EP2456877A1 - Verfahren zur genombearbeitung - Google Patents
Verfahren zur genombearbeitungInfo
- Publication number
- EP2456877A1 EP2456877A1 EP10803004A EP10803004A EP2456877A1 EP 2456877 A1 EP2456877 A1 EP 2456877A1 EP 10803004 A EP10803004 A EP 10803004A EP 10803004 A EP10803004 A EP 10803004A EP 2456877 A1 EP2456877 A1 EP 2456877A1
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- EP
- European Patent Office
- Prior art keywords
- sequence
- protein
- receptor
- cell
- alpha
- 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.)
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- 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
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
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- C—CHEMISTRY; METALLURGY
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- 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
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
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- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
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- A—HUMAN NECESSITIES
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
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- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A—HUMAN NECESSITIES
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A—HUMAN NECESSITIES
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
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- A01K2227/105—Murine
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- A—HUMAN NECESSITIES
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/107—Rabbit
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- A—HUMAN NECESSITIES
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A—HUMAN NECESSITIES
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/70—Invertebrates
- A01K2227/706—Insects, e.g. Drosophila melanogaster, medfly
Definitions
- the invention encompasses a method for creating an animal or cell with at least one chromosomal edit.
- the invention relates to the use of targeted zinc finger nucleases to edit chromosomal sequences.
- Rational genome engineering has enormous potential across basic research, drug discovery, and cell-based medicines.
- Existing methods for targeted gene knock-out or site-specific gene insertion rely on homologous recombination.
- the low rate of spontaneous recombination in certain cell types has been an enormous hurdle to universal genome editing.
- the scale of screening effort and the time required to isolate the targeted event was prohibitive.
- One aspect of the present invention encompasses a method for editing a chromosomal sequence.
- the method comprises, in part, (a) introducing into a cell comprising the chromosomal sequence at least one nucleic acid encoding a zinc finger nuclease that recognizes a target sequence in the chromosomal sequence and is able to cleave a cleavage site in the chromosomal sequence, and, optionally, (i) at least one donor polynucleotide comprising a donor sequence for integration, an upstream sequence, and a downstream sequence, wherein the donor sequence is flanked by the upstream sequence and the downstream sequence, and wherein the upstream sequence and the downstream sequence share substantial sequence identity with either side of the cleavage site, or (ii) at least one exchange polynucleotide comprising an exchange sequence that is substantially identical to a portion of the chromosomal sequence at the cleavage site, and further comprising at least one nucleotide change; and
- the non-human animal may be created in part, by (a) introducing into a cell comprising the chromosomal sequence at least one nucleic acid encoding a zinc finger nuclease that recognizes a target sequence in the chromosomal sequence and is able to cleave a cleavage site in the chromosomal sequence, and, optionally, (i) at least one donor polynucleotide comprising a donor sequence for integration, an upstream sequence, and a downstream sequence, wherein the donor sequence is flanked by the upstream sequence and the downstream sequence, and wherein the upstream sequence and the downstream sequence share substantial sequence identity with either side of the cleavage site, or (ii) at least one exchange polynucleotide comprising an exchange sequence that is substantially identical to a portion of the chromosomal sequence at the cleavage site, and further comprising at least one nucleotide change; and (b) at least one donor polynucleotide comprising an exchange sequence that is
- the cell may be created in part, by in part, by (a) introducing into the cell comprising the chromosomal sequence at least one nucleic acid encoding a zinc finger nuclease that recognizes a target sequence in the chromosomal sequence and is able to cleave a cleavage site in the chromosomal sequence, and, optionally, (i) at least one donor polynucleotide comprising a donor sequence for integration, an upstream sequence, and a downstream sequence, wherein the donor sequence is flanked by the upstream sequence and the downstream sequence, and wherein the upstream sequence and the downstream sequence share substantial sequence identity with either side of the cleavage site, or (ii) at least one exchange polynucleotide comprising an exchange sequence that is substantially identical to a portion of the chromosomal sequence at the cleavage site, and further comprising at least one nucleotide change; and (b)
- a further aspect of the present invention encompasses an embryo.
- the embryo comprises at least one nucleic acid encoding a zinc finger nuclease that recognizes a target sequence in the chromosomal sequence and is able to cleave a cleavage site in the chromosomal sequence, and, optionally, (i) at least one donor polynucleotide comprising a donor sequence for integration, an upstream sequence and a downstream sequence, wherein the donor sequence is flanked by the upstream sequence and the downstream sequence and wherein the upstream sequence and the downstream sequence share substantial sequence identity with either side of the cleavage site, or (ii) at least one exchange polynucleotide comprising an exchange sequence that is substantially identical to a portion of the chromosomal sequence at the cleavage site and which further comprises at least one nucleotide change.
- FIG. 1 is a schematic depicting the repair outcomes after a targeted ZFN-induced double stranded break. Shaded bars represent the donor fragment, whereas white bars depict target site for ZFN double stranded break.
- FIG. 2 is a schematic depicting the construction of RFLP donor plasmids. Shown, are the plasmid, and left and right PCR-amplified fragments homologous to the integration target site. Restriction enzymes used for cloning are denoted. The left fragment used Kpnl and Notl or Pmel. The right fragment used Notl or Pmel and Sacll.
- FIG. 3 is a schematic depicting the construction of GFP- expressing donor plasmids. The GFP cassette was PCR amplified from an existing plasmid and cloned into the Notl RFLP donor using a Notl site.
- FIG. 4 is a schematic depicting methods of detecting (A) RFLP integration and restriction enzyme digestion and (B) integration of the GFP expression cassette using PCR amplification.
- FIG. 5 is a photographic image of fluorescently stained PCR fragments resolved on an agarose gel.
- the leftmost lane contains a DNA ladder.
- Lanes 1 to 6 contain PCR fragments amplified using mouse Mdri a-specific primers from a whole or a fraction of a mouse blastocyst. Lanes 1 and 2 were amplified from 5/6 and 1/6 of a blastocyst, respectively. Lane 3 was from one whole blastocyst. Lanes 4 to 6 were from ⁇ A, 1/3, and 1/6 of the same blastocyst, respective. Lane 7 contains a positive control PCR fragment amplified using the same primers from extracted mouse toe DNA.
- FIG. 6 is a photographic image of fluorescently stained DNA fragments resolved on an agarose gel. The leftmost lanes contain a DNA ladder.
- Lanes 1 to 39 contain PCR fragments amplified using mMdri a-specific primers from 37 mouse embryos cultured in vitro after being microinjected with ZFN RNA against mouse MdM a and RFLP donor with Notl site, along with one positive and negative control for PCR amplification.
- Lanes 1 to 39 contain the PCR fragments in (A) after performing the Surveyor's mutation detection assay.
- FIG. 7 is a photographic image of fluorescently stained DNA fragments resolved on an agarose gel. The leftmost and rightmost lanes contain a DNA ladder.
- Lanes contain PCR fragments amplified using mMdria- specific primers from mouse embryos in FIG 6, and digested with Notl without purifying the PCR product.
- FIG. 7B is a longer run of the same gel in FIG. 7A. The uncut PCR products are around 1.8 kb, and the digested products are two bands around 900 bp.
- FIG. 8 is a photographic image of fluorescently stained DNA fragments resolved on an agarose gel. The leftmost lane contains a DNA ladder.
- Lanes 1 to 6 contain some of the PCR fragments from FIG 7 digested with Notl after the PCR products were column purified so that Notl can work in its optimal buffer.
- Lines 7 and 8 are two of the samples digested with Notl as in FIG 7. This gel shows Notl digestion in PCR reactions was complete.
- FIG. 9 is a photographic image of fluorescently stained PCR fragments resolved on an agarose gel.
- the leftmost lane contains a DNA ladder.
- Lanes 1 to 5 contain PCR fragments amplified using PXR-specific primers from 1 , 14, 1/6, 1/10, 1/30 of a rat blastocyst.
- Lane 6 is a positive control amplified using the same primers from purified Sprague Dawley genomic DNA.
- FIG. 10 is a photographic image of fluorescently stained
- Lanes contain PCR fragments amplified from rat embryos cultured in vitro after microinjection of PXR ZFN mRNA and the Notl RFLP donor, using PXR-specific primers and digested with Notl.
- Lanes contain the same PCR fragments as in FIG. 10A after performing the Surveyor's mutation detection assay.
