOHNSON, GENE, vol. 67, 1988, pages 31 - 40
SOMMNERFELT ET AL., VIROL., vol. 176, 1990, pages 58 - 59
STODDARD, B.L.: "Homing endonuclease structure and function", Q. REV. BIOPHYS., vol. 38, 2005, pages 49 - 95
STUDIER ET AL.: "GENE EXPRESSION TECHNOLOGY METHODS IN ENZYMOLOGY", vol. 185, 1990, ACADEMIC PRESS, pages: 60 - 89
SUNG, C.K.; LI, H.; CLAVERYS, J.P.; MORRISON, D.A: "An rpsL cassette, janus, for gene replacement through. negative selection in Streptococcus pneumoniae", APPL. ENVIRON. MICROBIOL., vol. 67, 2001, pages 5190 - 5196
TERNS, M.P.; TERNS, R.M.: "CRISPR-based adaptive immune systems", CURR. OPIN. MICROBIAL., vol. 14, 2011, pages 321 - 327
TRATSCHIN ET AL., MOL CELL BIOL., vol. 5, 1985, pages 3251 - 3260
TRATSCHIN ET AL., MOL. CELL. BIOL, vol. 4, 1984, pages 2072 - 2081
URNOV, F.D.; REBAR, E.J.; HOLMES, M.C.; ZHANG, H.S.; GREGORY, P.D.: "Genome editing with engineered zinc finger nucleases", NAT. REV. GENET., vol. 11, 2010, pages 636 - 646
VAN BRUNT, BIOTECHNOLOGY, vol. 6, no. 10, 1988, pages 1149 - 1154
VAN DER OOST, J.; JORE, M.M.; WESTRA, E.R.; LUNDGREN, M.; BROUNS, S.J.: "CRISPR-based adaptive and heritable immunity in prokaryotes", TRENDS. BIOCHEM. SCI., vol. 34, 2009, pages 401 - 407
VAN EMBDEN. ET AL., J. BACTERIOL., vol. 182, 2000, pages 2393 - 2401
VIGNE, RESTORATIVE NEUROLOGY AND NEUROSCIENCE, vol. 8, 1995, pages 35 - 36
WANG, H.H. ET AL.: "Genome-scale promoter engineering by coselection MAGE", NAT METHODS, vol. 9, 2012, pages 591 - 593
WEST ET AL., VIROLOGY, vol. 160, 1987, pages 38 - 47
WIEDENHEFT, B. ET AL.: "RNA-guided complex from a bacterial immune system enhances target recognition through seed sequence interactions", PROC. NATL. ACAD. SCI. U.S.A., 2011
WILSON ET AL., J VIROL., vol. 63, 1989, pages 2374 - 2378
WINOTO; BALTIMORE, EMBO J., vol. 8, 1989, pages 729 733
YU ET AL., GENE THERAPY, vol. 1, 1994, pages 13 - 26
ZAHNER, D.; HAKENBECK, R.: "The Streptococcus pneumoniae beta-galactosidase is a surface protein", J. BACTERIOL., vol. 182, 2000, pages 5919 - 5921
ZUKER; STIEGLER, NUCLEIC ACIDS RES., vol. 9, 1981, pages 133 - 148