- FIG. 11 is a photographic image of fluorescently stained
- DNA fragments resolved on an agarose gel The first 4 lanes are PCR amplified from 4 well developed fetus at 12.5 days post conception from embryos injected with mMdria ZFN mRNA with the Notl RFLP donor. The PCR was digested with Notl. Lane 4 is positive one. Lanes 5-8 are 4 decidua, aborted implantations. All four were negative.
- FIG. 12 is a schematic and photographic image of
- FIG. 13 is a photographic image of DNA fragments resolved on an agarose gel. Lane 8 represents a 13 dpc fetus positive for the Notl site.
- FIG. 14 illustrates ZFN-mediated cleavage of SMAD4 in human and feline cells, as detected by a Cel-1 surveyor nuclease assay.
- G GFP (no ZFN control).
- Z SMAD4 ZFN (191160/19159). Arrows denote cleavage products.
- FIG. 15 depicts Cel-1 assays confirming SMAD4 ZFN activity in cat embryos.
- FIG. 16 illustrates cleavage of FeI d1 in AKD cells.
- FIG. 17 illustrates cleavage of FeI d1 chain 1 -exon 2 in AKD cells by the FeI d1 ZFN pair 7, 9.
- FIG. 18 depicts Cel-1 analysis of the FeI d1 ZFN pair 12/13 cleavage of chain 1 -exon 2 in AKD cells.
- FIG. 19 illustrates cleavage of FeI d1 locus in cat embryos by ZFN pairs 17, 18 and 12, 13.
- Lanes 1 , 2, 7, and 8 contain samples from individual blastocysts derived from embryos injected with 40 ng/ ⁇ L of ZFNs.
- Lane 3 presents a sample from a blastocyst derived an embryo injected with 20 ng/ ⁇ L of ZFNs.
- Lanes 4, 9, and 10 contain samples from individual morulas derived from embryos injected with 40 ng/ ⁇ L of ZFNs.
- Lane 3 presents a sample from a morula derived an embryo injected with 20 ng/ ⁇ L of ZFNs.
- Lane 6 presents a sample from a control blastocyst.
- FIG. 20 presents the DNA sequence of an edited FeI d1 locus comprising a 4541 bp deletion (SEQ ID NO:51 ) between the regions coding for chain 2 and chain 1.
- FIG. 21 aligns the edited FeI d1 locus (designated by red dotted line, labeled "sample 5") comprising the 4541 bp deletion with the sequence of the wild-type FeI d1 locus (SEQ ID NO:52).
- the binding site for ZFN 13 is truncated (and the binding sire for ZFN 12 is missing), but the binding site for ZFN pair 17, 18 is intact.
- FIG. 22 depicts cleavage of the cauxin locus by cauxin ZFN pair 1/2 (lane 2), ZFN pair 9/10 (lane 4), and ZFN pair 17/18 (lane 5) in AKD cells.
- Lanes 1 and 3 contain samples from control (GFP) cells.
- FIG. 23 illustrates cleavage of the cauxin locus by cauxin
- Lane 2 contains a control (GFP) sample.
- FIG. 24 depicts integration at the TUBA1 B locus.
- A is a schematic showing the chromosome sequence (SEQ ID NO:85) at the target region for integration of the heterologous coding sequence, ZFN binding sites (yellow sequence) on the chromosome target region, the ZFN cut site (yellow arrow), and the integration site (green arrow).
- B presents schematics of the TUBA1 B locus, site of integration, design of the SH2 biosensor, and the proteins expressed after successful integration.
- C presents an image of a Western blot of wild-type and integrated cells.
- FIG. 25 depicts the map of a donor plasmid comprising the
- FIG. 26 presents differential interference contrast (DIC) and fluorescence microscopy images of individual isolated cell clones expressing the GFP-2xSH2-Grb1 -2A protein. Fluorescent images show a time course of biosensor translocation after exposure to 100 ng/mL of EGF.
- DIC differential interference contrast
- FIG. 27 presents the map of a donor plasmid comprising the
- FIG. 28 depicts fluorescence microscopy images of individual isolated cell clones expressing GFP-2xSH2-Grb1 -2A (upper panels) and RFP- ⁇ -actin (lower panels). Presented is a time course after exposure to 100 ng/mL of EGF.
- FIG. 29 presents the DNA sequences of two edited LRRK2 loci.
- the upper sequence (SEQ ID NO:92) has a 10 bp deletion in the target sequence of exon 30, and the lower sequence (SEQ ID NO:93) has a 8 bp deletion in the target sequence of exon 30.
- the exon is shown in green; the target site is presented in yellow, and the deletions are shown in dark blue.
- FIG. 30 presents the DNA sequences of two edited ApoE loci.
- the upper sequence (SEQ ID NO:114) has a 16 bp deletion in the target sequence of exon 2
- the lower sequence (SEQ ID NO:115) has a 1 bp deletion in the target sequence of exon 2.
- the exon sequence is shown in green; the target site is presented in yellow, and the deletions are shown in dark blue.
- FIG. 31 shows the DNA sequence of an edited leptin locus.
- FIG. 32 presents the DNA sequences of edited APP loci in two animals.
- A Shows a region of the rat APP locus (SEQ ID NO:127) in which 292 bp is deleted from exon 9.
- B Presents a region of the rat APP locus (SEQ ID NO:128) in which there is a 309 bp deletion in exon 9. The exon is shown in green; the target site is presented in yellow, and the deletion is shown in dark blue.
- FIG. 33 presents the DNA sequences of edited Rag1 loci in two animals.
- the upper sequence (SEQ ID NO:131 ) has a 808 bp deletion in exon 2
- the lower sequence (SEQ ID NO:132) has a 29 bp deletion in exon 2.
- the exon sequence is shown in green; the target site is presented in yellow, and the deletions are shown in dark blue.
- FIG. 34 presents the DNA sequences of edited Rag2 loci in two animals.
- the upper sequence (SEQ ID NO:133) has a 13 bp deletion in the target sequence in exon 3
- the lower sequence (SEQ ID NO:134) has a 2 bp deletion in the target sequence in exon 2.
- the exon sequence is shown in green; the target site is presented in yellow, and the deletions are shown in dark blue.
- FIG. 35 presents the DNA sequences of edited Mdri a loci in two animals.
- the upper sequence (SEQ ID NO:157) has a 20 bp deletion in exon 7
- the lower sequence (SEQ ID NO:158) has a 15 bp deletion and a 3 bp insertion (GCT) in exon 7.
- the exon sequence is shown in green; the target sequence is presented in yellow, and the deletions are shown in dark blue.
- FIG. 36 illustrates knockout of the Mdri a gene in rat.
- FIG. 37 presents the DNA sequences of edited Mrp1 loci in two animals.
- the upper sequence (SEQ ID NO:159) has a 43 bp deletion in exon 11
- the lower sequence (SEQ ID NO:160) has a 14 bp deletion in exon 11.
- the exon sequence is shown in green; the target sequence is presented in yellow, the deletions are shown in dark blue; and overlap between the target sequence and the exon is shown in grey.
- FIG. 38 shows the DNA sequence of an edited Mrp2 locus.
- the sequence (SEQ ID NO:161 ) has a 726 bp deletion in exon 7.
- the exon is shown in green; the target sequence is presented in yellow, and the deletion is shown in dark blue.
- FIG. 39 presents the DNA sequences of edited BCRP loci in two animals.
- A Shows a region of the rat BCRP locus (SEQ ID NO:162) comprising a 588 bp deletion in exon 7.
- B Presents a region of the rat BCRP locus (SEQ ID NO:163) comprising a 696 bp deletion in exon 7. The exon sequence is shown in green; the target site is presented in yellow, and the deletions are shown in dark blue.
- FIG. 40 presents target sites and ZFN validation of Mdri a, and two additional genes, Jag1 , and Notch3.
- A shows ZFN target sequences. The ZFN binding sites are underlined.
- B shows results of a mutation detection assay in NIH 3T3 cells to validate the ZFN mRNA activity. Each ZFN mRNA pair was cotransfected into NIH 3T3 cells. Transfected cells were harvested 24 h later. Genomic DNA was analyzed with the mutation detection assay to detect NHEJ products, indicative of ZFN activity.
- M PCR marker
- G las 1 , 3, and 5): GFP transfected control
- Z lanes 2, 4, and 6
- Uncut and cleaved bands are marked with respective sizes in base pairs.