Cited By (813)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12258584B2 (en) 2010-05-06 2025-03-25 Children's Hospital Medical Center Methods and systems for converting precursor cells into intestinal tissues through directed differentiation
US10920242B2 (en) 2011-02-25 2021-02-16 Recombinetics, Inc. Non-meiotic allele introgression
US9322006B2 (en) 2011-07-22 2016-04-26 President And Fellows Of Harvard College Evaluation and improvement of nuclease cleavage specificity
US10323236B2 (en) 2011-07-22 2019-06-18 President And Fellows Of Harvard College Evaluation and improvement of nuclease cleavage specificity
US12006520B2 (en) 2011-07-22 2024-06-11 President And Fellows Of Harvard College Evaluation and improvement of nuclease cleavage specificity
US12467086B2 (en) 2011-10-14 2025-11-11 President And Fellows Of Harvard College Sequencing by structure assembly
US11976318B2 (en) 2011-12-22 2024-05-07 President And Fellows Of Harvard College Compositions and methods for analyte detection
US12618099B2 (en) 2011-12-22 2026-05-05 President And Fellows Of Harvard College Compositions and methods for analyte detection
US11566277B2 (en) 2011-12-22 2023-01-31 President And Fellows Of Harvard College Compositions and methods for analyte detection
US11549136B2 (en) 2011-12-22 2023-01-10 President And Fellows Of Harvard College Compositions and methods for analyte detection
US11293051B2 (en) 2011-12-22 2022-04-05 President And Fellows Of Harvard College Compositions and methods for analyte detection
US11293052B2 (en) 2011-12-22 2022-04-05 President And Fellows Of Harvard College Compositions and methods for analyte detection
US11566276B2 (en) 2011-12-22 2023-01-31 President And Fellows Of Harvard College Compositions and methods for analyte detection
US11639518B2 (en) 2011-12-22 2023-05-02 President And Fellows Of Harvard College Compositions and methods for analyte detection
US11111521B2 (en) 2011-12-22 2021-09-07 President And Fellows Of Harvard College Compositions and methods for analyte detection
US10435678B2 (en) 2011-12-30 2019-10-08 Caribou Biosciences, Inc. Modified cascade ribonucleoproteins and uses thereof
US11939604B2 (en) 2011-12-30 2024-03-26 Caribou Biosciences, Inc. Modified cascade ribonucleoproteins and uses thereof
US10954498B2 (en) 2011-12-30 2021-03-23 Caribou Biosciences, Inc. Modified cascade ribonucleoproteins and uses thereof
US10711257B2 (en) 2011-12-30 2020-07-14 Caribou Biosciences, Inc. Modified cascade ribonucleoproteins and uses thereof
US9885026B2 (en) 2011-12-30 2018-02-06 Caribou Biosciences, Inc. Modified cascade ribonucleoproteins and uses thereof
US10301646B2 (en) 2012-04-25 2019-05-28 Regeneron Pharmaceuticals, Inc. Nuclease-mediated targeting with large targeting vectors
US9834786B2 (en) 2012-04-25 2017-12-05 Regeneron Pharmaceuticals, Inc. Nuclease-mediated targeting with large targeting vectors
US20210040460A1 (en) 2012-04-27 2021-02-11 Duke University Genetic correction of mutated genes
US11976307B2 (en) 2012-04-27 2024-05-07 Duke University Genetic correction of mutated genes
US10550407B2 (en) 2012-05-25 2020-02-04 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP2800811A4 (en) * 2012-05-25 2015-09-23 Univ California METHODS AND COMPOSITIONS FOR RNA-TARGETED TARGET DNA MODIFICATION AND RNA-TIED TRANSCRIPTION MODULATION
US10752920B2 (en) 2012-05-25 2020-08-25 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10358659B2 (en) 2012-05-25 2019-07-23 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11001863B2 (en) 2012-05-25 2021-05-11 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10358658B2 (en) 2012-05-25 2019-07-23 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP3401400B1 (en) 2012-05-25 2019-04-03 The Regents of The University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US10988782B2 (en) 2012-05-25 2021-04-27 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11008589B2 (en) 2012-05-25 2021-05-18 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11008590B2 (en) 2012-05-25 2021-05-18 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11028412B2 (en) 2012-05-25 2021-06-08 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10676759B2 (en) 2012-05-25 2020-06-09 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP3597749B1 (en) 2012-05-25 2023-07-26 The Regents of The University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US10669560B2 (en) 2012-05-25 2020-06-02 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10640791B2 (en) 2012-05-25 2020-05-05 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11634730B2 (en) 2012-05-25 2023-04-25 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10626419B2 (en) 2012-05-25 2020-04-21 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10612045B2 (en) 2012-05-25 2020-04-07 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10988780B2 (en) 2012-05-25 2021-04-27 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10597680B2 (en) 2012-05-25 2020-03-24 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10577631B2 (en) 2012-05-25 2020-03-03 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10570419B2 (en) 2012-05-25 2020-02-25 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10563227B2 (en) 2012-05-25 2020-02-18 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11186849B2 (en) 2012-05-25 2021-11-30 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10900054B2 (en) 2012-05-25 2021-01-26 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10351878B2 (en) 2012-05-25 2019-07-16 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10982231B2 (en) 2012-05-25 2021-04-20 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10266850B2 (en) 2012-05-25 2019-04-23 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP4289948B1 (en) 2012-05-25 2025-02-26 The Regents of the University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US10774344B1 (en) 2012-05-25 2020-09-15 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP3597749A1 (en) * 2012-05-25 2020-01-22 The Regents of The University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US10982230B2 (en) 2012-05-25 2021-04-20 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10533190B2 (en) 2012-05-25 2020-01-14 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10526619B2 (en) 2012-05-25 2020-01-07 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP2800811A1 (en) 2012-05-25 2014-11-12 The Regents of The University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US11479794B2 (en) 2012-05-25 2022-10-25 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11242543B2 (en) 2012-05-25 2022-02-08 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10519467B2 (en) 2012-05-25 2019-12-31 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10513712B2 (en) 2012-05-25 2019-12-24 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11970711B2 (en) 2012-05-25 2024-04-30 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10793878B1 (en) 2012-05-25 2020-10-06 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11274318B2 (en) 2012-05-25 2022-03-15 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10113167B2 (en) 2012-05-25 2018-10-30 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10487341B2 (en) 2012-05-25 2019-11-26 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11473108B2 (en) 2012-05-25 2022-10-18 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10301651B2 (en) 2012-05-25 2019-05-28 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11293034B2 (en) 2012-05-25 2022-04-05 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11549127B2 (en) 2012-05-25 2023-01-10 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10000772B2 (en) 2012-05-25 2018-06-19 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP2800811B1 (en) 2012-05-25 2017-05-10 The Regents of The University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US10443076B2 (en) 2012-05-25 2019-10-15 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11332761B2 (en) 2012-05-25 2022-05-17 The Regenis of Wie University of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10227611B2 (en) 2012-05-25 2019-03-12 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10428352B2 (en) 2012-05-25 2019-10-01 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US12123015B2 (en) 2012-05-25 2024-10-22 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP3401400A1 (en) * 2012-05-25 2018-11-14 The Regents of The University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US10421980B2 (en) 2012-05-25 2019-09-24 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10415061B2 (en) 2012-05-25 2019-09-17 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US12180503B2 (en) 2012-05-25 2024-12-31 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10385360B2 (en) 2012-05-25 2019-08-20 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11401532B2 (en) 2012-05-25 2022-08-02 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US12180504B2 (en) 2012-05-25 2024-12-31 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10308961B2 (en) 2012-05-25 2019-06-04 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP3241902A1 (en) * 2012-05-25 2017-11-08 The Regents of The University of California Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US11814645B2 (en) 2012-05-25 2023-11-14 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US12215343B2 (en) 2012-05-25 2025-02-04 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10407697B2 (en) 2012-05-25 2019-09-10 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US11674159B2 (en) 2012-05-25 2023-06-13 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10400253B2 (en) 2012-05-25 2019-09-03 The Regents Of The University Of California Methods and compositions or RNA-directed target DNA modification and for RNA-directed modulation of transcription
US10337029B2 (en) 2012-05-25 2019-07-02 The Regents Of The University Of California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
US20230374525A1 (en) * 2012-10-23 2023-11-23 Toolgen Incorporated Composition for cleaving a target dna comprising a guide rna specific for the target dna and cas protein-encoding nucleic acid or cas protein, and use thereof
US10851380B2 (en) 2012-10-23 2020-12-01 Toolgen Incorporated Methods for cleaving a target DNA using a guide RNA specific for the target DNA and Cas protein-encoding nucleic acid or Cas protein
US20210047648A1 (en) * 2012-10-23 2021-02-18 Toolgen Incorporated Composition for cleaving a target dna comprising a guide rna specific for the target dna and cas protein-encoding nucleic acid or cas protein, and use thereof
US12473559B2 (en) * 2012-10-23 2025-11-18 Toolgen Incorporated Cas9/RNA complexes for inducing modifications of target endogenous nucleic acid sequences in nucleuses of eukaryotic cells
EP2912175B1 (en) * 2012-10-23 2018-08-22 Toolgen Incorporated Composition for cleaving a target dna comprising a guide rna specific for the target dna and cas protein-encoding nucleic acid or cas protein, and use thereof
EP3346003B1 (en) 2012-10-23 2021-06-09 Toolgen Incorporated Composition for cleaving a target dna comprising a guide rna specific for the target dna and cas protein-encoding nucleic acid or cas protein, and use thereof
US10731181B2 (en) 2012-12-06 2020-08-04 Sigma, Aldrich Co. LLC CRISPR-based genome modification and regulation
US10745716B2 (en) 2012-12-06 2020-08-18 Sigma-Aldrich Co. Llc CRISPR-based genome modification and regulation
US12454687B2 (en) 2012-12-12 2025-10-28 The Broad Institute, Inc. Functional genomics using CRISPR-Cas systems, compositions, methods, knock out libraries and applications thereof
US10930367B2 (en) 2012-12-12 2021-02-23 The Broad Institute, Inc. Methods, models, systems, and apparatus for identifying target sequences for Cas enzymes or CRISPR-Cas systems for target sequences and conveying results thereof
EP2771468A1 (en) 2012-12-12 2014-09-03 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
EP2784162B1 (en) 2012-12-12 2015-04-08 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
US9840713B2 (en) 2012-12-12 2017-12-12 The Broad Institute Inc. CRISPR-Cas component systems, methods and compositions for sequence manipulation
US12252707B2 (en) 2012-12-12 2025-03-18 The Broad Institute, Inc. Delivery, Engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
US9822372B2 (en) 2012-12-12 2017-11-21 The Broad Institute Inc. CRISPR-Cas component systems, methods and compositions for sequence manipulation
EP2764103B1 (en) 2012-12-12 2015-08-19 The Broad Institute, Inc. Crispr-cas systems and methods for altering expression of gene products
EP2896697B1 (en) 2012-12-12 2015-09-02 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
EP2825654B1 (en) 2012-12-12 2017-04-26 The Broad Institute, Inc. Crispr-cas component systems, methods and compositions for sequence manipulation
EP2840140B1 (en) 2012-12-12 2016-11-16 The Broad Institute, Inc. Crispr-Cas component systems, methods and compositions for sequence manipulation
EP2931898B1 (en) 2012-12-12 2016-03-09 The Broad Institute, Inc. Engineering and optimization of systems, methods and compositions for sequence manipulation with functional domains
EP2898075B1 (en) 2012-12-12 2016-03-09 The Broad Institute, Inc. Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation
US11041173B2 (en) 2012-12-12 2021-06-22 The Broad Institute, Inc. Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications
EP2921557B1 (en) 2012-12-12 2016-07-13 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
US11299767B2 (en) 2013-03-12 2022-04-12 President And Fellows Of Harvard College Method for generating a three-dimensional nucleic acid containing matrix
US12264358B2 (en) 2013-03-12 2025-04-01 President And Fellows Of Harvard College Method of selectively sequencing amplicons in a biological sample
US9410198B2 (en) 2013-03-14 2016-08-09 Caribou Biosciences, Inc. Compostions and methods of nucleic acid-targeting nucleic acids
US9260752B1 (en) 2013-03-14 2016-02-16 Caribou Biosciences, Inc. Compositions and methods of nucleic acid-targeting nucleic acids
US9909122B2 (en) 2013-03-14 2018-03-06 Caribou Biosciences, Inc. Compositions and methods of nucleic acid-targeting nucleic acids
US9809814B1 (en) 2013-03-14 2017-11-07 Caribou Biosciences, Inc. Compositions and methods of nucleic acid-targeting nucleic acids
US10125361B2 (en) 2013-03-14 2018-11-13 Caribou Biosciences, Inc. Compositions and methods of nucleic acid-targeting nucleic acids
US11312953B2 (en) 2013-03-14 2022-04-26 Caribou Biosciences, Inc. Compositions and methods of nucleic acid-targeting nucleic acids
US9725714B2 (en) 2013-03-14 2017-08-08 Caribou Biosciences, Inc. Compositions and methods of nucleic acid-targeting nucleic acids
US9803194B2 (en) 2013-03-14 2017-10-31 Caribou Biosciences, Inc. Compositions and methods of nucleic acid-targeting nucleic acids
US10954522B2 (en) 2013-03-15 2021-03-23 Cibus Us Llc Methods and compositions for increasing efficiency of targeted gene modification using oligonucleotide-mediated gene repair
US9234213B2 (en) 2013-03-15 2016-01-12 System Biosciences, Llc Compositions and methods directed to CRISPR/Cas genomic engineering systems
US9738908B2 (en) 2013-03-15 2017-08-22 System Biosciences, Llc CRISPR/Cas systems for genomic modification and gene modulation
US11761011B2 (en) 2013-03-15 2023-09-19 Cibus Us Llc Methods and compositions for increasing efficiency of targeted gene modification using oligonucleotide-mediated gene repair
US9957515B2 (en) 2013-03-15 2018-05-01 Cibus Us Llc Methods and compositions for targeted gene modification
US10202619B2 (en) 2013-03-15 2019-02-12 System Biosciences, Llc Compositions and methods directed to CRISPR/Cas genomic engineering systems
US12215345B2 (en) 2013-03-19 2025-02-04 Duke University Compositions and methods for the induction and tuning of gene expression
US10975390B2 (en) 2013-04-16 2021-04-13 Regeneron Pharmaceuticals, Inc. Targeted modification of rat genome
US12037596B2 (en) 2013-04-16 2024-07-16 Regeneron Pharmaceuticals, Inc. Targeted modification of rat genome
US10385359B2 (en) 2013-04-16 2019-08-20 Regeneron Pharmaceuticals, Inc. Targeted modification of rat genome
JP2016521975A (ja) * 2013-05-15 2016-07-28 サンガモ バイオサイエンシーズ， インコーポレイテッド 遺伝的状態の処置のための方法および組成物
US10196651B2 (en) 2013-05-15 2019-02-05 Sangamo Therapeutics, Inc. Methods and compositions for treatment of a genetic condition
US10196652B2 (en) 2013-05-15 2019-02-05 Sangamo Therapeutics, Inc. Methods and compositions for treatment of a genetic condition
WO2014186686A3 (en) * 2013-05-17 2015-01-08 Two Blades Foundation Targeted mutagenesis and genome engineering in plants using rna-guided cas nucleases
WO2014194190A1 (en) * 2013-05-30 2014-12-04 The Penn State Research Foundation Gene targeting and genetic modification of plants via rna-guided genome editing
EP3603679A1 (en) * 2013-06-04 2020-02-05 President and Fellows of Harvard College Rna-guideded transcriptional regulation
US10767194B2 (en) 2013-06-04 2020-09-08 President And Fellows Of Harvard College RNA-guided transcriptional regulation
EP3003392A4 (en) * 2013-06-04 2017-05-03 President and Fellows of Harvard College Rna-guideded transcriptional regulation
EP4596565A3 (en) * 2013-06-04 2025-11-05 President And Fellows Of Harvard College Rna-guided transcriptional regulation
US11981917B2 (en) 2013-06-04 2024-05-14 President And Fellows Of Harvard College RNA-guided transcriptional regulation
US10640789B2 (en) 2013-06-04 2020-05-05 President And Fellows Of Harvard College RNA-guided transcriptional regulation
US10781444B2 (en) 2013-06-17 2020-09-22 The Broad Institute, Inc. Functional genomics using CRISPR-Cas systems, compositions, methods, screens and applications thereof
US10577630B2 (en) 2013-06-17 2020-03-03 The Broad Institute, Inc. Delivery and use of the CRISPR-Cas systems, vectors and compositions for hepatic targeting and therapy
US10711285B2 (en) 2013-06-17 2020-07-14 The Broad Institute, Inc. Optimized CRISPR-Cas double nickase systems, methods and compositions for sequence manipulation
US11008588B2 (en) 2013-06-17 2021-05-18 The Broad Institute, Inc. Delivery, engineering and optimization of tandem guide systems, methods and compositions for sequence manipulation
US12018275B2 (en) 2013-06-17 2024-06-25 The Broad Institute, Inc. Delivery and use of the CRISPR-CAS systems, vectors and compositions for hepatic targeting and therapy
US11597949B2 (en) 2013-06-17 2023-03-07 The Broad Institute, Inc. Optimized CRISPR-Cas double nickase systems, methods and compositions for sequence manipulation
US12441995B2 (en) 2013-06-17 2025-10-14 The Broad Institute, Inc. Functional genomics using CRISPR-Cas systems, compositions, methods, screens and applications thereof
US10946108B2 (en) 2013-06-17 2021-03-16 The Broad Institute, Inc. Delivery, use and therapeutic applications of the CRISPR-Cas systems and compositions for targeting disorders and diseases using viral components
US12553065B2 (en) 2013-06-17 2026-02-17 The Broad Institute, Inc. Optimized CRISPR-CAS double nickase systems, methods and compositions for sequence manipulation
US9163284B2 (en) 2013-08-09 2015-10-20 President And Fellows Of Harvard College Methods for identifying a target site of a Cas9 nuclease
US10508298B2 (en) 2013-08-09 2019-12-17 President And Fellows Of Harvard College Methods for identifying a target site of a CAS9 nuclease
US10954548B2 (en) 2013-08-09 2021-03-23 President And Fellows Of Harvard College Nuclease profiling system
US11920181B2 (en) 2013-08-09 2024-03-05 President And Fellows Of Harvard College Nuclease profiling system
US11046948B2 (en) 2013-08-22 2021-06-29 President And Fellows Of Harvard College Engineered transcription activator-like effector (TALE) domains and uses thereof
US9359599B2 (en) 2013-08-22 2016-06-07 President And Fellows Of Harvard College Engineered transcription activator-like effector (TALE) domains and uses thereof
US10227581B2 (en) 2013-08-22 2019-03-12 President And Fellows Of Harvard College Engineered transcription activator-like effector (TALE) domains and uses thereof
US10959414B2 (en) 2013-08-27 2021-03-30 Recombinetics, Inc. Efficient non-meiotic allele introgression
US11477969B2 (en) 2013-08-27 2022-10-25 Recombinetics, Inc. Efficient non-meiotic allele introgression in livestock
US9340800B2 (en) 2013-09-06 2016-05-17 President And Fellows Of Harvard College Extended DNA-sensing GRNAS
US12584118B2 (en) 2013-09-06 2026-03-24 President And Fellows Of Harvard College Cas9 variants and uses thereof
US9340799B2 (en) 2013-09-06 2016-05-17 President And Fellows Of Harvard College MRNA-sensing switchable gRNAs
US9737604B2 (en) 2013-09-06 2017-08-22 President And Fellows Of Harvard College Use of cationic lipids to deliver CAS9
US10912833B2 (en) 2013-09-06 2021-02-09 President And Fellows Of Harvard College Delivery of negatively charged proteins using cationic lipids
US10858639B2 (en) 2013-09-06 2020-12-08 President And Fellows Of Harvard College CAS9 variants and uses thereof
US9999671B2 (en) 2013-09-06 2018-06-19 President And Fellows Of Harvard College Delivery of negatively charged proteins using cationic lipids
US9228207B2 (en) 2013-09-06 2016-01-05 President And Fellows Of Harvard College Switchable gRNAs comprising aptamers
US11299755B2 (en) 2013-09-06 2022-04-12 President And Fellows Of Harvard College Switchable CAS9 nucleases and uses thereof
US10682410B2 (en) 2013-09-06 2020-06-16 President And Fellows Of Harvard College Delivery system for functional nucleases
US9322037B2 (en) 2013-09-06 2016-04-26 President And Fellows Of Harvard College Cas9-FokI fusion proteins and uses thereof
US12473573B2 (en) 2013-09-06 2025-11-18 President And Fellows Of Harvard College Switchable Cas9 nucleases and uses thereof
US9388430B2 (en) 2013-09-06 2016-07-12 President And Fellows Of Harvard College Cas9-recombinase fusion proteins and uses thereof
US9526784B2 (en) 2013-09-06 2016-12-27 President And Fellows Of Harvard College Delivery system for functional nucleases
US10597679B2 (en) 2013-09-06 2020-03-24 President And Fellows Of Harvard College Switchable Cas9 nucleases and uses thereof
US12559737B2 (en) 2013-09-06 2026-02-24 President And Fellows Of Harvard College Cas9 variants and uses thereof
US11920128B2 (en) 2013-09-18 2024-03-05 Kymab Limited Methods, cells and organisms
US11149267B2 (en) 2013-10-28 2021-10-19 The Broad Institute, Inc. Functional genomics using CRISPR-Cas systems, compositions, methods, screens and applications thereof
WO2015065964A1 (en) 2013-10-28 2015-05-07 The Broad Institute Inc. Functional genomics using crispr-cas systems, compositions, methods, screens and applications thereof
US9834791B2 (en) 2013-11-07 2017-12-05 Editas Medicine, Inc. CRISPR-related methods and compositions with governing gRNAS
US10640788B2 (en) 2013-11-07 2020-05-05 Editas Medicine, Inc. CRISPR-related methods and compositions with governing gRNAs
US11390887B2 (en) 2013-11-07 2022-07-19 Editas Medicine, Inc. CRISPR-related methods and compositions with governing gRNAS
US10190137B2 (en) 2013-11-07 2019-01-29 Editas Medicine, Inc. CRISPR-related methods and compositions with governing gRNAS
US9228208B2 (en) 2013-12-11 2016-01-05 Regeneron Pharmaceuticals, Inc. Methods and compositions for the targeted modification of a genome
US11820997B2 (en) 2013-12-11 2023-11-21 Regeneron Pharmaceuticals, Inc. Methods and compositions for the targeted modification of a genome
US10208317B2 (en) 2013-12-11 2019-02-19 Regeneron Pharmaceuticals, Inc. Methods and compositions for the targeted modification of a mouse embryonic stem cell genome
US10711280B2 (en) 2013-12-11 2020-07-14 Regeneron Pharmaceuticals, Inc. Methods and compositions for the targeted modification of a mouse ES cell genome
US11053481B2 (en) 2013-12-12 2021-07-06 President And Fellows Of Harvard College Fusions of Cas9 domains and nucleic acid-editing domains
US10851357B2 (en) 2013-12-12 2020-12-01 The Broad Institute, Inc. Compositions and methods of use of CRISPR-Cas systems in nucleotide repeat disorders
US12251450B2 (en) 2013-12-12 2025-03-18 The Broad Institute, Inc. Delivery, use and therapeutic applications of the CRISPR-Cas systems and compositions for HBV and viral diseases and disorders
US12258595B2 (en) 2013-12-12 2025-03-25 The Broad Institute, Inc. Systems, methods and compositions for sequence manipulation with optimized functional CRISPR-Cas systems
WO2015089486A2 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Systems, methods and compositions for sequence manipulation with optimized functional crispr-cas systems
EP3540051A1 (en) 2013-12-12 2019-09-18 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
US10377998B2 (en) 2013-12-12 2019-08-13 The Broad Institute, Inc. CRISPR-CAS systems and methods for altering expression of gene products, structural information and inducible modular CAS enzymes
EP4219699A1 (en) 2013-12-12 2023-08-02 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions with new architectures for sequence manipulation
US11155795B2 (en) 2013-12-12 2021-10-26 The Broad Institute, Inc. CRISPR-Cas systems, crystal structure and uses thereof
EP3653704A1 (en) 2013-12-12 2020-05-20 The Broad Institute, Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
WO2015089364A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Crystal structure of a crispr-cas system, and uses thereof
US11149259B2 (en) 2013-12-12 2021-10-19 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products, structural information and inducible modular Cas enzymes
EP3653703A1 (en) 2013-12-12 2020-05-20 The Broad Institute, Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
EP3653229A1 (en) 2013-12-12 2020-05-20 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for genome editing
US12410435B2 (en) 2013-12-12 2025-09-09 The Broad Institute, Inc. Compositions and methods of use of CRISPR-Cas systems in nucleotide repeat disorders
US12421506B2 (en) 2013-12-12 2025-09-23 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions with new architectures for sequence manipulation
WO2015089465A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
US10550372B2 (en) 2013-12-12 2020-02-04 The Broad Institute, Inc. Systems, methods and compositions for sequence manipulation with optimized functional CRISPR-Cas systems
WO2015089351A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
EP4183876A1 (en) 2013-12-12 2023-05-24 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
US11407985B2 (en) 2013-12-12 2022-08-09 The Broad Institute, Inc. Delivery, use and therapeutic applications of the CRISPR-Cas systems and compositions for genome editing
US9068179B1 (en) 2013-12-12 2015-06-30 President And Fellows Of Harvard College Methods for correcting presenilin point mutations
US10465176B2 (en) 2013-12-12 2019-11-05 President And Fellows Of Harvard College Cas variants for gene editing
US12215365B2 (en) 2013-12-12 2025-02-04 President And Fellows Of Harvard College Cas variants for gene editing
US11597919B2 (en) 2013-12-12 2023-03-07 The Broad Institute Inc. Systems, methods and compositions for sequence manipulation with optimized functional CRISPR-Cas systems
US11124782B2 (en) 2013-12-12 2021-09-21 President And Fellows Of Harvard College Cas variants for gene editing
EP3470089A1 (en) 2013-12-12 2019-04-17 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using particle delivery components
WO2015089419A2 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using particle delivery components
US9840699B2 (en) 2013-12-12 2017-12-12 President And Fellows Of Harvard College Methods for nucleic acid editing
WO2015089354A1 (en) 2013-12-12 2015-06-18 The Broad Institute Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
US10711284B2 (en) 2014-02-11 2020-07-14 The Regents Of The University Of Colorado CRISPR enabled multiplexed genome engineering
US10669559B2 (en) 2014-02-11 2020-06-02 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US10731180B2 (en) 2014-02-11 2020-08-04 The Regents Of The University Of Colorado CRISPR enabled multiplexed genome engineering
US9982278B2 (en) 2014-02-11 2018-05-29 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US11795479B2 (en) 2014-02-11 2023-10-24 The Regents Of The University Of Colorado CRISPR enabled multiplexed genome engineering
US11639511B2 (en) 2014-02-11 2023-05-02 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US10240167B2 (en) 2014-02-11 2019-03-26 Inscripta, Inc. CRISPR enabled multiplexed genome engineering
US10266849B2 (en) 2014-02-11 2019-04-23 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US11078498B2 (en) 2014-02-11 2021-08-03 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US11345933B2 (en) 2014-02-11 2022-05-31 The Regents Of The University Of Colorado CRISPR enabled multiplexed genome engineering
US10351877B2 (en) 2014-02-11 2019-07-16 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US10465207B2 (en) 2014-02-11 2019-11-05 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US10435715B2 (en) 2014-02-11 2019-10-08 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
US11702677B2 (en) 2014-02-11 2023-07-18 The Regents Of The University Of Colorado CRISPR enabled multiplexed genome engineering
US10364442B2 (en) 2014-02-11 2019-07-30 The Regents Of The University Of Colorado, A Body Corporate CRISPR enabled multiplexed genome engineering
EP3514246A1 (en) 2014-02-27 2019-07-24 The Broad Institute Inc. T cell balance gene expression and methods of use thereof
US11209440B2 (en) 2014-02-27 2021-12-28 The Broad Institute, Inc. T cell balance gene expression, compositions of matters and methods of use thereof
US11028388B2 (en) 2014-03-05 2021-06-08 Editas Medicine, Inc. CRISPR/Cas-related methods and compositions for treating Usher syndrome and retinitis pigmentosa
US11268086B2 (en) 2014-03-10 2022-03-08 Editas Medicine, Inc. CRISPR/CAS-related methods and compositions for treating Leber's Congenital Amaurosis 10 (LCA10)
US9938521B2 (en) 2014-03-10 2018-04-10 Editas Medicine, Inc. CRISPR/CAS-related methods and compositions for treating leber's congenital amaurosis 10 (LCA10)
US11141493B2 (en) 2014-03-10 2021-10-12 Editas Medicine, Inc. Compositions and methods for treating CEP290-associated disease
US12234449B2 (en) 2014-03-10 2025-02-25 Editas Medicine, Inc. CRISPR/Cas-related methods and compositions for treating Leber's congenital amaurosis 10 (LCA10)
US11339437B2 (en) 2014-03-10 2022-05-24 Editas Medicine, Inc. Compositions and methods for treating CEP290-associated disease
US10253312B2 (en) 2014-03-10 2019-04-09 Editas Medicine, Inc. CRISPR/CAS-related methods and compositions for treating Leber's Congenital Amaurosis 10 (LCA10)
EP4357452A2 (en) 2014-03-14 2024-04-24 Cibus US LLC Methods and compositions for increasing efficiency of targeted gene modification using oligonucleotide-mediated gene repair
WO2015139008A1 (en) 2014-03-14 2015-09-17 Cibus Us Llc Methods and compositions for increasing efficiency of targeted gene modification using oligonucleotide-mediated gene repair
US11242525B2 (en) 2014-03-26 2022-02-08 Editas Medicine, Inc. CRISPR/CAS-related methods and compositions for treating sickle cell disease
US12460231B2 (en) 2014-04-02 2025-11-04 Editas Medicine, Inc. Crispr/CAS-related methods and compositions for treating primary open angle glaucoma
US12241090B2 (en) 2014-05-28 2025-03-04 Children's Hospital Medical Center Methods and systems for converting precursor cells into gastric tissues through directed differentiation
JP2017518075A (ja) * 2014-05-30 2017-07-06 ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー 潜伏性ウイルス感染を処置するための組成物および方法
EP3708671A1 (en) 2014-06-06 2020-09-16 Regeneron Pharmaceuticals, Inc. Methods and compositions for modifying a targeted locus
WO2015188109A1 (en) 2014-06-06 2015-12-10 Regeneron Pharmaceuticals, Inc. Methods and compositions for modifying a targeted locus
EP3354732A1 (en) 2014-06-23 2018-08-01 Regeneron Pharmaceuticals, Inc. Nuclease-mediated dna assembly
EP3708663A1 (en) 2014-06-23 2020-09-16 Regeneron Pharmaceuticals, Inc. Nuclease-mediated dna assembly
JP2017518758A (ja) * 2014-06-26 2017-07-13 リジェネロン・ファーマシューティカルズ・インコーポレイテッドＲｅｇｅｎｅｒｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 標的化された遺伝子修飾のための方法及び組成物、並びに使用方法
KR20170023118A (ko) * 2014-06-26 2017-03-02 리제너론 파마슈티칼스 인코포레이티드 표적화된 유전자 변형을 위한 방법 및 그 조성물, 및 사용 방법
WO2015200805A2 (en) 2014-06-26 2015-12-30 Regeneron Pharmaceuticals, Inc. Methods and compositions for targeted genetic modifications and methods of use
EP3461885A1 (en) 2014-06-26 2019-04-03 Regeneron Pharmaceuticals, Inc. Methods and compositions for targeted genetic modifications and methods of use
KR102386101B1 (ko) 2014-06-26 2022-04-14 리제너론 파마슈티칼스 인코포레이티드 표적화된 유전자 변형을 위한 방법 및 그 조성물, 및 사용 방법
US10793874B2 (en) 2014-06-26 2020-10-06 Regeneron Pharmaceuticals, Inc. Methods and compositions for targeted genetic modifications and methods of use
US12331347B2 (en) 2014-07-11 2025-06-17 President And Fellows Of Harvard College Methods for high-throughput labelling and detection of biological features in situ using microscopy
US10704062B2 (en) 2014-07-30 2020-07-07 President And Fellows Of Harvard College CAS9 proteins including ligand-dependent inteins
US12398406B2 (en) 2014-07-30 2025-08-26 President And Fellows Of Harvard College CAS9 proteins including ligand-dependent inteins
US10077453B2 (en) 2014-07-30 2018-09-18 President And Fellows Of Harvard College CAS9 proteins including ligand-dependent inteins
US11578343B2 (en) 2014-07-30 2023-02-14 President And Fellows Of Harvard College CAS9 proteins including ligand-dependent inteins
EP3686279A1 (en) 2014-08-17 2020-07-29 The Broad Institute, Inc. Genome editing using cas9 nickases
WO2016036754A1 (en) 2014-09-02 2016-03-10 The Regents Of The University Of California Methods and compositions for rna-directed target dna modification
US11124796B2 (en) 2014-09-24 2021-09-21 The Broad Institute, Inc. Delivery, use and therapeutic applications of the CRISPR-Cas systems and compositions for modeling competition of multiple cancer mutations in vivo
US11459557B2 (en) 2014-09-24 2022-10-04 The Broad Institute, Inc. Use and production of CHD8+/− transgenic animals with behavioral phenotypes characteristic of autism spectrum disorder
US11197467B2 (en) 2014-09-24 2021-12-14 The Broad Institute, Inc. Delivery, use and therapeutic applications of the CRISPR-cas systems and compositions for modeling mutations in leukocytes
WO2016049251A1 (en) 2014-09-24 2016-03-31 The Broad Institute Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for modeling mutations in leukocytes
WO2016049163A2 (en) 2014-09-24 2016-03-31 The Broad Institute Inc. Use and production of chd8+/- transgenic animals with behavioral phenotypes characteristic of autism spectrum disorder