- FIG. 41 presents identification of genetically engineered
- Mdri a founders using a mutation detection assay. Uncut and cleaved bands are marked with respective sizes in base pairs. Cleaved bands indicate a mutation is present at the target site. M, PCR marker. 1 -44, 44 pups born from injected eggs. The numbers of founders are underlined.
- FIG. 42 presents amplification of large deletions in MdM a founders. PCR products were amplified using primers located 800 bp upstream and downstream of the ZFN target site. Bands significantly smaller than the 1.6 kb wild-type band indicate large deletions in the target locus. Four founders that were not identified in Figure 7 are underlined.
- FIG. 43 presents the results of a mutation detection assay at the Mdri b site in 44 MdM a ZFN injected pups.
- M PCR marker
- WT toe DNA from FVB/N mice that were not injected with Mdri a ZFNs
- FIG. 44 presents detection of Mdri a expression by using
- RT-PCR in MdM a-/- mice is a schematic illustration of Mdria genomic and mRNA structures around the target site. Exons are represented by open rectangles with respective numbers. The size of each exon in base pairs is labeled directly underneath, lntron sequences are represented by broken bars with size in base pairs underneath. The ZFN target site in exon 7 is marked with a solid rectangle. The position of the 396 bp deletion in founder #23 is labeled above intron 6 and exon 7.
- RT-F and RT-R are the primers used in RT-PCR, located in exons 5 and 9, respectively. In the RT reaction, 40 ng of total RNA was used as template. Normalization of the input RNA is confirmed by GAPDH amplification with or without RT.
- FIG. 45 presents the results of band isolation following isolation and purification of the species at the wild-type size in the MdM a-/- samples, and then use as a template in a nested PCR.
- FIG. 46 shows the DNA sequences of edited BDNF loci in two animals. The upper sequence (SEQ ID NO:211 ) has a 14 bp deletion in the target sequence in exon 2, and the lower sequence (SEQ ID NO:212) has a 7 bp deletion in the target sequence in exon 2. The exon is shown in green; the target site is presented in yellow, and the deletions are shown in dark blue.
- FIG. 47 presents the DNA sequence of an edited DISC1 locus.
- a region of the rat DISC1 (SEQ ID NO:225) in which there is a 20 bp deletion in the target sequence in exon 5. The exon is shown in green; the target site is presented in yellow, and the deletion is shown in dark blue.
- FIG. 48 illustrates editing of the p53 locus in rats.
- a Cel-1 assay in which the presence of cleavage products indicated editing of the p53 gene.
- FIG. 49 illustrates knockout of the p53 gene in rats.
- the present disclosure provides a method for creating a genetically modified animal or animal cell comprising at least one edited chromosomal sequence.
- the edited chromosomal sequence may be (1 ) inactivated, (2) modified, or (3) comprise an integrated sequence.
- An inactivated chromosomal sequence is altered such that a functional protein is not made or a control sequence no longer functions the same as a wild-type control sequence.
- a genetically modified animal comprising an inactivated chromosomal sequence may be termed a "knock-out” or a “conditional knock-out.”
- a genetically modified animal comprising an integrated sequence may be termed a "knock-in” or a “conditional knock-in.”
- a knock-in animal may be a humanized animal.
- a genetically modified animal comprising a modified chromosomal sequence may comprise a targeted point mutation(s) or other modification such that an altered protein product is produced.
- chromosomal sequence generally is edited using a zinc finger nuclease- mediated process.
- the process comprises introducing into a cell at least one nucleic acid encoding a targeted zinc finger nuclease and, optionally, at least one accessory polynucleotide.
- the method further comprises incubating the cell to allow expression of the zinc finger nuclease, wherein a double-stranded break introduced into the targeted chromosomal sequence by the zinc finger nuclease is repaired by an error-prone non-homologous end-joining DNA repair process or a homology-directed DNA repair process.
- the cell is an embryo.
- the method of editing chromosomal sequences using targeted zinc finger nuclease technology as described herein is rapid, precise, and highly efficient.
- the invention encompasses an animal or a cell comprising at least one edited chromosomal sequence.
- a method of the invention, an animal of the invention, a cell of the invention, and applications thereof are described in more detail below.
- chromosomal editing refers to editing a chromosomal sequence such that the sequence is (1 ) inactivated, (2) modified, or (3) comprises an integrated sequence.
- a method for editing a chromosomal sequence comprises: (a) introducing into a cell at least one nucleic acid encoding a zinc finger nuclease that recognizes a target sequence in the chromosomal sequence and is able to cleave a site in the chromosomal sequence, and, optionally, (i) at least one donor polynucleotide comprising a sequence for integration, the sequence flanked by an upstream sequence and a downstream sequence that share substantial sequence identity with either side of the cleavage site, or (ii) at least one exchange polynucleotide comprising a sequence that is substantially identical to a portion of the
- chromosomal sequence at the cleavage site and which further comprises at least one nucleotide change and (b) culturing the cell to allow expression of the zinc finger nuclease such that the zinc finger nuclease introduces a double-stranded break into the chromosomal sequence, and wherein the double-stranded break is repaired by (i) a non-homologous end-joining repair process such that a mutation is introduced into the chromosomal sequence, or (ii) a homology-directed repair process such that the sequence in the donor polynucleotide is integrated into the chromosomal sequence or the sequence in the exchange polynucleotide is exchanged with the portion of the chromosomal sequence.
- the method comprises, in part, introducing into a cell at least one nucleic acid encoding a zinc finger nuclease.
- a zinc finger nuclease comprises a DNA binding domain (i.e., zinc finger) and a cleavage domain (i.e., nuclease).
- the DNA binding and cleavage domains are described below.
- the nucleic acid encoding a zinc finger nuclease may comprise DNA or RNA.
- the nucleic acid encoding a zinc finger nuclease may comprise mRNA.
- the nucleic acid encoding a zinc finger nuclease comprises mRNA
- the mRNA molecule may be 5' capped.
- the nucleic acid encoding a zinc finger nuclease comprises mRNA
- the mRNA molecule may be polyadenylated.
- An exemplary nucleic acid according to the method is a capped and polyadenylated mRNA molecule encoding a zinc finger nuclease. Methods for capping and polyadenylating mRNA are known in the art.
- a zinc finger nuclease of the invention once introduced into a cell, creates a double-stranded break in the chromosomal sequence.
- the double-stranded break may be repaired, in certain embodiments, by a non-homologous end-joining repair process of the cell, such that a mutation is introduced into the chromosomal sequence.
- a homology-directed repair process is used to edit the chromosomal sequence.
- Zinc finger binding domains may be engineered to recognize and bind to any nucleic acid sequence of choice. See, for example, Beerli et al. (2002) Nat. Biotechnol. 20:135-141 ; Pabo et al. (2001 ) Ann. Rev. Biochem. 70:313-340; lsalan et al. (2001 ) Nat. Biotechnol. 19:656-660; Segal et al. (2001 ) Curr. Opin. Biotechnol. 12:632-637; Choo et al. (2000) Curr. Opin. Struct. Biol. 10:411 -416; Zhang et al. (2000) J. Biol. Chem.
- An engineered zinc finger binding domain may have a novel binding specificity compared to a naturally-occurring zinc finger protein.
- Engineering methods include, but are not limited to, rational design and various types of selection.
- Rational design includes, for example, using databases comprising doublet, triplet, and/or quadruplet nucleotide sequences and individual zinc finger amino acid sequences, in which each doublet, triplet or quadruplet nucleotide sequence is associated with one or more amino acid sequences of zinc fingers which bind the particular triplet or quadruplet sequence.
- databases comprising doublet, triplet, and/or quadruplet nucleotide sequences and individual zinc finger amino acid sequences, in which each doublet, triplet or quadruplet nucleotide sequence is associated with one or more amino acid sequences of zinc fingers which bind the particular triplet or quadruplet sequence.
- U.S. Patent Nos. 6,453,242 and 6,534,261 the disclosures of which are incorporated by reference herein in their entireties.
- the algorithm described in U.S. Patent No. 6,453,242 may be used to design a zinc finger binding domain to target a preselected sequence.
- a zinc finger DNA binding domain may be designed to recognize a DNA sequence ranging from about 3 nucleotides to about 21 nucleotides in length, or from about 8 to about 19 nucleotides in length.
- the zinc finger binding domains of the zinc finger nucleases disclosed herein comprise at least three zinc finger recognition regions (i.e., zinc fingers).
- the zinc finger binding domain may comprise four zinc finger recognition regions.
- the zinc finger binding domain may comprise five zinc finger recognition regions.
- the zinc finger binding domain may comprise six zinc finger recognition regions.
- a zinc finger binding domain may be designed to bind to any suitable target DNA sequence. See for example, U.S. Patent Nos. 6,607,882; 6,534,261 and
- Exemplary methods of selecting a zinc finger recognition region may include phage display and two-hybrid systems, and are disclosed in U.S. Patent. Nos. 5,789,538; 5,925,523; 6,007,988; 6,013,453; 6,410,248;
- Zinc finger binding domains and methods for design and construction of fusion proteins are known to those of skill in the art and are described in detail in U.S. Patent Application Publication Nos. 20050064474 and 20060188987, each incorporated by reference herein in its entirety.
- Zinc finger recognition regions and/or multi- fingered zinc finger proteins may be linked together using suitable linker sequences, including for example, linkers of five or more amino acids in length. See, U.S. Patent Nos. 6,479,626; 6,903,185; and 7,153,949, the disclosures of which are incorporated by reference herein in their entireties, for non-limiting examples of linker sequences of six or more amino acids in length.
- the zinc finger binding domain described herein may include a combination of suitable linkers between the individual zinc fingers of the protein.
- the zinc finger nuclease may further comprise a nuclear localization signal or sequence (NLS).
- NLS nuclear localization signal or sequence
- a NLS is an amino acid sequence which facilitates targeting the zinc finger nuclease protein into the nucleus to introduce a double stranded break at the target sequence in the chromosome.
- Nuclear localization signals are known in the art. See, for example, Makkerh et al. (1996) Current Biology 6:1025-1027.
- a zinc finger nuclease also includes a cleavage domain.
- the cleavage domain portion of the zinc finger nucleases disclosed herein may be obtained from any endonuclease or exonuclease.
- Non-limiting examples of endonucleases from which a cleavage domain may be derived include, but are not limited to, restriction endonucleases and homing endonucleases. See, for example, 2002-2003 Catalog, New England Biolabs, Beverly, Mass.; and Belfort et al. (1997) Nucleic Acids Res. 25:3379-3388 or www.neb.com.
- cleave DNA e.g., S1 Nuclease; mung bean nuclease; pancreatic DNase I; micrococcal nuclease; yeast HO endonuclease. See also Linn et al. (eds.) Nucleases, Cold Spring Harbor Laboratory Press, 1993. One or more of these enzymes (or functional fragments thereof) may be used as a source of cleavage domains.
- a cleavage domain also may be derived from an enzyme or portion thereof, as described above, that requires dimehzation for cleavage activity.
- Two zinc finger nucleases may be required for cleavage, as each nuclease comprises a monomer of the active enzyme dimer.
- a single zinc finger nuclease may comprise both monomers to create an active enzyme dimer.
- an "active enzyme dimer” is an enzyme dimer capable of cleaving a nucleic acid molecule.
- the two cleavage monomers may be derived from the same endonuclease (or functional fragments thereof), or each monomer may be derived from a different endonuclease (or functional fragments thereof).
- the recognition sites for the two zinc finger nucleases are preferably disposed such that binding of the two zinc finger nucleases to their respective recognition sites places the cleavage monomers in a spatial orientation to each other that allows the cleavage monomers to form an active enzyme dimer, e.g., by dimerizing.
- the near edges of the recognition sites may be separated by about 5 to about 18 nucleotides. For instance, the near edges may be separated by about 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17 or 18 nucleotides.
- any integral number of nucleotides or nucleotide pairs may intervene between two recognition sites (e.g., from about 2 to about 50 nucleotide pairs or more).
- the near edges of the recognition sites of the zinc finger nucleases such as for example those described in detail herein, may be separated by 6 nucleotides.
- the site of cleavage lies between the recognition sites.
- Restriction endonucleases are present in many species and are capable of sequence-specific binding to DNA (at a recognition site), and cleaving DNA at or near the site of binding.
- Certain restriction enzymes e.g., Type IIS
- Fok I catalyzes double-stranded cleavage of DNA, at 9 nucleotides from its recognition site on one strand and 13 nucleotides from its recognition site on the other. See, for example, U.S. Patent Nos.
- a zinc finger nuclease may comprise the cleavage domain from at least one Type IIS restriction enzyme and one or more zinc finger binding domains, which may or may not be engineered.
- Exemplary Type IIS restriction enzymes are described for example in
- An exemplary Type MS restriction enzyme whose cleavage domain is separable from the binding domain, is Fok I.
- This particular enzyme is active as a dimer (Bitinaite et al. (1998) Proc. Natl. Acad. Sci. USA 95: 10, 570- 10, 575).
- the portion of the Fok I enzyme used in a zinc finger nuclease is considered a cleavage monomer.
- two zinc finger nucleases each comprising a Fokl cleavage monomer, may be used to reconstitute an active enzyme dimer.
- a single polypeptide molecule containing a zinc finger binding domain and two Fok I cleavage monomers may also be used.
- the cleavage domain may comprise one or more engineered cleavage monomers that minimize or prevent
- amino acid residues at positions 446, 447, 479, 483, 484, 486, 487, 490, 491 , 496, 498, 499, 500, 531 , 534, 537, and 538 of Fok I are all targets for influencing dimehzation of the Fok I cleavage half-domains.
- Exemplary engineered cleavage monomers of Fok I that form obligate heterodimers include a pair in which a first cleavage monomer includes mutations at amino acid residue positions 490 and 538 of Fok I and a second cleavage monomer that includes mutations at amino-acid residue positions 486 and 499.
- the engineered cleavage monomers may be prepared by mutating positions 490 from E to K and 538 from I to K in one cleavage monomer to produce an engineered cleavage monomer designated "E49OK:I538K” and by mutating positions 486 from Q to E and 499 from I to L in another cleavage monomer to produce an engineered cleavage monomer designated "Q486E:I499L.”
- the above described engineered cleavage monomers are obligate heterodimer mutants in which aberrant cleavage is minimized or abolished.
- Engineered cleavage monomers may be prepared using a suitable method, for example, by site-directed mutagenesis of wild-type cleavage monomers (Fok I) as described in U.S. Patent Publication No. 20050064474 (see Example 5).
- the zinc finger nuclease described above may be any zinc finger nuclease.
- the double stranded break may be at the targeted site of integration, or it may be up to 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 nucleotides away from the site of integration. In some embodiments, the double stranded break may be up to 1 , 2, 3, 4, 5, 10, 15, or 20 nucleotides away from the site of integration. In other embodiments, the double stranded break may be up to 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides away from the site of integration. In yet other embodiments, the double stranded break may be up to 50, 100, or 1000 nucleotides away from the site of integration.
- a zinc finger nuclease of the invention may have an amino acid sequence that is at least 80% identical to a sequence chosen from a zinc finger nuclease having a SEQ ID NO chosen from 53, 54, 57- 62, 69-76, 104-113, 123-126, 147-156, 201 -210, 219-222, 223-224, 230-233, 240-243.
- sequence identity may be about 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, or 100%.
- NO chosen from 53, 54, 57-62, 69-76, 104-113, 123-126, 147-156, 201 -210, 219-222, 223-224, 230-233, 240-243 may recognize and bind a chromosomal sequence having at least about 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, or 100% sequence identity to a chromosomal SEQ ID NO 55, 56, 63-68, 77-84, 86- 91 , 94-103, 117-122, 129, 130, 135, 136, 137, 138, 139-146, 164-173, 213-218, 226-229, 234, 235, 236, 237, 238, 239.
- nuclease having a target site in a chromosome may be used in the methods disclosed herein.
- homing endonucleases and meganucleases have very long recognition sequences, some of which are likely to be present, on a statistical basis, once in a human-sized genome.
- Any such nuclease having a unique target site in a genome may be used instead of, or in addition to, a zinc finger nuclease, for targeted cleavage of a chromosome.
- Non-limiting examples of homing endonucleases include I-
- endonucleases is not absolute with respect to their recognition sites, the sites are of sufficient length that a single cleavage event per mammalian-sized genome may be obtained by expressing a homing endonuclease in a cell containing a single copy of its recognition site. It has also been reported that the specificity of homing endonucleases and meganucleases may be engineered to bind non- natural target sites. See, for example, Chevalier et al. (2002) Molec. Cell 10:895- 905; Epinat et al. (2003) Nucleic Acids Res. 31 :2952-2962; Ashworth et al.