US11001829B2 (en) 2014-09-25 2021-05-11 The Broad Institute, Inc. Functional screening with optimized functional CRISPR-Cas systems
US12201699B2 (en) 2014-10-10 2025-01-21 Editas Medicine, Inc. Compositions and methods for promoting homology directed repair
WO2016061374A1 (en) 2014-10-15 2016-04-21 Regeneron Pharmaceuticals, Inc. Methods and compositions for generating or maintaining pluripotent cells
EP3561052A1 (en) 2014-10-15 2019-10-30 Regeneron Pharmaceuticals, Inc. Methods and compositions for generating or maintaining pluripotent cells
WO2016069591A2 (en) 2014-10-27 2016-05-06 The Broad Institute Inc. Compositions, methods and use of synthetic lethal screening
US11680268B2 (en) 2014-11-07 2023-06-20 Editas Medicine, Inc. Methods for improving CRISPR/Cas-mediated genome-editing
US10457960B2 (en) 2014-11-21 2019-10-29 Regeneron Pharmaceuticals, Inc. Methods and compositions for targeted genetic modification using paired guide RNAs
WO2016081923A2 (en) 2014-11-21 2016-05-26 Regeneron Pharmaceuticals, Inc. METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATION USING PAIRED GUIDE RNAs
US11697828B2 (en) 2014-11-21 2023-07-11 Regeneran Pharmaceuticals, Inc. Methods and compositions for targeted genetic modification using paired guide RNAs
EP3521437A1 (en) 2014-11-21 2019-08-07 Regeneron Pharmaceuticals, Inc. Methods and compositions for targeted genetic modification using paired guide rnas
EP3626832A2 (en) 2014-11-25 2020-03-25 The Brigham and Women's Hospital, Inc. Method of identifying and treating a person having a predisposition to or afflicted with a cardiometabolic disease
WO2016086197A1 (en) 2014-11-25 2016-06-02 The Brigham And Women's Hospital, Inc. Method of identifying and treating a person having a predisposition to or afflicted with a cardiometabolic disease
WO2016086227A2 (en) 2014-11-26 2016-06-02 The Regents Of The University Of California Therapeutic compositions comprising transcription factors and methods of making and using the same
WO2016083811A1 (en) 2014-11-27 2016-06-02 Imperial Innovations Limited Genome editing methods
US10337001B2 (en) 2014-12-03 2019-07-02 Agilent Technologies, Inc. Guide RNA with chemical modifications
US10900034B2 (en) 2014-12-03 2021-01-26 Agilent Technologies, Inc. Guide RNA with chemical modifications
US11234418B2 (en) 2014-12-10 2022-02-01 Regents Of The University Of Minnesota Genetically modified cells, tissues, and organs for treating disease
US10993419B2 (en) 2014-12-10 2021-05-04 Regents Of The University Of Minnesota Genetically modified cells, tissues, and organs for treating disease
US10278372B2 (en) 2014-12-10 2019-05-07 Regents Of The University Of Minnesota Genetically modified cells, tissues, and organs for treating disease
US9888673B2 (en) 2014-12-10 2018-02-13 Regents Of The University Of Minnesota Genetically modified cells, tissues, and organs for treating disease
US12465029B2 (en) 2014-12-10 2025-11-11 Regents Of The University Of Minnesota Genetically modified cells, tissues, and organs for treating disease
EP3889260A1 (en) 2014-12-12 2021-10-06 The Broad Institute, Inc. Protected guide rnas (pgrnas)
US12571005B2 (en) 2014-12-12 2026-03-10 The Broad Institute, Inc. Protected guide RNAs (pgRNAs)
WO2016094880A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Delivery, use and therapeutic applications of crispr systems and compositions for genome editing as to hematopoietic stem cells (hscs)
WO2016094872A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Dead guides for crispr transcription factors
WO2016094874A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Escorted and functionalized guides for crispr-cas systems
US11624078B2 (en) 2014-12-12 2023-04-11 The Broad Institute, Inc. Protected guide RNAS (pgRNAS)
US10696986B2 (en) 2014-12-12 2020-06-30 The Board Institute, Inc. Protected guide RNAS (PGRNAS)
EP3985115A1 (en) 2014-12-12 2022-04-20 The Broad Institute, Inc. Protected guide rnas (pgrnas)
WO2016094867A1 (en) 2014-12-12 2016-06-16 The Broad Institute Inc. Protected guide rnas (pgrnas)
JP2017538425A (ja) * 2014-12-16 2017-12-28 ダニスコ・ユーエス・インク 真菌ゲノム改変システムおよび使用方法
JP2017537647A (ja) * 2014-12-16 2017-12-21 ダニスコ・ユーエス・インク 真菌ゲノム改変システムおよび使用方法
JP2018504895A (ja) * 2014-12-16 2018-02-22 ダニスコ・ユーエス・インク 真菌ゲノム改変システムおよび使用方法
WO2016100857A1 (en) 2014-12-19 2016-06-23 Regeneron Pharmaceuticals, Inc. Stem cells for modeling type 2 diabetes
WO2016100974A1 (en) 2014-12-19 2016-06-23 The Broad Institute Inc. Unbiased identification of double-strand breaks and genomic rearrangement by genome-wide insert capture sequencing
EP3653048A1 (en) 2014-12-19 2020-05-20 Regeneron Pharmaceuticals, Inc. Methods and compositions for targeted genetic modification through single-step multiple targeting
WO2016106236A1 (en) 2014-12-23 2016-06-30 The Broad Institute Inc. Rna-targeting system
US12215326B2 (en) 2014-12-23 2025-02-04 The Broad Institute, Inc. RNA-targeting system
US12435320B2 (en) 2014-12-24 2025-10-07 The Broad Institute, Inc. CRISPR having or associated with destabilization domains
WO2016106244A1 (en) 2014-12-24 2016-06-30 The Broad Institute Inc. Crispr having or associated with destabilization domains
EP3702456A1 (en) 2014-12-24 2020-09-02 The Broad Institute, Inc. Crispr having or associated with destabilization domains
WO2016108926A1 (en) 2014-12-30 2016-07-07 The Broad Institute Inc. Crispr mediated in vivo modeling and genetic screening of tumor growth and metastasis
US12116619B2 (en) 2014-12-30 2024-10-15 The Broad Institute, Inc. CRISPR mediated in vivo modeling and genetic screening of tumor growth and metastasis
US11236364B2 (en) 2015-01-28 2022-02-01 Caribou Biosciences, Inc. CRISPR hybrid DNA/RNA polynucleotides and methods of use
US11459588B2 (en) 2015-01-28 2022-10-04 Caribou Biosciences, Inc. Methods of use of CRISPR CPF1 hybrid DNA/RNA polynucleotides
RU2713328C2 (ru) * 2015-01-28 2020-02-04 Пайонир Хай-Бред Интернэшнл, Инк. Гибридные днк/рнк-полинуклеотиды crispr и способы применения
US10519468B2 (en) 2015-01-28 2019-12-31 Pioneer Hi-Bred International, Inc. Cells containing CRISPR hybrid DNA/RNA polynucleotides
US10988781B2 (en) 2015-01-28 2021-04-27 Caribou Biosciences, Inc. Method of target cleaving using CRISPR hybrid DNA/RNA polynucleotides
US12215366B2 (en) 2015-02-09 2025-02-04 Duke University Compositions and methods for epigenome editing
WO2016138488A2 (en) 2015-02-26 2016-09-01 The Broad Institute Inc. T cell balance gene expression, compositions of matters and methods of use thereof
US11427869B2 (en) 2015-02-26 2022-08-30 The Broad Institute, Inc. T cell balance gene expression, compositions of matters and methods of use thereof
WO2016138574A1 (en) 2015-03-02 2016-09-09 Sinai Health System Homologous recombination factors
US11535846B2 (en) 2015-04-06 2022-12-27 The Board Of Trustees Of The Leland Stanford Junior University Chemically modified guide RNAS for CRISPR/Cas-mediated gene regulation
US11851652B2 (en) 2015-04-06 2023-12-26 The Board Of Trustees Of The Leland Stanford Junior Compositions comprising chemically modified guide RNAs for CRISPR/Cas-mediated editing of HBB
US11306309B2 (en) 2015-04-06 2022-04-19 The Board Of Trustees Of The Leland Stanford Junior University Chemically modified guide RNAs for CRISPR/CAS-mediated gene regulation
US11180793B2 (en) 2015-04-24 2021-11-23 Editas Medicine, Inc. Evaluation of Cas9 molecule/guide RNA molecule complexes
US11642363B2 (en) 2015-05-06 2023-05-09 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US12514867B2 (en) 2015-05-06 2026-01-06 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US12226430B2 (en) 2015-05-06 2025-02-18 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US10624349B2 (en) 2015-05-06 2020-04-21 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US11547716B2 (en) 2015-05-06 2023-01-10 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US11400110B2 (en) 2015-05-06 2022-08-02 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US10524477B2 (en) 2015-05-06 2020-01-07 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US10582712B2 (en) 2015-05-06 2020-03-10 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US11612617B2 (en) 2015-05-06 2023-03-28 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US11517582B2 (en) 2015-05-06 2022-12-06 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US12502401B2 (en) 2015-05-06 2025-12-23 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US11844760B2 (en) 2015-05-06 2023-12-19 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US10561148B2 (en) 2015-05-06 2020-02-18 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US10463049B2 (en) 2015-05-06 2019-11-05 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US12514869B2 (en) 2015-05-06 2026-01-06 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US11147830B2 (en) 2015-05-06 2021-10-19 Snipr Technologies Limited Altering microbial populations and modifying microbiota
US10506812B2 (en) 2015-05-06 2019-12-17 Snipr Technologies Limited Altering microbial populations and modifying microbiota
WO2016182893A1 (en) 2015-05-08 2016-11-17 Teh Broad Institute Inc. Functional genomics using crispr-cas systems for saturating mutagenesis of non-coding elements, compositions, methods, libraries and applications thereof
US11390884B2 (en) 2015-05-11 2022-07-19 Editas Medicine, Inc. Optimized CRISPR/cas9 systems and methods for gene editing in stem cells
US11911415B2 (en) 2015-06-09 2024-02-27 Editas Medicine, Inc. CRISPR/Cas-related methods and compositions for improving transplantation
US11643669B2 (en) 2015-06-17 2023-05-09 Massachusetts Institute Of Technology CRISPR mediated recording of cellular events
WO2016205728A1 (en) 2015-06-17 2016-12-22 Massachusetts Institute Of Technology Crispr mediated recording of cellular events
WO2016205764A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Novel crispr enzymes and systems
EP4159856A1 (en) 2015-06-18 2023-04-05 The Broad Institute, Inc. Novel crispr enzymes and systems
US11180751B2 (en) 2015-06-18 2021-11-23 The Broad Institute, Inc. CRISPR enzymes and systems
WO2016205745A2 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Cell sorting
US11773412B2 (en) 2015-06-18 2023-10-03 The Broad Institute, Inc. Crispr enzymes and systems
EP3666895A1 (en) 2015-06-18 2020-06-17 The Broad Institute, Inc. Novel crispr enzymes and systems
US10494621B2 (en) 2015-06-18 2019-12-03 The Broad Institute, Inc. Crispr enzyme mutations reducing off-target effects
US11236327B2 (en) 2015-06-18 2022-02-01 The Broad Institute, Inc. Cell sorting
US11578312B2 (en) 2015-06-18 2023-02-14 The Broad Institute Inc. Engineering and optimization of systems, methods, enzymes and guide scaffolds of CAS9 orthologs and variants for sequence manipulation
US12123032B2 (en) 2015-06-18 2024-10-22 The Broad Institute, Inc. CRISPR enzyme mutations reducing off-target effects
US10876100B2 (en) 2015-06-18 2020-12-29 The Broad Institute, Inc. Crispr enzyme mutations reducing off-target effects
US20180127745A1 (en) * 2015-06-18 2018-05-10 The Broad Institute Inc. Cell sorting
US11060115B2 (en) 2015-06-18 2021-07-13 The Broad Institute, Inc. CRISPR enzymes and systems
US12168789B2 (en) 2015-06-18 2024-12-17 The Broad Institute, Inc. Engineering and optimization of systems, methods, enzymes and guide scaffolds of CAS9 orthologs and variants for sequence manipulation
US11421250B2 (en) 2015-06-18 2022-08-23 The Broad Institute, Inc. CRISPR enzymes and systems
US11414657B2 (en) 2015-06-29 2022-08-16 Ionis Pharmaceuticals, Inc. Modified CRISPR RNA and modified single CRISPR RNA and uses thereof
US11642374B2 (en) 2015-07-31 2023-05-09 Intima Bioscience, Inc. Intracellular genomic transplant and methods of therapy
US11903966B2 (en) 2015-07-31 2024-02-20 Regents Of The University Of Minnesota Intracellular genomic transplant and methods of therapy
US11147837B2 (en) 2015-07-31 2021-10-19 Regents Of The University Of Minnesota Modified cells and methods of therapy
US11925664B2 (en) 2015-07-31 2024-03-12 Intima Bioscience, Inc. Intracellular genomic transplant and methods of therapy
US11642375B2 (en) 2015-07-31 2023-05-09 Intima Bioscience, Inc. Intracellular genomic transplant and methods of therapy
US10406177B2 (en) 2015-07-31 2019-09-10 Regents Of The University Of Minnesota Modified cells and methods of therapy
US11583556B2 (en) 2015-07-31 2023-02-21 Regents Of The University Of Minnesota Modified cells and methods of therapy
US11266692B2 (en) 2015-07-31 2022-03-08 Regents Of The University Of Minnesota Intracellular genomic transplant and methods of therapy
US10166255B2 (en) 2015-07-31 2019-01-01 Regents Of The University Of Minnesota Intracellular genomic transplant and methods of therapy
EP4512819A2 (en) 2015-08-12 2025-02-26 The General Hospital Corporation Compositions and methods that promote hypoxia or the hypoxia response for treatment and prevention of mitochondrial dysfunction and oxidative stress disorders
WO2017027910A1 (en) 2015-08-14 2017-02-23 The University Of Sydney Connexin 45 inhibition for therapy
EP4043074A1 (en) 2015-08-14 2022-08-17 The University of Sydney Connexin 45 inhibition for therapy
US11214800B2 (en) 2015-08-18 2022-01-04 The Broad Institute, Inc. Methods and compositions for altering function and structure of chromatin loops and/or domains
US11427817B2 (en) 2015-08-25 2022-08-30 Duke University Compositions and methods of improving specificity in genomic engineering using RNA-guided endonucleases
US11667911B2 (en) 2015-09-24 2023-06-06 Editas Medicine, Inc. Use of exonucleases to improve CRISPR/CAS-mediated genome editing
WO2017069958A2 (en) 2015-10-09 2017-04-27 The Brigham And Women's Hospital, Inc. Modulation of novel immune checkpoint targets
US11421251B2 (en) 2015-10-13 2022-08-23 Duke University Genome engineering with type I CRISPR systems in eukaryotic cells
WO2017070605A1 (en) 2015-10-22 2017-04-27 The Broad Institute Inc. Type vi-b crispr enzymes and systems
US12234454B2 (en) 2015-10-22 2025-02-25 The Broad Institute, Inc. Crispr enzymes and systems
US12215318B2 (en) 2015-10-22 2025-02-04 The Broad Institute, Inc. Crispr enzymes and systems
US12043852B2 (en) 2015-10-23 2024-07-23 President And Fellows Of Harvard College Evolved Cas9 proteins for gene editing
US12344869B2 (en) 2015-10-23 2025-07-01 President And Fellows Of Harvard College Nucleobase editors and uses thereof
US10167457B2 (en) 2015-10-23 2019-01-01 President And Fellows Of Harvard College Nucleobase editors and uses thereof
EP3159407A1 (en) 2015-10-23 2017-04-26 Silence Therapeutics (London) Ltd Guide rnas, methods and uses
US11214780B2 (en) 2015-10-23 2022-01-04 President And Fellows Of Harvard College Nucleobase editors and uses thereof
WO2017074788A1 (en) 2015-10-27 2017-05-04 The Broad Institute Inc. Compositions and methods for targeting cancer-specific sequence variations
WO2017075465A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting gata3
US11180730B2 (en) 2015-10-28 2021-11-23 The Broad Institute, Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting GATA3
US11186825B2 (en) 2015-10-28 2021-11-30 The Broad Institute, Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting POU2AF1
WO2017075294A1 (en) 2015-10-28 2017-05-04 The Board Institute Inc. Assays for massively combinatorial perturbation profiling and cellular circuit reconstruction
WO2017075478A2 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by use of immune cell gene signatures
WO2017075451A1 (en) 2015-10-28 2017-05-04 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses by detecting and targeting pou2af1
US11092607B2 (en) 2015-10-28 2021-08-17 The Board Institute, Inc. Multiplex analysis of single cell constituents
US11542554B2 (en) 2015-11-03 2023-01-03 President And Fellows Of Harvard College Method and apparatus for volumetric imaging
US10669320B2 (en) 2015-11-18 2020-06-02 The Regents Of The University Of Michigan Mps1 and KNL1 phosphorylation system
US12454559B2 (en) 2015-11-18 2025-10-28 The Regents Of The University Of Michigan Activating mitotic checkpoint control mechanisms
US11884717B2 (en) 2015-11-19 2024-01-30 The Brigham And Women's Hospital, Inc. Method of treating autoimmune disease with lymphocyte antigen CD5-like (CD5L) protein
US11001622B2 (en) 2015-11-19 2021-05-11 The Brigham And Women's Hospital, Inc. Method of treating autoimmune disease with lymphocyte antigen CD5-like (CD5L) protein
WO2017087708A1 (en) 2015-11-19 2017-05-26 The Brigham And Women's Hospital, Inc. Lymphocyte antigen cd5-like (cd5l)-interleukin 12b (p40) heterodimers in immunity
JP2022081503A (ja) * 2015-11-23 2022-05-31 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア ＣＲＩＳＰＲ／Ｃａｓ９の核送達を通じた細胞ＲＮＡの追跡と操作
US11667903B2 (en) 2015-11-23 2023-06-06 The Regents Of The University Of California Tracking and manipulating cellular RNA via nuclear delivery of CRISPR/CAS9
JP2019500899A (ja) * 2015-11-23 2019-01-17 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア ＣＲＩＳＰＲ／Ｃａｓ９の核送達を通じた細胞ＲＮＡの追跡と操作
EP4219689A2 (en) 2015-12-30 2023-08-02 Novartis AG Immune effector cell therapies with enhanced efficacy
WO2017114497A1 (en) 2015-12-30 2017-07-06 Novartis Ag Immune effector cell therapies with enhanced efficacy
US11542515B2 (en) 2016-02-09 2023-01-03 Cibus Us Llc Methods and compositions for increasing efficiency of targeted gene modification using oligonucleotide-mediated gene repair