- a method for editing chromosomal sequences may further comprise introducing into a cell at least one exchange polynucleotide comprising a sequence that is substantially identical to the chromosomal sequence at the site of cleavage and which further comprises at least one specific nucleotide change.
- the exchange polynucleotide will be DNA.
- the exchange polynucleotide may be a DNA plasmid, a bacterial artificial
- chromosome BAC
- yeast artificial chromosome a viral vector
- BAC chromosome
- YAC yeast artificial chromosome
- viral vector a linear piece of DNA, a PCR fragment, a naked nucleic acid, or a nucleic acid
- An exemplary exchange polynucleotide may be a DNA plasmid.
- sequence of the exchange polynucleotide will share enough sequence identity with the chromosomal sequence such that the two sequences may be exchanged by homologous recombination.
- sequence in the exchange polynucleotide may be at least about 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, or 99% identical to a region of the chromosomal sequence.
- the sequence in the exchange polynucleotide comprises at least one specific nucleotide change with respect to the sequence of the corresponding chromosomal sequence.
- one nucleotide in a specific codon may be changed to another nucleotide such that the codon codes for a different amino acid.
- the sequence in the exchange polynucleotide may comprise one specific nucleotide change such that the encoded protein comprises one amino acid change.
- the sequence in the exchange polynucleotide may comprise two, three, four, or more specific nucleotide changes such that the encoded protein comprises one, two, three, four, or more amino acid changes.
- sequence in the exchange polynucleotide may comprise a three nucleotide deletion or insertion such that the reading frame of the coding reading is not altered (and a functional protein may be produced).
- the expressed protein would comprise a single amino acid deletion or insertion.
- the length of the sequence in the exchange polynucleotide that is substantially identical to a portion of the chromosomal sequence at the site of cleavage can and will vary.
- the sequence in the exchange polynucleotide may range from about 25 bp to about 10,000 bp in length.
- the sequence in the exchange polynucleotide may be about 50, 100, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200, 4400, 4600, 4800, or 5000 bp in length.
- the sequence in the exchange polynucleotide may be about 5500, 6000, 6500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, or 10,000 bp in length.
- a double stranded break introduced into the chromosomal sequence by the zinc finger nuclease is repaired, via homologous recombination with the exchange polynucleotide, such that the sequence in the exchange polynucleotide may be exchanged with a portion of the chromosomal sequence.
- the presence of the double stranded break facilitates homologous recombination and repair of the break.
- the exchange polynucleotide may be physically integrated or, alternatively, the exchange polynucleotide may be used as a template for repair of the break, resulting in the exchange of the sequence information in the exchange polynucleotide with the sequence information in that portion of the chromosomal sequence.
- a portion of the endogenous chromosomal sequence may be converted to the sequence of the exchange polynucleotide.
- the changed nucleotide(s) may be at or near the site of cleavage. Alternatively, the changed nucleotide(s) may be anywhere in the exchanged sequences. As a consequence of the exchange, however, the chromosomal sequence is modified.
- a method for editing chromosomal sequences may alternatively comprise introducing at least one donor polynucleotide comprising a sequence for integration into a cell.
- a donor polynucleotide comprises at least three components: the sequence to be integrated that is flanked by an upstream sequence and a downstream sequence, wherein the upstream and downstream sequences share sequence similarity with either side of the site of integration in the chromosome.
- the donor polynucleotide will be DNA.
- the donor polynucleotide may be a DNA plasmid, a bacterial artificial chromosome (BAC), a yeast artificial chromosome (YAC), a viral vector, a linear piece of DNA, a PCR fragment, a naked nucleic acid, or a nucleic acid complexed with a delivery vehicle such as a liposome or poloxamer.
- An exemplary donor polynucleotide may be a DNA plasmid.
- the donor polynucleotide comprises a sequence for integration.
- the sequence for integration may be a sequence endogenous to the animal or cell or it may be an exogenous sequence.
- the sequence for integration may encode a protein or a non-coding RNA (e.g., a microRNA).
- sequence for integration may be operably linked to an appropriate control sequence or sequences.
- sequence for integration may provide a regulatory function. Accordingly, the size of the sequence for integration can and will vary. In general, the sequence for integration may range from about one nucleotide to several million nucleotides.
- the donor polynucleotide also comprises upstream and downstream sequence flanking the sequence to be integrated.
- the upstream and downstream sequences in the donor polynucleotide are selected to promote recombination between the chromosomal sequence of interest and the donor polynucleotide.
- the upstream sequence refers to a nucleic acid sequence that shares sequence similarity with the chromosomal sequence upstream of the targeted site of integration.
- the downstream sequence refers to a nucleic acid sequence that shares sequence similarity with the chromosomal sequence downstream of the targeted site of integration.
- the upstream and downstream sequences in the donor polynucleotide may share about 75%, 80%, 85%, 90%, 95%, or 100% sequence identity with the targeted chromosomal sequence. In other embodiments, the upstream and downstream sequences in the donor polynucleotide may share about 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the targeted chromosomal sequence. In an exemplary embodiment, the upstream and downstream sequences in the donor polynucleotide may share about 99% or 100% sequence identity with the targeted chromosomal sequence.
- An upstream or downstream sequence may comprise from about 20 bp to about 2500 bp.
- an upstream or downstream sequence may comprise about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or 2500 bp.
- An exemplary upstream or downstream sequence may comprise about 200 bp to about 2000 bp, about 600 bp to about 1000 bp, or more particularly about 700 bp to about 1000 bp.
- the donor polynucleotide may further comprise a marker.
- a marker may make it easy to screen for targeted integrations.
- suitable markers include restriction sites, fluorescent proteins, or selectable markers.
- a donor polynucleotide may be physically integrated or, alternatively, the donor polynucleotide may be used as a template for repair of the break, resulting in the introduction of the sequence as well as all or part of the upstream and downstream sequences of the donor polynucleotide into the chromosome.
- the endogenous chromosomal sequence may be converted to the sequence of the donor polynucleotide.
- At least one nucleic acid molecule encoding a zinc finger nuclease and, optionally, at least one exchange polynucleotide or at least one donor polynucleotide is introduced into a cell.
- the term "cell” encompasses any animal cell that comprises a chromosomal sequence.
- the term "cell” may refer to an embryo.
- the embryo is a fertilized one-cell stage embryo. In other exemplary embodiments, the embryo may be an embryo of any stage.
- Suitable methods of introducing the nucleic acids to the embryo or cell may include microinjection, electroporation, sonoporation, biolistics, calcium phosphate-mediated transfection, cationic transfection, liposome transfection, dendrimer transfection, heat shock transfection, nucleofection transfection, magnetofection, lipofection, impalefection, optical transfection, proprietary agent-enhanced uptake of nucleic acids, and delivery via liposomes, immunoliposomes, virosomes, or artificial virions.
- biolistics calcium phosphate-mediated transfection, cationic transfection, liposome transfection, dendrimer transfection, heat shock transfection, nucleofection transfection, magnetofection, lipofection, impalefection, optical transfection, proprietary agent-enhanced uptake of nucleic acids, and delivery via liposomes, immunoliposomes, virosomes, or artificial virions.
- the nucleic acids may be introduced into an embryo by
- the nucleic acids may be microinjected into the nucleus or the cytoplasm of the embryo. In another embodiment, the nucleic acids may be introduced into a cell by nucleofection.
- the ratio of exchange (or donor) polynucleotide to nucleic acid encoding a zinc finger nuclease may range from about 1 :10 to about 10:1.
- the ratio of exchange (or donor) polynucleotide to nucleic acid encoding a zinc finger nuclease may be about 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2, 1 :1 , 2:1 , 3:1 , 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , or 10:1.
- the ratio of exchange (or donor) polynucleotide to nucleic acid encoding a zinc finger nuclease may be about 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2, 1 :1 , 2:1 , 3:1 , 4:1 , 5:1 , 6:1 , 7:1 , 8:1 , 9:1 , or 10:1.
- the ratio may be about 1 :1.
- nucleic acids may be introduced simultaneously or sequentially.
- nucleic acids encoding the zinc finger nucleases, each specific for a distinct recognition sequence, as well as the optional exchange (or donor) polynucleotides may be introduced at the same time.
- each nucleic acid encoding a zinc finger nuclease, as well as the optional exchange (or donor) polynucleotides may be introduced sequentially.