WO2017147196A1 (en) 2016-02-22 2017-08-31 Massachusetts Institute Of Technology Methods for identifying and modulating immune phenotypes
EP3219799A1 (en) 2016-03-17 2017-09-20 IMBA-Institut für Molekulare Biotechnologie GmbH Conditional crispr sgrna expression
WO2017161325A1 (en) 2016-03-17 2017-09-21 Massachusetts Institute Of Technology Methods for identifying and modulating co-occurant cellular phenotypes
WO2017158153A1 (en) 2016-03-17 2017-09-21 Imba - Institut Für Molekulare Biotechnologie Gmbh Conditional crispr sgrna expression
US11427861B2 (en) 2016-03-17 2022-08-30 Massachusetts Institute Of Technology Methods for identifying and modulating co-occurant cellular phenotypes
US11597924B2 (en) 2016-03-25 2023-03-07 Editas Medicine, Inc. Genome editing systems comprising repair-modulating enzyme molecules and methods of their use
US11512311B2 (en) 2016-03-25 2022-11-29 Editas Medicine, Inc. Systems and methods for treating alpha 1-antitrypsin (A1AT) deficiency
US12428631B2 (en) 2016-04-13 2025-09-30 Duke University CRISPR/Cas9-based repressors for silencing gene targets in vivo and methods of use
US12049651B2 (en) 2016-04-13 2024-07-30 Editas Medicine, Inc. Cas9 fusion molecules, gene editing systems, and methods of use thereof
US11236313B2 (en) 2016-04-13 2022-02-01 Editas Medicine, Inc. Cas9 fusion molecules, gene editing systems, and methods of use thereof
US11713485B2 (en) 2016-04-25 2023-08-01 President And Fellows Of Harvard College Hybridization chain reaction methods for in situ molecular detection
EP4368637A2 (en) 2016-05-20 2024-05-15 Regeneron Pharmaceuticals, Inc. Methods for breaking immunological tolerance using multiple guide rnas
WO2017201476A1 (en) 2016-05-20 2017-11-23 Regeneron Pharmaceuticals, Inc. Methods for breaking immunological tolerance using multiple guide rnas
US11291723B2 (en) 2016-06-05 2022-04-05 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US12318445B2 (en) 2016-06-05 2025-06-03 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US11471530B2 (en) 2016-06-05 2022-10-18 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10603379B2 (en) 2016-06-05 2020-03-31 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10596255B2 (en) 2016-06-05 2020-03-24 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10195273B2 (en) 2016-06-05 2019-02-05 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10300139B2 (en) 2016-06-05 2019-05-28 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US11141481B2 (en) 2016-06-05 2021-10-12 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10363308B2 (en) 2016-06-05 2019-07-30 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US11351252B2 (en) 2016-06-05 2022-06-07 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US11471531B2 (en) 2016-06-05 2022-10-18 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10765740B2 (en) 2016-06-05 2020-09-08 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10953090B2 (en) 2016-06-05 2021-03-23 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10300138B2 (en) 2016-06-05 2019-05-28 Snipr Technologies Limited Selectively altering microbiota for immune modulation
US10767175B2 (en) 2016-06-08 2020-09-08 Agilent Technologies, Inc. High specificity genome editing using chemically modified guide RNAs
WO2017219027A1 (en) 2016-06-17 2017-12-21 The Broad Institute Inc. Type vi crispr orthologs and systems
US12612620B2 (en) 2016-06-17 2026-04-28 The Broad Institute, Inc. Type VI CRISPR orthologs and systems
US11788083B2 (en) 2016-06-17 2023-10-17 The Broad Institute, Inc. Type VI CRISPR orthologs and systems
US10017760B2 (en) 2016-06-24 2018-07-10 Inscripta, Inc. Methods for generating barcoded combinatorial libraries
US10287575B2 (en) 2016-06-24 2019-05-14 The Regents Of The University Of Colorado, A Body Corporate Methods for generating barcoded combinatorial libraries
US11584928B2 (en) 2016-06-24 2023-02-21 The Regents Of The University Of Colorado, A Body Corporate Methods for generating barcoded combinatorial libraries
US10294473B2 (en) 2016-06-24 2019-05-21 The Regents Of The University Of Colorado, A Body Corporate Methods for generating barcoded combinatorial libraries
US12595478B2 (en) 2016-06-29 2026-04-07 The Broad Institute, Inc. Crispr-Cas systems having destabilization domain
EP4219462A1 (en) 2016-07-13 2023-08-02 Vertex Pharmaceuticals Incorporated Methods, compositions and kits for increasing genome editing efficiency
US12031150B2 (en) 2016-07-13 2024-07-09 Vertex Pharmaceuticals Incorporated Methods, compositions and kits for increasing genome editing efficiency
WO2018013840A1 (en) 2016-07-13 2018-01-18 Vertex Pharmaceuticals Incorporated Methods, compositions and kits for increasing genome editing efficiency
US12214056B2 (en) 2016-07-19 2025-02-04 Duke University Therapeutic applications of CPF1-based genome editing
WO2018023014A1 (en) 2016-07-29 2018-02-01 Regeneron Pharmaceuticals, Inc. Mice comprising mutations resulting in expression of c-truncated fibrillin-1
US11566263B2 (en) 2016-08-02 2023-01-31 Editas Medicine, Inc. Compositions and methods for treating CEP290 associated disease
US11999947B2 (en) 2016-08-03 2024-06-04 President And Fellows Of Harvard College Adenosine nucleobase editors and uses thereof
US11912987B2 (en) 2016-08-03 2024-02-27 KSQ Therapeutics, Inc. Methods for screening for cancer targets
US10947530B2 (en) 2016-08-03 2021-03-16 President And Fellows Of Harvard College Adenosine nucleobase editors and uses thereof
US10113163B2 (en) 2016-08-03 2018-10-30 President And Fellows Of Harvard College Adenosine nucleobase editors and uses thereof
US11702651B2 (en) 2016-08-03 2023-07-18 President And Fellows Of Harvard College Adenosine nucleobase editors and uses thereof
US11078481B1 (en) 2016-08-03 2021-08-03 KSQ Therapeutics, Inc. Methods for screening for cancer targets
US11661590B2 (en) 2016-08-09 2023-05-30 President And Fellows Of Harvard College Programmable CAS9-recombinase fusion proteins and uses thereof
WO2018035250A1 (en) 2016-08-17 2018-02-22 The Broad Institute, Inc. Methods for identifying class 2 crispr-cas systems
US11630103B2 (en) 2016-08-17 2023-04-18 The Broad Institute, Inc. Product and methods useful for modulating and evaluating immune responses
US12305204B2 (en) 2016-08-17 2025-05-20 The Broad Institute, Inc. CRISPR enzymes and systems
US12559774B2 (en) 2016-08-17 2026-02-24 The Broad Institute, Inc. CRISPR enzymes and systems
WO2018035364A1 (en) 2016-08-17 2018-02-22 The Broad Institute Inc. Product and methods useful for modulating and evaluating immune responses
US11352647B2 (en) 2016-08-17 2022-06-07 The Broad Institute, Inc. Crispr enzymes and systems
US12431216B2 (en) 2016-08-17 2025-09-30 Broad Institute, Inc. Methods for identifying class 2 crispr-cas systems
US12084663B2 (en) 2016-08-24 2024-09-10 President And Fellows Of Harvard College Incorporation of unnatural amino acids into proteins using base editing
US11542509B2 (en) 2016-08-24 2023-01-03 President And Fellows Of Harvard College Incorporation of unnatural amino acids into proteins using base editing
US12565671B2 (en) 2016-08-31 2026-03-03 President And Fellows Of Harvard College Methods of combining the detection of biomolecules into a single assay using fluorescent in situ sequencing
US11946163B2 (en) 2016-09-02 2024-04-02 KSQ Therapeutics, Inc. Methods for measuring and improving CRISPR reagent function
US11078483B1 (en) 2016-09-02 2021-08-03 KSQ Therapeutics, Inc. Methods for measuring and improving CRISPR reagent function
WO2018048828A1 (en) 2016-09-06 2018-03-15 The Children's Medical Center Corporation Immune cells derived from induced pluripotent stem cell
WO2018049025A2 (en) 2016-09-07 2018-03-15 The Broad Institute Inc. Compositions and methods for evaluating and modulating immune responses
WO2018054911A1 (en) 2016-09-23 2018-03-29 Bayer Cropscience Nv Targeted genome optimization in plants
US12499971B2 (en) 2016-09-28 2025-12-16 The Broad Institute, Inc. Systematic screening and mapping of regulatory elements in non-coding genomic regions, methods, compositions, and applications thereof
WO2018067991A1 (en) 2016-10-07 2018-04-12 The Brigham And Women's Hospital, Inc. Modulation of novel immune checkpoint targets
US12447213B2 (en) 2016-10-07 2025-10-21 The Broad Institute, Inc. Modulation of novel immune checkpoint targets
US11306324B2 (en) 2016-10-14 2022-04-19 President And Fellows Of Harvard College AAV delivery of nucleobase editors
US11154574B2 (en) 2016-10-18 2021-10-26 Regents Of The University Of Minnesota Tumor infiltrating lymphocytes and methods of therapy
US10912797B2 (en) 2016-10-18 2021-02-09 Intima Bioscience, Inc. Tumor infiltrating lymphocytes and methods of therapy
WO2018083606A1 (en) 2016-11-01 2018-05-11 Novartis Ag Methods and compositions for enhancing gene editing
US12414967B2 (en) 2016-11-04 2025-09-16 Children's Hospital Medical Center Compositions and methods of treating liver disease
US12227578B2 (en) 2016-11-11 2025-02-18 The Broad Institute, Inc. Modulation of intestinal epithelial cell differentiation, maintenance and/or function through T cell action
US12404514B2 (en) 2016-12-09 2025-09-02 The Broad Institute, Inc. CRISPR-systems for modifying a trait of interest in a plant
US12286727B2 (en) 2016-12-19 2025-04-29 Editas Medicine, Inc. Assessing nuclease cleavage
US11820969B2 (en) 2016-12-23 2023-11-21 President And Fellows Of Harvard College Editing of CCR2 receptor gene to protect against HIV infection
US10745677B2 (en) 2016-12-23 2020-08-18 President And Fellows Of Harvard College Editing of CCR5 receptor gene to protect against HIV infection
US12110545B2 (en) 2017-01-06 2024-10-08 Editas Medicine, Inc. Methods of assessing nuclease cleavage
WO2018136758A1 (en) 2017-01-23 2018-07-26 Regeneron Pharmaceuticals, Inc. Hsd17b13 variants and uses thereof
US11466271B2 (en) 2017-02-06 2022-10-11 Novartis Ag Compositions and methods for the treatment of hemoglobinopathies
US12559748B2 (en) 2017-02-06 2026-02-24 Novartis Ag Compositions and methods for the treatment of hemoglobinopathies
US12390514B2 (en) 2017-03-09 2025-08-19 President And Fellows Of Harvard College Cancer vaccine
US12516308B2 (en) 2017-03-09 2026-01-06 President And Fellows Of Harvard College Suppression of pain by gene editing
US11898179B2 (en) 2017-03-09 2024-02-13 President And Fellows Of Harvard College Suppression of pain by gene editing
US11542496B2 (en) 2017-03-10 2023-01-03 President And Fellows Of Harvard College Cytosine to guanine base editor
US12435331B2 (en) 2017-03-10 2025-10-07 President And Fellows Of Harvard College Cytosine to guanine base editor
US11851690B2 (en) 2017-03-14 2023-12-26 Editas Medicine, Inc. Systems and methods for the treatment of hemoglobinopathies
US11739308B2 (en) 2017-03-15 2023-08-29 The Broad Institute, Inc. Cas13b orthologues CRISPR enzymes and systems
EP4361261A2 (en) 2017-03-15 2024-05-01 The Broad Institute Inc. Novel cas13b orthologues crispr enzymes and systems
WO2018170333A1 (en) 2017-03-15 2018-09-20 The Broad Institute, Inc. Novel cas13b orthologues crispr enzymes and systems
WO2018170515A1 (en) 2017-03-17 2018-09-20 The Broad Institute, Inc. Methods for identifying and modulating co-occurant cellular phenotypes
US12180546B2 (en) 2017-03-17 2024-12-31 Massachusetts Institute Of Technology Methods for identifying and modulating co-occurant cellular phenotypes
US11268082B2 (en) 2017-03-23 2022-03-08 President And Fellows Of Harvard College Nucleobase editors comprising nucleic acid programmable DNA binding proteins
US12161694B2 (en) 2017-03-24 2024-12-10 The Broad Institute, Inc. Methods and compositions for regulating innate lymphoid cell inflammatory responses
US11963966B2 (en) 2017-03-31 2024-04-23 Dana-Farber Cancer Institute, Inc. Compositions and methods for treating ovarian tumors
US11913075B2 (en) 2017-04-01 2024-02-27 The Broad Institute, Inc. Methods and compositions for detecting and modulating an immunotherapy resistance gene signature in cancer
WO2018191520A1 (en) 2017-04-12 2018-10-18 The Broad Institute, Inc. Respiratory and sweat gland ionocytes
US12590288B2 (en) 2017-04-12 2026-03-31 The Broad Institute, Inc. Method of treating an inflammatory disease by administering an agent which binds a surface receptor on a tuft cell that induces an ILC class 2 inflammatory response
US12331319B2 (en) 2017-04-12 2025-06-17 The Broad Institute, Inc. Respiratory and sweat gland ionocytes
WO2018191553A1 (en) 2017-04-12 2018-10-18 Massachusetts Eye And Ear Infirmary Tumor signature for metastasis, compositions of matter methods of use thereof
WO2018191388A1 (en) 2017-04-12 2018-10-18 The Broad Institute, Inc. Novel type vi crispr orthologs and systems
WO2018191750A2 (en) 2017-04-14 2018-10-18 The Broad Institute Inc. Novel delivery of large payloads
US12350368B2 (en) 2017-04-14 2025-07-08 The Broad Institute, Inc. Delivery of large payloads
US12281334B2 (en) 2017-04-14 2025-04-22 Children's Hospital Medical Center Multi donor stem cell compositions and methods of making same
US11913015B2 (en) 2017-04-17 2024-02-27 University Of Maryland, College Park Embryonic cell cultures and methods of using the same
WO2018195019A1 (en) 2017-04-18 2018-10-25 The Broad Institute Inc. Compositions for detecting secretion and methods of use
US11834670B2 (en) 2017-04-19 2023-12-05 Global Life Sciences Solutions Usa Llc Site-specific DNA modification using a donor DNA repair template having tandem repeat sequences
US12058986B2 (en) 2017-04-20 2024-08-13 Egenesis, Inc. Method for generating a genetically modified pig with inactivated porcine endogenous retrovirus (PERV) elements
WO2018195486A1 (en) 2017-04-21 2018-10-25 The Broad Institute, Inc. Targeted delivery to beta cells
US11499151B2 (en) 2017-04-28 2022-11-15 Editas Medicine, Inc. Methods and systems for analyzing guide RNA molecules
US11591601B2 (en) 2017-05-05 2023-02-28 The Broad Institute, Inc. Methods for identification and modification of lncRNA associated with target genotypes and phenotypes
US11963982B2 (en) 2017-05-10 2024-04-23 Editas Medicine, Inc. CRISPR/RNA-guided nuclease systems and methods
US11453891B2 (en) 2017-05-10 2022-09-27 The Regents Of The University Of California Directed editing of cellular RNA via nuclear delivery of CRISPR/CAS9
US12163148B2 (en) 2017-05-10 2024-12-10 The Regents Of The University Of California Directed editing of cellular RNA via nuclear delivery of CRISPR/Cas9
US12226479B2 (en) 2017-05-11 2025-02-18 The General Hospital Corporation Methods and compositions of use of CD8+ tumor infiltrating lymphocyte subtypes and gene signatures thereof
US11560566B2 (en) 2017-05-12 2023-01-24 President And Fellows Of Harvard College Aptazyme-embedded guide RNAs for use with CRISPR-Cas9 in genome editing and transcriptional activation
US11866697B2 (en) 2017-05-18 2024-01-09 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
US12297436B2 (en) 2017-05-18 2025-05-13 The Broad Institute, Inc. Systems, methods, and compositions for targeted nucleic acid editing
WO2018221685A1 (ja) 2017-05-31 2018-12-06 国立大学法人 東京大学 改変されたＣａｓ９タンパク質及びその用途
US11702645B2 (en) 2017-05-31 2023-07-18 The University Of Tokyo Polynucleotide encoding modified CAS9 protein
US11371030B2 (en) 2017-05-31 2022-06-28 The University Of Tokyo Modified Cas9 protein and use thereof
US11603544B2 (en) 2017-06-05 2023-03-14 Fred Hutchinson Cancer Center Genomic safe harbors for genetic therapies in human stem cells and engineered nanoparticles to provide targeted genetic therapies
US12442021B2 (en) 2017-06-05 2025-10-14 Fred Hutchinson Cancer Center Genomic safe harbors for genetic therapies in human stem cells and engineered nanoparticles to provide targeted genetic therapies
US12297466B2 (en) 2017-06-09 2025-05-13 Editas Medicine, Inc. Engineered Cas9 nucleases
US11098297B2 (en) 2017-06-09 2021-08-24 Editas Medicine, Inc. Engineered Cas9 nucleases
US10428319B2 (en) 2017-06-09 2019-10-01 Editas Medicine, Inc. Engineered Cas9 nucleases
US11897953B2 (en) 2017-06-14 2024-02-13 The Broad Institute, Inc. Compositions and methods targeting complement component 3 for inhibiting tumor growth
US12234461B2 (en) 2017-06-15 2025-02-25 The Regents Of The University Of California, A California Corporation Targeted non-viral DNA insertions
US11814624B2 (en) 2017-06-15 2023-11-14 The Regents Of The University Of California Targeted non-viral DNA insertions
US12195749B2 (en) 2017-06-23 2025-01-14 Inscripta, Inc. Nucleic acid-guided nucleases
US10337028B2 (en) 2017-06-23 2019-07-02 Inscripta, Inc. Nucleic acid-guided nucleases
US10011849B1 (en) 2017-06-23 2018-07-03 Inscripta, Inc. Nucleic acid-guided nucleases
US9982279B1 (en) 2017-06-23 2018-05-29 Inscripta, Inc. Nucleic acid-guided nucleases
US11697826B2 (en) 2017-06-23 2023-07-11 Inscripta, Inc. Nucleic acid-guided nucleases
US10626416B2 (en) 2017-06-23 2020-04-21 Inscripta, Inc. Nucleic acid-guided nucleases
US12180502B2 (en) 2017-06-23 2024-12-31 Inscripta, Inc. Nucleic acid-guided nucleases
US10435714B2 (en) 2017-06-23 2019-10-08 Inscripta, Inc. Nucleic acid-guided nucleases
WO2019005884A1 (en) 2017-06-26 2019-01-03 The Broad Institute, Inc. CRISPR / CAS-ADENINE DEAMINASE COMPOSITIONS, SYSTEMS AND METHODS FOR TARGETED NUCLEIC ACID EDITION