- At least one nucleic acid molecule encoding a zinc finger nuclease is introduced into a cell. In another embodiment, at least 2, 3, 4, 5, or more than 5 nucleic acid molecules encoding a zinc finger nuclease are introduced into a cell. In each of the above embodiments, one or more corresponding donor or exchange polynucleotides may also be introduced into the cell, in a ratio from about 1 : 10 to about 10:1 donor or exchange
- polynucleotides to zinc finger nuclease nucleic acids as described above.
- a method for editing a chromosomal sequence using a zinc finger nuclease-mediated process as described herein further comprises culturing the cell comprising the introduced nucleic acid(s) to allow expression of the at least one zinc finger nuclease.
- Cells comprising the introduced nucleic acids may be cultured using standard procedures to allow expression of the zinc finger nuclease. Standard cell culture techniques are described, for example, in
- the embryo may be cultured in vitro (e.g., in cell culture). Typically, the embryo is cultured for a short period of time at an appropriate temperature and in appropriate media with the necessary O2/CO2 ratio to allow the expression of the zinc finger nuclease.
- culture conditions can and will vary depending on the embryo species. Routine optimization may be used, in all cases, to determine the best culture conditions for a particular species of embryo.
- a cell line may be derived from an in vitro-cultured embryo (e.g., an embryonic stem cell line).
- the embryo will be cultured in vivo by transferring the embryo into the uterus of a female host.
- the female host is from the same or a similar species as the embryo.
- the female host is pseudo-pregnant. Methods of preparing pseudo-pregnant female hosts are known in the art. Additionally, methods of transferring an embryo into a female host are known. Culturing an embryo in vivo permits the embryo to develop and may result in a live birth of an animal derived from the embryo. Such an animal generally will comprise the disrupted chromosomal sequence(s) in every cell of its body.
- the chromosomal sequence of the cell may be edited.
- the zinc finger nuclease recognizes, binds, and cleaves the target sequence in the chromosomal sequence of interest.
- the double-stranded break introduced by the zinc finger nuclease is repaired by an error-prone nonhomologous end-joining DNA repair process. Consequently, a deletion, or insertion resulting in a missense or nonsense mutation may be introduced in the chromosomal sequence such that the sequence is inactivated.
- the zinc finger nuclease recognizes, binds, and cleaves the target sequence in the chromosome.
- the double-stranded break introduced by the zinc finger nuclease is repaired, via homologous recombination with the exchange (or donor) polynucleotide, such that a portion of the chromosomal sequence is converted to the sequence in the exchange polynucleotide or the sequence in the donor polynucleotide is integrated into the chromosomal sequence.
- the chromosomal sequence is edited.
- the genetically modified animals disclosed herein may be crossbred to create animals comprising more than one edited chromosomal sequence or to create animals that are homozygous for one or more edited chromosomal sequences. Those of skill in the art will appreciate that many combinations are possible. Moreover, the genetically modified animals disclosed herein may be crossed with other animals to combine the edited chromosomal sequence with other genetic backgrounds.
- suitable genetic backgrounds include wild-type, natural mutations giving rise to known phenotypes, targeted chromosomal integration, non-targeted integrations, etc.
- an edited chromosomal sequence may be inactivated such that the sequence is not transcribed, the coded protein is not produced, or the sequence does not function as the wild-type sequence does.
- a protein coding sequence may be inactivated such that the protein is not produced.
- a microRNA coding sequence may be inactivated such that the microRNA is not produced.
- a control sequence may be inactivated such that it no longer functions as a control sequence.
- control sequence refers to any nucleic acid sequence that effects the transcription, translation, or accessibility of a nucleic acid sequence.
- a promoter, a transcription terminator, and an enhancer are control sequences.
- the inactivated chromosomal sequence may include a deletion mutation (i.e., deletion of one or more nucleotides), an insertion mutation (i.e., insertion of one or more nucleotides), or a nonsense mutation (i.e., substitution of a single nucleotide for another nucleotide such that a stop codon is introduced).
- a chromosomal sequence that is inactivated may be termed a "knock-out.”
- a "knock-out" animal created by a method of the invention does not comprise any exogenous sequence.
- an edited chromosomal sequence may be modified such that it codes for an altered gene product or the function of the sequence is altered.
- a chromosomal sequence encoding a protein may be modified to include at least one changed nucleotide such that the codon comprising the changed nucleotide codes for a different amino acid.
- the resultant protein therefore, comprises at least one amino acid change.
- a protein coding sequence may be modified by insertions or deletions such that the reading from of the sequence is not altered and a modified protein is produced.
- the modified sequence may result in a phenotype change.
- a chromosomal sequence that functions as a control sequence may be modified.
- a promoter may be modified such that it is always active or is regulated by an exogenous signal.
- At least one chromosomal sequence encoding a protein of interest may be edited such that the expression pattern of the protein is altered.
- regulatory regions controlling the expression of the protein such as a promoter or transcription factor binding site, may be altered such that the protein of interest is over-produced, or the tissue- specific or temporal expression of the protein is altered, or a combination thereof. / ' / ' / ' . integrate a sequence
- an edited chromosomal sequence may comprise an integrated sequence.
- Such a sequence may encode an endogenous protein, an exogenous or heterologous protein, a wild-type protein, a modified protein, a fusion protein, a microRNA, or the like.
- An integrated protein coding sequence may be linked to a reporter sequence (the reporter sequence may be linked 5' or 3' to the protein coding sequence).
- An integrated protein coding sequence may also be placed under control of an endogenous promoter, may be operably linked to an exogenous promoter, or may be fused in-frame with an endogenous protein coding sequence.
- the integrated sequence may function as a control element.
- the integrated sequence may be endogenous or exogenous to the cell.
- An animal or cell comprising such an integrated sequence may be termed "knock-in.” In one iteration of the above embodiments, it should be understood that no selectable marker is present.
- a sequence may be integrated to alter the expression pattern of a protein of interest. For instance, a conditional knock-out system may be created.
- a sequence may be edited to alter the expression pattern of a protein of interest. For instance, a conditional knockout system may be created.
- conditional knock-out system is a model where the expression of a nucleic acid molecule is disrupted in a particular organ, tissue, or cell type, as opposed to the entire animal, and/or in a temporally controlled manner.
- a conditional knock-out allows, for example, the study of a gene function even when global disruption of the gene is lethal.
- a non-limiting example of a conditional knock-out system includes a Cre-lox recombination system.
- a Cre-lox recombination system comprises a Cre recombinase enzyme, a site-specific DNA recombinase that can catalyse the recombination of a nucleic acid sequence between specific sites (lox sites) in a nucleic acid molecule.
- Methods of using this system to produce temporal and tissue specific expression are known in the art.
- a genetically modified cell is generated with lox sites flanking a chromosomal sequence of interest.
- a genetically modified animal comprising a cell with the lox-flanked chromosomal sequence of interest may then be crossed with another genetically modified animal expressing Cre recombinase in one or more cells.
- Progeny animals comprising one or more cells comprising a lox-flanked chromosomal sequence and one or more cells comprising a Cre recombinase are then produced.
- the lox-flanked chromosomal sequence encoding a protein of interest is recombined, leading to deletion or inversion of the chromosomal sequence encoding the protein of interest.
- Expression of Cre recombinase may be temporally and conditionally regulated to effect temporally and conditionally regulated recombination of the chromosomal sequence encoding the protein of interest.
- a method of the invention may be used to integrate a mutation that disrupts an endogenous locus.
- a chromosomal sequence may be disrupted by the substitution of an exogenous sequence for an endogenous sequence, such that the exogenous sequence is under the control of the endogenous promoter.
- the disrupted endogenous sequence would not be expressed, but the integrated exogenous sequence would be expressed.
- the exogenous sequence may be a homolog of the endogenous sequence.
- the exogenous sequence may be a human sequence when the endogenous sequence is non-human.
- the exogenous sequence may be unrelated to the endogenous sequence it is replacing.
- an endogenous sequence may be substituted for an exogenous marker such that when the endogenous promoter is active, the marker is detectable.
- the marker may be an enzymatic marker that can amplify the detectable signal of the marker.
- a method of the invention may be used to substitute an endogenous promoter or other regulatory sequence with an exogenous promoter or regulator sequence.
- the expression pattern of the locus would be dictated by the exogenous promoter or regulatory sequence, as opposed to the endogenous promoter or regulatory sequence.