WO2019003193A1 (en) 2017-06-30 2019-01-03 Novartis Ag METHODS FOR TREATING DISEASES USING GENE EDITING SYSTEMS
US11098325B2 (en) 2017-06-30 2021-08-24 Intima Bioscience, Inc. Adeno-associated viral vectors for gene therapy
US11866726B2 (en) 2017-07-14 2024-01-09 Editas Medicine, Inc. Systems and methods for targeted integration and genome editing and detection thereof using integrated priming sites
US12049643B2 (en) 2017-07-14 2024-07-30 The Broad Institute, Inc. Methods and compositions for modulating cytotoxic lymphocyte activity
WO2019018440A1 (en) 2017-07-17 2019-01-24 The Broad Institute, Inc. HUMAN COLON CELL ATLAS IN GOOD HEALTH AND WITH HEMORRHAGIC RECTO-COLITIS
US12105089B2 (en) 2017-07-17 2024-10-01 The Broad Institute, Inc. Cell atlas of the healthy and ulcerative colitis human colon
US12239646B2 (en) 2017-07-19 2025-03-04 Dana-Farber Cancer Institute, Inc. Cancer diagnostic and treatment
US12359218B2 (en) 2017-07-28 2025-07-15 President And Fellows Of Harvard College Methods and compositions for evolving base editors using phage-assisted continuous evolution (PACE)
US11732274B2 (en) 2017-07-28 2023-08-22 President And Fellows Of Harvard College Methods and compositions for evolving base editors using phage-assisted continuous evolution (PACE)
WO2019028032A1 (en) 2017-07-31 2019-02-07 Regeneron Pharmaceuticals, Inc. EMBRYONIC STEM CELLS OF TRANSGENIC MOUSE CASES AND MICE AND USES THEREOF
WO2019028029A1 (en) 2017-07-31 2019-02-07 Regeneron Pharmaceuticals, Inc. EVALUATION OF CRISPR / CAS INDUCED RECOMBINATION WITH IN VIVO EXOGENIC DONOR NUCLEIC ACID
WO2019028023A2 (en) 2017-07-31 2019-02-07 Regeneron Pharmaceuticals, Inc. METHODS AND COMPOSITIONS FOR EVALUATING CRISPR / CAS MEDIATED DISRUPTION OR EXCISION AND CRISPR / CAS INDUCED RECOMBINATION USING IN VIVO EXOGENIC DONOR NUCLEIC ACID
US11932884B2 (en) 2017-08-30 2024-03-19 President And Fellows Of Harvard College High efficiency base editors comprising Gam
US11319532B2 (en) 2017-08-30 2022-05-03 President And Fellows Of Harvard College High efficiency base editors comprising Gam
WO2019049913A1 (ja) 2017-09-05 2019-03-14 国立大学法人 東京大学 改変されたＣａｓ９タンパク質及びその用途
US12152259B2 (en) 2017-09-05 2024-11-26 The University Of Tokyo Modified CAS9 protein, and use thereof
US11530396B2 (en) 2017-09-05 2022-12-20 The University Of Tokyo Modified CAS9 protein, and use thereof
WO2019060746A1 (en) 2017-09-21 2019-03-28 The Broad Institute, Inc. SYSTEMS, METHODS, AND COMPOSITIONS FOR THE TARGETED EDITING OF NUCLEIC ACIDS
WO2019067875A1 (en) 2017-09-29 2019-04-04 Regeneron Pharmaceuticals, Inc. NON-HUMAN ANIMALS COMPRISING A HUMANIZED TTR LOCUS AND METHODS OF USE
EP4276185A2 (en) 2017-09-29 2023-11-15 Regeneron Pharmaceuticals, Inc. Rodents comprising a humanized ttr locus and methods of use
WO2019070755A1 (en) 2017-10-02 2019-04-11 The Broad Institute, Inc. METHODS AND COMPOSITIONS FOR DETECTING AND MODULATING A GENETIC SIGNATURE OF IMMUNOTHERAPY RESISTANCE IN CANCER
US12043870B2 (en) 2017-10-02 2024-07-23 The Broad Institute, Inc. Methods and compositions for detecting and modulating an immunotherapy resistance gene signature in cancer
WO2019071054A1 (en) 2017-10-04 2019-04-11 The Broad Institute, Inc. METHODS AND COMPOSITIONS FOR MODIFYING THE FUNCTION AND STRUCTURE OF BUCKLES AND / OR CHROMATIN DOMAINS
US12297457B2 (en) 2017-10-10 2025-05-13 Children's Hospital Medical Center Esophageal tissue and/or organoid compositions and methods of making same
US11795443B2 (en) 2017-10-16 2023-10-24 The Broad Institute, Inc. Uses of adenosine base editors
US11680296B2 (en) 2017-10-16 2023-06-20 Massachusetts Institute Of Technology Mycobacterium tuberculosis host-pathogen interaction
US12589145B2 (en) 2017-10-20 2026-03-31 Fred Hutchinson Cancer Center Systems to produce B cells genetically modified to express selected antibodies
US11578118B2 (en) 2017-10-20 2023-02-14 Fred Hutchinson Cancer Center Systems and methods to produce B cells genetically modified to express selected antibodies
US12227742B2 (en) 2017-10-23 2025-02-18 The Broad Institute, Inc. Nucleic acid modifiers
US12398193B2 (en) 2017-10-27 2025-08-26 The Regents Of The University Of California Targeted replacement of endogenous T cell receptors
US11083753B1 (en) 2017-10-27 2021-08-10 The Regents Of The University Of California Targeted replacement of endogenous T cell receptors
US11331346B2 (en) 2017-10-27 2022-05-17 The Regents Of The University Of California Targeted replacement of endogenous T cell receptors
US11033584B2 (en) 2017-10-27 2021-06-15 The Regents Of The University Of California Targeted replacement of endogenous T cell receptors
US11590171B2 (en) 2017-10-27 2023-02-28 The Regents Of The University Of California Targeted replacement of endogenous T cell receptors
US11547614B2 (en) 2017-10-31 2023-01-10 The Broad Institute, Inc. Methods and compositions for studying cell evolution
US12433803B2 (en) 2017-10-31 2025-10-07 The Broad Institute, Inc. Methods and compositions for studying cell evolution
WO2019087113A1 (en) 2017-11-01 2019-05-09 Novartis Ag Synthetic rnas and methods of use
WO2019094983A1 (en) 2017-11-13 2019-05-16 The Broad Institute, Inc. Methods and compositions for treating cancer by targeting the clec2d-klrb1 pathway
US12171783B2 (en) 2017-11-13 2024-12-24 The Broad Institute, Inc. Methods and compositions for targeting developmental and oncogenic programs in H3K27M gliomas
US12221720B2 (en) 2017-11-13 2025-02-11 The Broad Institute, Inc. Methods for determining spatial and temporal gene expression dynamics during adult neurogenesis in single cells
US11332736B2 (en) 2017-12-07 2022-05-17 The Broad Institute, Inc. Methods and compositions for multiplexing single cell and single nuclei sequencing
US12406749B2 (en) 2017-12-15 2025-09-02 The Broad Institute, Inc. Systems and methods for predicting repair outcomes in genetic engineering
US12379372B2 (en) 2017-12-21 2025-08-05 Children's Hospital Medical Center Digitalized human organoids and methods of using same
US11994512B2 (en) 2018-01-04 2024-05-28 Massachusetts Institute Of Technology Single-cell genomic methods to generate ex vivo cell systems that recapitulate in vivo biology with improved fidelity
US11359208B2 (en) 2018-01-09 2022-06-14 Cibus Us Llc Shatterproof genes and mutations
WO2019138083A1 (en) 2018-01-12 2019-07-18 Basf Se Gene underlying the number of spikelets per spike qtl in wheat on chromosome 7a
US12269804B2 (en) 2018-01-17 2025-04-08 Vertex Pharmaceuticals Incorporated Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
WO2019143677A1 (en) 2018-01-17 2019-07-25 Vertex Pharmaceuticals Incorporated Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency
WO2019143675A1 (en) 2018-01-17 2019-07-25 Vertex Pharmaceuticals Incorporated Dna-pk inhibitors
US12005127B2 (en) 2018-01-17 2024-06-11 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
WO2019143678A1 (en) 2018-01-17 2019-07-25 Vertex Pharmaceuticals Incorporated Dna-pk inhibitors
US12121524B2 (en) 2018-01-17 2024-10-22 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US12031132B2 (en) 2018-03-14 2024-07-09 Editas Medicine, Inc. Systems and methods for the treatment of hemoglobinopathies
WO2019183123A1 (en) 2018-03-19 2019-09-26 Regeneron Pharmaceuticals, Inc. Transcription modulation in animals using crispr/cas systems
WO2019195611A1 (en) 2018-04-04 2019-10-10 Cibus Us Llc Fad2 genes and mutations
US12559763B2 (en) 2018-04-04 2026-02-24 Cibus Us Llc FAD2 genes and mutations
WO2019204585A1 (en) 2018-04-19 2019-10-24 Massachusetts Institute Of Technology Single-stranded break detection in double-stranded dna
WO2019206927A1 (en) 2018-04-24 2019-10-31 KWS SAAT SE & Co. KGaA Plants with improved digestibility and marker haplotypes
EP3560330A1 (en) 2018-04-24 2019-10-30 KWS SAAT SE & Co. KGaA Plants with improved digestibility and marker haplotypes
US12180490B2 (en) 2018-04-24 2024-12-31 KWS SAAT SE & Co. KGaA Plants with improved digestibility and marker haplotypes
US11957695B2 (en) 2018-04-26 2024-04-16 The Broad Institute, Inc. Methods and compositions targeting glucocorticoid signaling for modulating immune responses
WO2019210268A2 (en) 2018-04-27 2019-10-31 The Broad Institute, Inc. Sequencing-based proteomics
WO2019206236A1 (zh) * 2018-04-28 2019-10-31 中国科学院上海生命科学研究院 通过Tild-CRISPR实现高效精确的靶向整合
US11485973B2 (en) 2018-04-30 2022-11-01 Snipr Biome Aps Treating and preventing microbial infections
US10920222B2 (en) 2018-04-30 2021-02-16 Snipr Biome Aps Treating and preventing microbial infections
US10760075B2 (en) 2018-04-30 2020-09-01 Snipr Biome Aps Treating and preventing microbial infections
US11788085B2 (en) 2018-04-30 2023-10-17 Snipr Biome Aps Treating and preventing microbial infections
US11421227B2 (en) 2018-04-30 2022-08-23 Snipr Biome Aps Treating and preventing microbial infections
US12448619B2 (en) 2018-04-30 2025-10-21 Snipr Biome Aps Treating and preventing microbial infections
US11643653B2 (en) 2018-04-30 2023-05-09 Snipr Biome Aps Treating and preventing microbial infections
WO2019213660A2 (en) 2018-05-04 2019-11-07 The Broad Institute, Inc. Compositions and methods for modulating cgrp signaling to regulate innate lymphoid cell inflammatory responses
US12371467B2 (en) 2018-05-11 2025-07-29 Memorial Sloan-Kettering Cancer Center T cell receptors targeting PIK3CA mutations and uses thereof
EP4252759A2 (en) 2018-05-11 2023-10-04 Memorial Sloan Kettering Cancer Center T cell receptors targeting pik3ca mutations and uses thereof
EP4656196A2 (en) 2018-05-11 2025-12-03 Memorial Sloan-Kettering Cancer Center T cell receptors targeting pik3ca mutations and uses thereof
US12157760B2 (en) 2018-05-23 2024-12-03 The Broad Institute, Inc. Base editors and uses thereof
WO2019232542A2 (en) 2018-06-01 2019-12-05 Massachusetts Institute Of Technology Methods and compositions for detecting and modulating microenvironment gene signatures from the csf of metastasis patients
US12036240B2 (en) 2018-06-14 2024-07-16 The Broad Institute, Inc. Compositions and methods targeting complement component 3 for inhibiting tumor growth
WO2020006036A1 (en) 2018-06-26 2020-01-02 Massachusetts Institute Of Technology Crispr effector system based amplification methods, systems, and diagnostics
WO2020006049A1 (en) 2018-06-26 2020-01-02 The Broad Institute, Inc. Crispr/cas and transposase based amplification compositions, systems and methods
WO2020002592A1 (en) 2018-06-29 2020-01-02 Stichting Het Nederlands Kanker Instituut - Antoni Van Leeuwenhoek Ziekenhuis Traf2 inhibitors for use in the treatment of a cancer
US12338436B2 (en) 2018-06-29 2025-06-24 Editas Medicine, Inc. Synthetic guide molecules, compositions and methods relating thereto
US12522807B2 (en) 2018-07-09 2026-01-13 The Broad Institute, Inc. RNA programmable epigenetic RNA modifiers and uses thereof
US12421500B2 (en) 2018-07-26 2025-09-23 Children's Hospital Medical Center Hepato-biliary-pancreatic tissues and methods of making same
WO2020028555A2 (en) 2018-07-31 2020-02-06 The Broad Institute, Inc. Novel crispr enzymes and systems
WO2020033601A1 (en) 2018-08-07 2020-02-13 The Broad Institute, Inc. Novel cas12b enzymes and systems
WO2020041380A1 (en) 2018-08-20 2020-02-27 The Broad Institute, Inc. Methods and compositions for optochemical control of crispr-cas9
US12421507B2 (en) 2018-08-20 2025-09-23 The Broad Institute, Inc. Methods and compositions for optochemical control of CRISPR-CAS9
WO2020041387A1 (en) 2018-08-20 2020-02-27 The Brigham And Women's Hospital, Inc. Degradation domain modifications for spatio-temporal control of rna-guided nucleases
WO2020051507A1 (en) 2018-09-06 2020-03-12 The Broad Institute, Inc. Nucleic acid assemblies for use in targeted delivery
US12428622B2 (en) 2018-09-12 2025-09-30 Children's Hospital Medical Center Organoid compositions for the production of hematopoietic stem cells and derivatives thereof
EP4268831A2 (en) 2018-09-12 2023-11-01 Fred Hutchinson Cancer Center Reducing cd33 expression to selectively protect therapeutic cells
US12617822B2 (en) 2018-09-18 2026-05-05 Aera Therapeutics, Inc. Arc-based capsids and uses thereof
US11447527B2 (en) 2018-09-18 2022-09-20 Vnv Newco Inc. Endogenous Gag-based capsids and uses thereof
US11505578B2 (en) 2018-09-18 2022-11-22 Vnv Newco Inc. Endogenous Gag-based capsids and uses thereof
US12098425B2 (en) 2018-10-10 2024-09-24 Readcoor, Llc Three-dimensional spatial molecular indexing
WO2020077236A1 (en) 2018-10-12 2020-04-16 The Broad Institute, Inc. Method for extracting nuclei or whole cells from formalin-fixed paraffin-embedded tissues
WO2020081730A2 (en) 2018-10-16 2020-04-23 Massachusetts Institute Of Technology Methods and compositions for modulating microenvironment
US12281338B2 (en) 2018-10-29 2025-04-22 The Broad Institute, Inc. Nucleobase editors comprising GeoCas9 and uses thereof
US12165743B2 (en) 2018-11-09 2024-12-10 The Broad Institute, Inc. Compressed sensing for screening and tissue imaging
US12402610B2 (en) 2018-11-09 2025-09-02 The Broad Institute, Inc. Methods and compositions for modulating innate lymphoid cell pathogenic effectors
US20220017896A1 (en) * 2018-11-26 2022-01-20 Joint Stock Company "Biocad" Dna cutting means based on cas9 protein from defluviimonas sp.
CN113614247A (zh) * 2018-11-26 2021-11-05 拜奥卡德联合股份公司 Dna切割剂
EP3889270A4 (en) * 2018-11-26 2022-08-24 Joint Stock Company "Biocad" DNA CUTTING AGENT
US12612648B2 (en) 2018-12-12 2026-04-28 Kyushu University, National University Corporation Production method for genome-edited cells
WO2020122195A1 (ja) 2018-12-12 2020-06-18 国立大学法人九州大学 ゲノム編集された細胞の製造方法
US11384344B2 (en) 2018-12-17 2022-07-12 The Broad Institute, Inc. CRISPR-associated transposase systems and methods of use thereof
WO2020131586A2 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Methods for identifying neoantigens
WO2020131862A1 (en) 2018-12-17 2020-06-25 The Broad Institute, Inc. Crispr-associated transposase systems and methods of use thereof
US12264323B2 (en) 2018-12-17 2025-04-01 The Broad Institute, Inc. CRISPR CPF1 direct repeat variants
WO2020131632A1 (en) 2018-12-20 2020-06-25 Regeneron Pharmaceuticals, Inc. Nuclease-mediated repeat expansion
US11739156B2 (en) 2019-01-06 2023-08-29 The Broad Institute, Inc. Massachusetts Institute of Technology Methods and compositions for overcoming immunosuppression
US12351837B2 (en) 2019-01-23 2025-07-08 The Broad Institute, Inc. Supernegatively charged proteins and uses thereof
US12600943B2 (en) 2019-02-01 2026-04-14 The University Of Hong Kong Innervated organoid compositions and methods of making same
WO2020168315A1 (en) 2019-02-15 2020-08-20 Just-Evotec Biologics, Inc. Automated biomanufacturing systems, facilities, and processes
EP4729947A2 (en) 2019-03-18 2026-04-22 Regeneron Pharmaceuticals, Inc. Crispr/cas screening platform to identify genetic modifiers of tau seeding or aggregation
WO2020190927A1 (en) 2019-03-18 2020-09-24 Regeneron Pharmaceuticals, Inc. Crispr/cas dropout screening platform to reveal genetic vulnerabilities associated with tau aggregation
US12534714B2 (en) 2019-03-18 2026-01-27 The Broad Institute, Inc. Type VII CRISPR proteins and systems
EP4317950A2 (en) 2019-03-18 2024-02-07 Regeneron Pharmaceuticals, Inc. Crispr/cas screening platform to identify genetic modifiers of tau seeding or aggregation
WO2020190932A1 (en) 2019-03-18 2020-09-24 Regeneron Pharmaceuticals, Inc. Crispr/cas screening platform to identify genetic modifiers of tau seeding or aggregation
US12624354B2 (en) 2019-03-19 2026-05-12 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
US11643652B2 (en) 2019-03-19 2023-05-09 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
US12624353B2 (en) 2019-03-19 2026-05-12 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
US12509680B2 (en) 2019-03-19 2025-12-30 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
US12281303B2 (en) 2019-03-19 2025-04-22 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
US12570972B2 (en) 2019-03-19 2026-03-10 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
US11447770B1 (en) 2019-03-19 2022-09-20 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
US11795452B2 (en) 2019-03-19 2023-10-24 The Broad Institute, Inc. Methods and compositions for prime editing nucleotide sequences
WO2020206036A1 (en) 2019-04-01 2020-10-08 The Broad Institute, Inc. Novel nucleic acid modifier
WO2020206162A1 (en) 2019-04-03 2020-10-08 Regeneron Pharmaceuticals, Inc. Methods and compositions for insertion of antibody coding sequences into a safe harbor locus
WO2020206134A1 (en) 2019-04-04 2020-10-08 Regeneron Pharmaceuticals, Inc. Methods for scarless introduction of targeted modifications into targeting vectors
WO2020206139A1 (en) 2019-04-04 2020-10-08 Regeneron Pharmaceuticals, Inc. Non-human animals comprising a humanized coagulation factor 12 locus
US12473543B2 (en) 2019-04-17 2025-11-18 The Broad Institute, Inc. Adenine base editors with reduced off-target effects
WO2020229533A1 (en) 2019-05-13 2020-11-19 KWS SAAT SE & Co. KGaA Drought tolerance in corn
WO2020236967A1 (en) 2019-05-20 2020-11-26 The Broad Institute, Inc. Random crispr-cas deletion mutant
WO2020236972A2 (en) 2019-05-20 2020-11-26 The Broad Institute, Inc. Non-class i multi-component nucleic acid targeting systems
WO2020239680A2 (en) 2019-05-25 2020-12-03 KWS SAAT SE & Co. KGaA Haploid induction enhancer
US12497597B2 (en) 2019-05-31 2025-12-16 Children's Hospital Medical Center Methods of generating and expanding hematopoietic stem cells
WO2020243661A1 (en) 2019-05-31 2020-12-03 The Broad Institute, Inc. Methods for treating metabolic disorders by targeting adcy5
US12534709B2 (en) 2019-05-31 2026-01-27 Children's Hospital Medical Center Shaped organoid compositions and methods of making same
WO2020247452A1 (en) 2019-06-04 2020-12-10 Regeneron Pharmaceuticals, Inc. Non-human animals comprising a humanized ttr locus with a beta-slip mutation and methods of use
WO2020247812A1 (en) 2019-06-07 2020-12-10 Regeneron Pharmaceuticals, Inc. Non-human animals comprising a humanized albumin locus
RU2722933C1 (ru) * 2019-06-11 2020-06-05 Автономная некоммерческая образовательная организация высшего образования Сколковский институт науки и технологий Средство разрезания днк на основе cas9 белка из бактерии demequina sediminicola
US12351815B2 (en) 2019-06-13 2025-07-08 The General Hospital Corporation Engineered human-endogenous virus-like particles and methods of use thereof for delivery to cells
US12404525B2 (en) 2019-06-13 2025-09-02 The General Hospital Corporation Engineered human-endogenous virus-like particles and methods of use thereof for delivery to cells
US12351814B2 (en) 2019-06-13 2025-07-08 The General Hospital Corporation Engineered human-endogenous virus-like particles and methods of use thereof for delivery to cells
WO2020252340A1 (en) 2019-06-14 2020-12-17 Regeneron Pharmaceuticals, Inc. Models of tauopathy
US12492237B2 (en) 2019-06-20 2025-12-09 Memorial Sloan-Kettering Cancer Center T cell receptors targeting PIK3CA mutations and uses thereof
WO2021003432A1 (en) 2019-07-02 2021-01-07 Fred Hutchinson Cancer Research Center Recombinant ad35 vectors and related gene therapy improvements
EP3772542A1 (en) 2019-08-07 2021-02-10 KWS SAAT SE & Co. KGaA Modifying genetic variation in crops by modulating the pachytene checkpoint protein 2
WO2021041922A1 (en) 2019-08-30 2021-03-04 The Broad Institute, Inc. Crispr-associated mu transposase systems
WO2021050940A1 (en) 2019-09-13 2021-03-18 Regeneron Pharmaceuticals, Inc. Transcription modulation in animals using crispr/cas systems delivered by lipid nanoparticles
WO2021055874A1 (en) 2019-09-20 2021-03-25 The Broad Institute, Inc. Novel type vi crispr enzymes and systems
US11981922B2 (en) 2019-10-03 2024-05-14 Dana-Farber Cancer Institute, Inc. Methods and compositions for the modulation of cell interactions and signaling in the tumor microenvironment
US12435330B2 (en) 2019-10-10 2025-10-07 The Broad Institute, Inc. Methods and compositions for prime editing RNA
WO2021074367A1 (en) 2019-10-17 2021-04-22 KWS SAAT SE & Co. KGaA Enhanced disease resistance of crops by downregulation of repressor genes
WO2021092513A1 (en) 2019-11-08 2021-05-14 Regeneron Pharmaceuticals, Inc. Crispr and aav strategies for x-linked juvenile retinoschisis therapy
WO2021108363A1 (en) 2019-11-25 2021-06-03 Regeneron Pharmaceuticals, Inc. Crispr/cas-mediated upregulation of humanized ttr allele
WO2021108647A1 (en) 2019-11-27 2021-06-03 Crispr Therapeutics Ag Methods of synthesizing rna molecules
WO2021148447A1 (en) 2020-01-21 2021-07-29 Limagrain Europe Wheat haploid inducer plant and uses
WO2021150919A1 (en) 2020-01-23 2021-07-29 The Children's Medical Center Corporation Stroma-free t cell differentiation from human pluripotent stem cells
US12559790B2 (en) 2020-01-29 2026-02-24 10X Genomics, Inc. Compositions and methods for analyte detection
WO2021165508A1 (en) 2020-02-21 2021-08-26 Biogemma Prime editing technology for plant genome engineering
EP3872190A1 (en) 2020-02-26 2021-09-01 Antibodies-Online GmbH A method of using cut&run or cut&tag to validate crispr-cas targeting
WO2021178556A1 (en) 2020-03-04 2021-09-10 Regeneron Pharmaceuticals, Inc. Methods and compositions for sensitization of tumor cells to immune therapy
WO2021195079A1 (en) 2020-03-23 2021-09-30 Regeneron Pharmaceuticals, Inc. Non-human animals comprising a humanized ttr locus comprising a v30m mutation and methods of use
US12057197B2 (en) 2020-04-03 2024-08-06 Creyon Bio, Inc. Oligonucleotide-based machine learning
WO2021202938A1 (en) 2020-04-03 2021-10-07 Creyon Bio, Inc. Oligonucleotide-based machine learning
US12400739B2 (en) 2020-04-03 2025-08-26 Creyon Bio, Inc. Oligonucleotide-based machine learning
WO2021206054A1 (ja) 2020-04-06 2021-10-14 株式会社Ｌｏｇｏｍｉｘ ゲノム改変方法及びゲノム改変キット
KR20220164748A (ko) 2020-04-06 2022-12-13 가부시키가이샤 로고믹스 게놈 개변 방법 및 게놈 개변 키트
US12629428B2 (en) 2020-04-14 2026-05-19 Duke University AAV vector-mediated deletion of large mutational hotspot for treatment of Duchenne muscular dystrophy
US12031126B2 (en) 2020-05-08 2024-07-09 The Broad Institute, Inc. Methods and compositions for simultaneous editing of both strands of a target double-stranded nucleotide sequence
US11912985B2 (en) 2020-05-08 2024-02-27 The Broad Institute, Inc. Methods and compositions for simultaneous editing of both strands of a target double-stranded nucleotide sequence
WO2021239986A1 (en) 2020-05-29 2021-12-02 KWS SAAT SE & Co. KGaA Plant haploid induction
US12319938B2 (en) 2020-07-24 2025-06-03 The General Hospital Corporation Enhanced virus-like particles and methods of use thereof for delivery to cells
US12203136B2 (en) 2020-08-17 2025-01-21 Readcoor, Llc Methods and systems for spatial mapping of genetic variants
WO2022069756A1 (en) 2020-10-02 2022-04-07 Limagrain Europe Crispr-mediated directed codon re-write
EP4001429A1 (en) 2020-11-16 2022-05-25 Antibodies-Online GmbH Analysis of crispr-cas binding and cleavage sites followed by high-throughput sequencing (abc-seq)
WO2022120022A1 (en) 2020-12-02 2022-06-09 Regeneron Pharmaceuticals, Inc. Crispr sam biosensor cell lines and methods of use thereof
WO2022137760A1 (ja) 2020-12-25 2022-06-30 株式会社Logomix ゲノムｄｎａに大規模な欠失を生じさせる方法およびゲノムｄｎａの分析方法
WO2022165001A1 (en) 2021-01-29 2022-08-04 Merck Sharp & Dohme Llc Compositions of programmed death receptor 1 (pd-1) antibodies and methods of obtaining the compositions thereof
US12110330B2 (en) 2021-01-29 2024-10-08 Merck Sharp & Dohme Llc Compositions of programmed death receptor 1 (PD-1) antibodies and methods of obtaining the compositions thereof
WO2022186233A1 (ja) 2021-03-03 2022-09-09 株式会社Logomix ゲノムｄｎａを改変する方法および改変を検出する方法
WO2022221699A1 (en) 2021-04-16 2022-10-20 Beam Therapeutics, Inc. Genetic modification of hepatocytes
WO2023287707A1 (en) 2021-07-15 2023-01-19 Just-Evotec Biologics, Inc. Bidirectional tangential flow filtration (tff) perfusion system
WO2023006933A1 (en) 2021-07-30 2023-02-02 KWS SAAT SE & Co. KGaA Plants with improved digestibility and marker haplotypes
WO2023010135A1 (en) 2021-07-30 2023-02-02 Tune Therapeutics, Inc. Compositions and methods for modulating expression of methyl-cpg binding protein 2 (mecp2)
WO2023010133A2 (en) 2021-07-30 2023-02-02 Tune Therapeutics, Inc. Compositions and methods for modulating expression of frataxin (fxn)
US11884915B2 (en) 2021-09-10 2024-01-30 Agilent Technologies, Inc. Guide RNAs with chemical modification for prime editing
US12037407B2 (en) 2021-10-14 2024-07-16 Arsenal Biosciences, Inc. Immune cells having co-expressed shRNAS and logic gate systems
WO2023077053A2 (en) 2021-10-28 2023-05-04 Regeneron Pharmaceuticals, Inc. Crispr/cas-related methods and compositions for knocking out c5
WO2023093862A1 (en) 2021-11-26 2023-06-01 Epigenic Therapeutics Inc. Method of modulating pcsk9 and uses thereof
WO2023108047A1 (en) 2021-12-08 2023-06-15 Regeneron Pharmaceuticals, Inc. Mutant myocilin disease model and uses thereof
WO2023137472A2 (en) 2022-01-14 2023-07-20 Tune Therapeutics, Inc. Compositions, systems, and methods for programming t cell phenotypes through targeted gene repression
WO2023137471A1 (en) 2022-01-14 2023-07-20 Tune Therapeutics, Inc. Compositions, systems, and methods for programming t cell phenotypes through targeted gene activation
WO2023150620A1 (en) 2022-02-02 2023-08-10 Regeneron Pharmaceuticals, Inc. Crispr-mediated transgene insertion in neonatal cells
KR20240166013A (ko) 2022-04-01 2024-11-25 가부시키가이샤 로고믹스 유전자 공학, 세포 공학, 및 세포 의약에 적합한 세포 및 그 제조 방법
WO2023191063A1 (ja) 2022-04-01 2023-10-05 株式会社Logomix 遺伝子工学、細胞工学、および細胞医薬に適した細胞およびその製造方法
WO2023212677A2 (en) 2022-04-29 2023-11-02 Regeneron Pharmaceuticals, Inc. Identification of tissue-specific extragenic safe harbors for gene therapy approaches
WO2023220603A1 (en) 2022-05-09 2023-11-16 Regeneron Pharmaceuticals, Inc. Vectors and methods for in vivo antibody production
WO2023235726A2 (en) 2022-05-31 2023-12-07 Regeneron Pharmaceuticals, Inc. Crispr interference therapeutics for c9orf72 repeat expansion disease
WO2023235725A2 (en) 2022-05-31 2023-12-07 Regeneron Pharmaceuticals, Inc. Crispr-based therapeutics for c9orf72 repeat expansion disease
US12098399B2 (en) 2022-06-24 2024-09-24 Tune Therapeutics, Inc. Compositions, systems, and methods for epigenetic regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression
WO2023250511A2 (en) 2022-06-24 2023-12-28 Tune Therapeutics, Inc. Compositions, systems, and methods for reducing low-density lipoprotein through targeted gene repression
US12076375B2 (en) 2022-06-29 2024-09-03 Snipr Biome Aps Treating and preventing E coli infections
WO2024005186A1 (ja) 2022-06-30 2024-01-04 リージョナルフィッシュ株式会社 ｔｒａｃｒＲＮＡユニット、及びゲノム編集方法
KR20250029023A (ko) 2022-06-30 2025-03-04 리저널 피쉬 가부시키가이샤 tracrRNA 유닛, 및 게놈 편집 방법
WO2024015881A2 (en) 2022-07-12 2024-01-18 Tune Therapeutics, Inc. Compositions, systems, and methods for targeted transcriptional activation
WO2024026474A1 (en) 2022-07-29 2024-02-01 Regeneron Pharmaceuticals, Inc. Compositions and methods for transferrin receptor (tfr)-mediated delivery to the brain and muscle
US12325858B1 (en) 2022-08-19 2025-06-10 Tune Therapeutics, Inc. Compositions, systems, and methods for regulation of Hepatitis B virus through targeted gene repression
WO2024039576A2 (en) 2022-08-19 2024-02-22 Memorial Sloan-Kettering Cancer Center T cell receptors targeting ras mutations and uses thereof
US12252692B2 (en) 2022-08-19 2025-03-18 Tune Therapeutics, Inc. Compositions, systems, and methods for regulation of hepatitis B virus through targeted gene repression
US12398394B2 (en) 2022-08-19 2025-08-26 Tune Therapeutics, Inc. Compositions, systems, and methods for regulation of Hepatitis B virus through targeted gene repression
WO2024040254A2 (en) 2022-08-19 2024-02-22 Tune Therapeutics, Inc. Compositions, systems, and methods for regulation of hepatitis b virus through targeted gene repression
US12325857B2 (en) 2022-08-19 2025-06-10 Tune Therapeutics, Inc. Compositions, systems, and methods for regulation of Hepatitis b virus through targeted gene repression
US12221608B2 (en) 2022-08-19 2025-02-11 Tune Therapeutics, Inc. Compositions, systems, and methods for regulation of hepatitis b virus through targeted gene repression
WO2024042199A1 (en) 2022-08-26 2024-02-29 KWS SAAT SE & Co. KGaA Use of paired genes in hybrid breeding
WO2024228717A2 (en) 2022-09-07 2024-11-07 Quantitative Biosciences, Inc. Fentanyl-specific single variable-domain antibodies and use in a continuous agglutination assay
WO2024064642A2 (en) 2022-09-19 2024-03-28 Tune Therapeutics, Inc. Compositions, systems, and methods for modulating t cell function
WO2024073606A1 (en) 2022-09-28 2024-04-04 Regeneron Pharmaceuticals, Inc. Antibody resistant modified receptors to enhance cell-based therapies
WO2024080067A1 (ja) 2022-10-14 2024-04-18 株式会社インプランタイノベーションズ ゲノム編集方法およびゲノム編集用組成物
WO2024098002A1 (en) 2022-11-04 2024-05-10 Regeneron Pharmaceuticals, Inc. Calcium voltage-gated channel auxiliary subunit gamma 1 (cacng1) binding proteins and cacng1-mediated delivery to skeletal muscle
WO2024107765A2 (en) 2022-11-14 2024-05-23 Regeneron Pharmaceuticals, Inc. Compositions and methods for fibroblast growth factor receptor 3-mediated delivery to astrocytes
WO2024105633A1 (en) 2022-11-18 2024-05-23 Kyoto Prefectural Public University Corporation Compositions for mitophagy induction and uses thereof
WO2024163678A2 (en) 2023-02-01 2024-08-08 Tune Therapeutics, Inc. Fusion proteins and systems for targeted activation of frataxin (fxn) and related methods
WO2024163683A2 (en) 2023-02-01 2024-08-08 Tune Therapeutics, Inc. Systems, compositions, and methods for modulating expression of methyl-cpg binding protein 2 (mecp2) and x-inactive specific transcript (xist)
WO2024168253A1 (en) 2023-02-10 2024-08-15 Possible Medicines Llc Delivery of an rna guided recombination system
WO2024168265A1 (en) 2023-02-10 2024-08-15 Possible Medicines Llc Aav delivery of rna guided recombination system
WO2024206911A2 (en) 2023-03-30 2024-10-03 Children's Hospital Medical Center Clinical-grade organoids
WO2024211887A1 (en) * 2023-04-07 2024-10-10 Genentech, Inc. Modified guide rnas
WO2024220741A1 (en) 2023-04-19 2024-10-24 Flagship Pioneering Innovations Vii, Llc Compositions and methods for the production of libraries
WO2024236547A1 (en) 2023-05-18 2024-11-21 Inceptor Bio, Llc Modified phagocytic cells expressing chimeric antigen receptors comprising a herpes virus entry mediator (hvem) co-stimulatory domain and uses thereof
WO2024238977A2 (en) 2023-05-18 2024-11-21 Children's Hospital Medical Center Liver organoids with intrahepatic sympathetic nerves, and methods of use thereof
US12630838B2 (en) 2023-06-01 2026-05-19 Egenesis, Inc. Cells, tissues, organs, and animals having one or more modified genes for enhanced xenograft survival and tolerance
WO2024263961A2 (en) 2023-06-23 2024-12-26 Children's Hospital Medical Center Methods of matrix-free suspension culture
WO2025006419A1 (en) 2023-06-26 2025-01-02 Flagship Pioneering Innovations Vii, Llc Engineered plasmodia and related methods
WO2025006963A1 (en) 2023-06-30 2025-01-02 Regeneron Pharmaceuticals, Inc. Methods and compositions for increasing homology-directed repair
WO2025029657A2 (en) 2023-07-28 2025-02-06 Regeneron Pharmaceuticals, Inc. Anti-tfr:gaa and anti-cd63:gaa insertion for treatment of pompe disease
WO2025029654A2 (en) 2023-07-28 2025-02-06 Regeneron Pharmaceuticals, Inc. Use of bgh-sv40l tandem polya to enhance transgene expression during unidirectional gene insertion
WO2025029662A1 (en) 2023-07-28 2025-02-06 Regeneron Pharmaceuticals, Inc. Anti-tfr: acid sphingomyelinase for treatment of acid sphingomyelinase deficiency
WO2025029840A1 (en) 2023-07-31 2025-02-06 Tune Therapeutics, Inc. Compositions and methods for multiplexed activation and repression of t cell gene expression
WO2025029835A1 (en) 2023-07-31 2025-02-06 Tune Therapeutics, Inc. Compositions and methods for modulating il-2 gene expression
WO2025038494A1 (en) 2023-08-11 2025-02-20 Tune Therapeutics, Inc. Compositions, systems, and methods for lymphoid cell differentiation using targeted gene activation
WO2025049524A1 (en) 2023-08-28 2025-03-06 Regeneron Pharmaceuticals, Inc. Cxcr4 antibody-resistant modified receptors
WO2025046513A1 (en) 2023-08-29 2025-03-06 Inceptor Bio, Llc Methods of manufacturing myeloid-derived cells from hematopoietic stem cells and compositions and uses thereof
WO2025059073A1 (en) 2023-09-11 2025-03-20 Tune Therapeutics, Inc. Epigenetic editing methods and systems for differentiating stem cells
WO2025072803A1 (en) 2023-09-29 2025-04-03 Children's Hospital Medical Center Ntrk2 signaling-mediated alveolar capillary injury and repair
WO2025096638A2 (en) 2023-10-30 2025-05-08 Turnstone Biologics Corp. Genetically modified tumor infilitrating lymphocytes and methods of producing and using the same
WO2025128343A1 (en) 2023-12-11 2025-06-19 Just-Evotec Biologics, Inc. Protein expression using trans-splicing and split selectable markers
WO2025184567A1 (en) 2024-03-01 2025-09-04 Regeneron Pharmaceuticals, Inc. Methods and compositions for re-dosing aav using anti-cd40 antagonistic antibody to suppress host anti-aav antibody response
WO2025212920A1 (en) 2024-04-03 2025-10-09 Children's Hospital Medical Center Multi-zonal liver organoids
WO2025217202A1 (en) 2024-04-08 2025-10-16 Children's Hospital Medical Center Bile duct organoid
WO2025235388A1 (en) 2024-05-06 2025-11-13 Regeneron Pharmaceuticals, Inc. Transgene genomic identification by nuclease-mediated long read sequencing
WO2025260068A1 (en) 2024-06-14 2025-12-18 Tune Therapeutics, Inc. Lipid nanoparticle formulation for delivery of nucleic acids to cells
WO2025265017A1 (en) 2024-06-20 2025-12-26 Regeneron Pharmaceuticals, Inc. Ass1 gene insertion for the treatment of citrullinemia type i
WO2026015647A1 (en) 2024-07-09 2026-01-15 Tune Therapeutics, Inc. Compositions, systems, and methods for cell differentiation using targeted gene activation of dll4 and/or vcam1
WO2026047626A1 (en) 2024-08-30 2026-03-05 Inceptor Bio, Llc Compositions and methods involving immune cells engineered for binding bispecific antibodies for use in cell therapy
EP4711442A1 (en) 2024-09-15 2026-03-18 Quantitative Biosciences, Inc. Microfluidic chip for the parallel culture of microbial biosensor strains
WO2026064753A1 (en) 2024-09-23 2026-03-26 Tune Therapeutics, Inc. Dna methyltransferase-like protein (dnmt3l) or dna methyltransferase 3a (dnmt3a) repressor systems for epigenetic editing
WO2026072529A1 (en) 2024-09-24 2026-04-02 University Of Florida Research Foundation, Incorporated Mettl7a for improved embryo competence
WO2026080515A2 (en) 2024-10-08 2026-04-16 Regeneron Pharmaceuticals, Inc. Crispr sam biosensor cells and cell lines and methods of use thereof