- Such an exogenous promoter or regulatory sequence may be a homolog of the endogenous promoter or regulatory sequence.
- the exogenous sequence may be a human sequence when the endogenous sequence is non-human.
- the exogenous sequence may be unrelated to the endogenous sequence it is replacing.
- a method of the invention may be used to integrate an exogenous sequence, with or without a promoter, into a chromosomal sequence without disrupting the expression of an endogenous locus.
- integration may be in a "safe harbor" locus, such as Rosa26 locus in the rat (or an equivalent in another animal) or the HPRT locus on the X chromosome in the rat (or an equivalent in another animal).
- a cassette comprising an exogenous promoter operably linked to an exogenous nucleic acid sequence may be integrated into a safe harbor locus.
- the exogenous promoter may be conditional.
- a conditional promoter may be a tissue-specific promoter, an organ specific promoter, or a cell-type specific promoter (such as a stem cell promoter, a B-cell promoter, a hair cell promoter, etc.) or an inducible promoter.
- An inducible promoter is a promoter that is active only in the presence of a particular substance, such as an antibiotic, a drug, or other exogenous compound.
- the integration of a cassette comprising a conditional promoter may be used to track cell lineages.
- an exogenous nucleic acid sequence may be integrated to serve as a detectable marker for a particular nucleic acid sequence.
- the genetically modified animal may be a "humanized" animal comprising at least one chromosomally integrated sequence encoding a functional human protein.
- the functional human protein may have no corresponding ortholog in the genetically modified animal.
- the wild-type animal from which the genetically modified animal is derived may comprise an ortholog corresponding to the functional human protein.
- the orthologous sequence in the "humanized” animal is inactivated such that no endogenous functional protein is made and the "humanized” animal comprises at least one chromosomally integrated sequence encoding the human protein.
- "humanized” animals may be generated by crossing a knock-out animal with a knock-in animal comprising the chromosomally integrated sequence.
- a further embodiment of the above invention comprises performing a method of the invention serially, such that a cell is developed with more than one chromosomal edit. For instance, an embryo with a first edit may be cultured to produce an animal comprising the first genomic edit. An embryo deriving from this animal may then be used in a method of the invention to create a second genomic edit. The same process may be repeated to create an embryo with three, four, five, six, seven, eight, nine, ten or more than ten genomic edits.
- a cell with multiple genomic edits may be developed by simultaneoulsy introducing more than one zinc finger nuclease, each specific for a distinct edit site.
- a corresponding number of donor and/or exchange polynucleotides may optionally be introduced as well. The number of zinc finger nucleases and optional corresponding donor or exchange
- polynucleotides introduced into a cell may be two, three, four, five or more than five.
- a method of the invention may be used to create an animal or cell comprising an edited chromosomal sequence.
- Such an animal or cell may be used for several different applications, including, for instance, research applications, livestock applications, companion animal applications, or
- biomolecule production applications Non-limiting examples of such applications are detailed in sections (a) - (d) below.
- a method of the invention may be used to create an animal or cell that may be used in research applications.
- Such applications may include disease models, pharmacological models,
- a method of the invention may be used to create an animal or cell that may be used as a disease model.
- disease refers to a disease, disorder, or indication in a subject.
- a method of the invention may be used to create an animal or cell that comprises a chromosomal edit in one or more nucleic acid sequences associated with a disease.
- nucleic acid sequence may encode a disease associated protein sequence or may be a disease associated control sequence.
- an animal or cell created by a method of the invention may be used to study the effects of mutations on the animal or cell and development and/or progression of the disease using measures commonly used in the study of the disease.
- such an animal or cell may be used to study the effect of a pharmaceutically active compound on the disease.
- an animal or cell created by a method of the invention may be used to assess the efficacy of a potential gene therapy strategy. That is, a chromosomal sequence encoding a protein associated with a disease may be modified such that the disease development and/or progression is inhibited or reduced.
- the method comprises editing a chromosomal sequence encoding a protein associated with the disease such that an altered protein is produced and, as a result, the animal or cell has an altered response.
- a genetically modified animal may be compared with an animal predisposed to development of the disease such that the effect of the gene therapy event may be assessed.
- a method of the invention may be used to create an animal or cell that maybe used as a disease model for a disease listed in Table A. Such an animal or cell may comprise a chromosomal edit in a gene listed in Table A. In another embodiment, a method of the invention may be used to create an animal or cell that maybe used as a disease model for a disease listed in Table B. Such an animal or cell may comprise a chromosomal edit in a gene listed in Table B. In Table B, a six-digit number following an entry in the Disease/Disorder/Indication column is an OMIM number (Online Mendelian Inheritance in Man, OMIM (TM).
- OMIM number Online Mendelian Inheritance in Man
- disease models created by a method of the invention include a Parkinson's disease model, an addiction model, an inflammation model, a cardiovascular disease model, an Alzheimer's disease model, an autism spectrum disorder model, a macular degeneration model, a schizophrenia model, a tumor suppression model, a trinucleotide repeat disorder model, a neurotransmission disorder model, a secretase-associated disorder model, an ALS model, a prion disease model, on ABC transporter protein - associated disorder model, and an immunodeficiency model.
- a Parkinson's disease model an addiction model, an inflammation model, a cardiovascular disease model, an Alzheimer's disease model, an autism spectrum disorder model, a macular degeneration model, a schizophrenia model, a tumor suppression model, a trinucleotide repeat disorder model, a neurotransmission disorder model, a secretase-associated disorder model, an ALS model, a prion disease model, on ABC transporter protein - associated disorder model, and an immunodeficiency model.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with Parkinsons disease (PD) has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- one or more chromosomal cells are selected from one or more chromosomal cells.
- sequences encoding a protein or control sequence associated with PD may be edited.
- a PD-associated protein or control sequence may typically be selected based on an experimental association of the PD-associated protein or control sequence to PD.
- the production rate or circulating concentration of a PD-related protein may be elevated or depressed in a population having PD relative to a population not having PD. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- Parkinson's disease include but are not limited to ⁇ -synuclein, DJ-1 , LRRK2, PINK1 , Parkin, UCHL1 , Synphilin-1 , and NURR1.
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of PD using measures commonly used in the study of PD.
- measures commonly used in the study of PD are known in the art.
- Commonly used measures in the study of PD may include without limit, amyloidogenesis or protein aggregation, dopamine response, neurodegeneration, development of mitochondrial related dysfunction
- PD phenotypes, as well as functional, pathological or biochemical assays.
- Other relevant indicators regarding development or progression of PD include
- Addiction is defined as a chronic disease of brain reward, motivation, memory, and related neuronal circuitry contained within various brain structures.
- Specific examples of brain structures that may experience dysfunction associated with an addiction disorder include nucleus accumbens, ventral pallidum, dorsal thalamus, prefrontal cortex, striatum, substantia nigra, pontine reticular formation, amygdala, and ventral tegmental area. Dysfunction in these neural circuits may lead to various biological, psychological, social and behavioral symptoms of addiction.
- Biological symptoms of addiction may include
- addiction-related proteins overproduction or underproduction of one or more addiction-related proteins; redistribution of one or more addiction-related proteins within the brain; the development of tolerance, reverse tolerance, or other changes in sensitivity to the effects of an addictive substance or a neurotransmitter within the brain; high blood pressure; and withdrawal symptoms such as insomnia, restlessness, loss of appetite, depression, weakness, irritability, anger, pain, and craving.
- Psychological symptoms of addiction may vary depending on the particular addictive substance and the duration of the addiction.
- Non-limiting examples of psychological symptoms of addiction include mood swings, paranoia, insomnia, psychosis, schizophrenia, tachycardia panic attacks, cognitive impairments, and drastic changes in the personality that can lead to aggressive, compulsive, criminal and/or erratic behaviors.
- Social symptoms of addiction may include low self-esteem, verbal hostility, ignorance of interpersonal means, focal anxiety such as fear of crowds, rigid interpersonal behavior, grossly playful behavior, rebelliousness, and diminished recognition of significant problems with an individual's behaviors and interpersonal relationships.
- Non-limiting examples of behavioral symptoms of addiction include impairment in behavioral control, inability to consistently abstain from the use of addictive substances, cycles of relapse and remission, risk-taking behavior, pleasure-seeking behavior, novelty-seeking behavior, relief-seeking behavior, and reward-seeking behavior.
- Addictions may be substance addictions typically associated with the ingestion of addictive substances.