Also Published As

Publication number Publication date
CN106480080B (zh) 2020-02-28
US20140170753A1 (en) 2014-06-19
AU2022201052A1 (en) 2022-03-10
AU2022201052B2 (en) 2025-01-23
AU2013359238B2 (en) 2016-07-14
JP6870015B2 (ja) 2021-05-12
JP2016171817A (ja) 2016-09-29
CA2894688A1 (en) 2014-06-19
CN106170549A (zh) 2016-11-30
CN118879746A (zh) 2024-11-01
EP2764103B1 (en) 2015-08-19
AU2016244244B2 (en) 2018-12-13
US20160281072A1 (en) 2016-09-29
CN106170549B (zh) 2020-02-21
RU2019112514A (ru) 2019-06-13
US8771945B1 (en) 2014-07-08
BR112015013785A2 (pt) 2017-07-11
PT2764103E (pt) 2015-11-18
JP2024088668A (ja) 2024-07-02
EP2764103A2 (en) 2014-08-13
HK1216259A1 (en) 2016-10-28
US8697359B1 (en) 2014-04-15
EP2998400A1 (en) 2016-03-23
AU2016244244A1 (en) 2016-11-03
WO2014093661A3 (en) 2014-08-07
AU2025202729A1 (en) 2025-05-08
AU2019201608B2 (en) 2021-12-09
AU2019201608A1 (en) 2019-04-04
KR20150107739A (ko) 2015-09-23
CN106480080A (zh) 2017-03-08
US8945839B2 (en) 2015-02-03
HK1201290A1 (en) 2015-08-28
JP2019115348A (ja) 2019-07-18
JP7090775B2 (ja) 2022-06-24
JP2021104055A (ja) 2021-07-26
ES2552535T3 (es) 2015-11-30
US20140227787A1 (en) 2014-08-14
AU2025202729A9 (en) 2026-03-05
WO2014093661A9 (en) 2014-10-16
AU2013359238A1 (en) 2015-07-30
US20150203872A1 (en) 2015-07-23
PL2764103T3 (pl) 2016-05-31
CN111187772B (zh) 2024-07-19
JP6723094B2 (ja) 2020-07-15
JP7463436B2 (ja) 2024-04-08
JP2016500262A (ja) 2016-01-12
JP6545621B2 (ja) 2019-07-17
US20170175142A1 (en) 2017-06-22
RU2687451C1 (ru) 2019-05-13
CN111187772A (zh) 2020-05-22
US20150184139A1 (en) 2015-07-02
JP2022113799A (ja) 2022-08-04
DK2764103T3 (en) 2015-11-16
US20190153476A1 (en) 2019-05-23

Similar Documents

Publication Publication Date Title
AU2013359238B2 (en) CRISPR-Cas systems and methods for altering expression of gene products
US20250250553A1 (en) Engineering of systems, methods and optimized guide compositions for sequence manipulation
EP2896697B1 (en) Engineering of systems, methods and optimized guide compositions for sequence manipulation
WO2014204727A1 (en) Functional genomics using crispr-cas systems, compositions methods, screens and applications thereof
WO2014093694A1 (en) Crispr-cas nickase systems, methods and compositions for sequence manipulation in eukaryotes
HK1209153B (en) Engineering of systems, methods and optimized guide compositions for sequence manipulation
HK1201290B (en) Crispr-cas systems and methods for altering expression of gene products
HK1202586B (en) Engineering of systems, methods and optimized guide compositions for sequence manipulation

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2013824232

Country of ref document: EP

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13824232

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 2894688

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2015547555

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: P791/2015

Country of ref document: AE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015013785

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 20157018654

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2015128100

Country of ref document: RU

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2013359238

Country of ref document: AU

Date of ref document: 20131212

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112015013785

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150611