- Addictive substances may include psychoactive substances capable of crossing the blood-brain barrier and temporarily altering the chemical milieu of the brain.
- addictive substances include alcohol; opioid compounds such as opium and heroin; sedative, hypnotic, or anxiolytic compounds such as benzodiazepine and barbiturate compounds; cocaine and related compounds; cannabis and related compounds; amphetamine and amphetamine-like compounds; hallucinogen compounds; inhalants such as glue or aerosol propellants; phencyclidine or phencyclidine-like compounds; and nicotine.
- addictions may be behavioral addictions associated with compulsions that are not substance- related, such as problem gambling and computer addiction.
- a method of the invention may be used to create an animal or cell in which at least one addiction-related chromosomal sequence has been edited.
- Suitable edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- Addiction-related nucleic acid sequences are a diverse set of sequences associated with susceptibility for developing an addiction, the presence of an addiction, the severity of an addiction or any combination thereof.
- An addiction-related nucleic acid sequence may typically be selected based on an experimental association of the addiction-related nucleic acid sequence to an addiction disorder.
- An addiction-related nucleic acid sequence may encode an addiction-related protein or may be an addiction-related control sequence.
- the production rate or circulating concentration of an addiction-related protein may be elevated or depressed in a population having an addiction disorder relative to a population lacking the addiction disorder.
- Non-limiting examples of addiction-related proteins include
- ABAT (4-aminobutyrate aminotransferase); ACN9 (ACN9 homolog (S.
- ADCYAP1 Addenylate cyclase activating polypeptide 1
- ADH1 B Alcohol dehydrogenase IB (class I), beta polypeptide
- ADH1 C Alcohol dehydrogenase 1 C (class I), gamma polypeptide
- ADH4 Alcohol
- ADH7 Alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide); ADORA1 (Adenosine A1 receptor); ADRA1A (Adrenergic, alpha- 1A-, receptor); ALDH2 (Aldehyde dehydrogenase 2 family); ANKK1 (Ankyrin repeat, Taql A1 allele); ARC (Activity-regulated cytoskeleton-associated protein); ATF2 (Corticotropin in-releasing factor); AVPR1A (Arginine vasopressin receptor 1A); BDNF (Brain-derived neurotrophic factor); BMAL1 (Aryl hydrocarbon receptor nuclear translocator-like); CDK5 (Cyclin-dependent kinase 5); CHRM2 (Cholinergic receptor, muscarinic 2); CHRNA3 (Cholinergic receptor, nicotinic, alpha 3); CHRNA4 (Cholinergic receptor, nicotinic
- Responsive element binding protein 1 Responsive element binding protein 1 ); CREB2 (Activating transcription factor 2); CRHR1 (Corticotropin releasing hormone receptor 1 ); CRY1 (Cryptochrome 1 ); CSNK1 E (Casein kinase 1 , epsilon); CSPG5 (Chondroitin sulfate proteoglycan 5); CTNNB1 (Catenin (cadherin-associated protein), beta 1 , 88kDa); DBI
- DRD1 Dopamine receptor D1
- DRD2 Dopamine receptor D2
- DRD3 Dopamine receptor D3
- EGR1 Early growth response 1
- ELTD1 EGF, latrophilin and seven transmembrane domain containing 1
- FAAH Fatty acid amide hydrolase
- FOSB FBJ murine osteosarcoma viral oncogene homolog
- FOSB FBJ murine osteosarcoma viral oncogene homolog B
- GABBR2 GABBR2
- GABA Gamma-aminobutyric acid
- GABRA2 Gamma- aminobutyric acid (GABA) A receptor, alpha 2
- GABRA4 Gamma-aminobutyric acid (GABA) A receptor, alpha 4
- GABRA6 Gamma-aminobutyric acid (GABA) A receptor, alpha 6
- GABRB3 Gamma-aminobutyric acid (GABA) A receptor, alpha 3
- GABRE Gamma-aminobutyric acid (GABA) A receptor, epsilon);
- GABRG1 Gamma-aminobutyric acid (GABA) A receptor, gamma 1 ); GAD1 (Glutamate decarboxylase 1 ); GAD2 (Glutamate decarboxylase 2); GAL (Galanin prepropeptide); GDNF (Glial cell derived neurotrophic factor); GRIA1 (Glutamate receptor, ionotropic, AMPA 1 ); GRIA2 (Glutamate receptor, ionotropic, AMPA 2); GRIN1 (Glutamate receptor, ionotropic, N-methyl D-aspartate 1 ); GRIN2A
- Glutamate receptor ionotropic, N-methyl D-aspartate 2A
- GRM2 Glutamate receptor, metabotropic 2, mGluR2
- GRM5 Metabotropic glutamate receptor 5
- GRM6 Glutamate receptor, metabotropic 6
- GRM8 Glutamate receptor, metabotropic 8
- HTR1 B (5-Hydroxytryptamine (serotonin) receptor 1 B
- HTR3A 5-Hydroxytryptamine (serotonin) receptor 3A
- IL1 Interleukin 1
- IL15 Interleukin 1
- IL15 Interleukin 1
- IL15 Interleukin 1
- IL15 Interleukin 1
- IL15 Interleukin 15
- IL1 A Interleukin 1 alpha
- IL1 B Interleukin 1 beta
- KCNMA1 Potassium large conductance calcium-activated channel, subfamily M, alpha member 1
- LGALS1 lectin galactoside-binding soluble 1
- MAOA Monoamine oxidase A
- MAOB Monoamine oxidase B
- MAPK1 Mitogen-activated protein kinase 1
- MAPK3 Mitogen-activated protein kinase 3
- MBP Myelin basic protein
- MC2R Melanocortin receptor type 2
- MGLL Monoglyceride lipase
- MOBP Myelin-associated oligodendrocyte basic protein
- NPY Neuropeptide Y
- NR4A1 Nuclear receptor subfamily 4, group A, member 1
- NR4A2 Nuclear receptor subfamily 4, group A, member 2
- NRXN Neuropeptide Y
- NR4A1 Nu
- NTRK2 Neurotrophic tyrosine kinase, receptor, type 2
- NTRK2 Neurotrophin receptor
- OPRD1 delta-Opioid receptor
- OPRK1 kappa-Opioid receptor
- OPRM 1 mi-Opioid receptor
- PDYN kappa-Opioid receptor
- PENK Enkephalin
- PER2 Period homolog 2 ⁇ Drosophila
- PKNOX2 PBX/knotted 1 homeobox 2
- PLP1 Proteolipid protein 1
- POMC Proopiomelanocortin
- PRKCE Protein kinase C, epsilon
- PROKR2 Protein kinase C, epsilon
- SLC17A6 Solute carrier family 17 (sodium- dependent inorganic phosphate cotransporter), member 6
- SLC17A7 Solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 7
- SLC1 A2 Solute carrier family 1 (glial high affinity glutamate transporter), member 2
- SLC1A3 Solute carrier family 1 (glial high affinity glutamate transporter), member 3
- SLC29A1 solute carrier family 29
- SLC4A7 Solute carrier family 4, sodium bicarbonate cotransporter, member 7
- SLC6A3 Solute carrier family 6
- Neurotransmitter transporter dopamine
- SLC6A4 Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4); SNCA (Synuclein, alpha (non A4 component of amyloid precursor)); TFAP2B (Transcription factor AP-2 beta); and TRPV1 (Transient receptor potential cation channel, subfamily V, member 1 ).
- Preferred addiction-related proteins may include ABAT (4- aminobutyrate aminotransferase), DRD2 (Dopamine receptor D2), DRD3
- GRIA1 Glutamate receptor, ionotropic, AMPA 1
- GRIA2 Glutamate receptor, ionotropic, AMPA 2
- GRIN1 Glutamate receptor, ionotropic, N-methyl D-aspartate 1
- GRIN2A Glutamate receptor, ionotropic, N-methyl D-aspartate 2A
- GRM5 Metalabotropic glutamate receptor 5
- HTR1 B (5-Hydroxytryptamine (serotonin) receptor 1 B), PDYN (Dynorphin), PRKCE (Protein kinase C, epsilon), LGALS1 (lectin galactoside-binding soluble 1 ), TRPV1 (transient receptor potential cation channel subfamily V member 1 ), SCN9A (sodium channel voltage-gated type IX alpha subunit), OPRD1 (opio
- an animal created by a method of the invention may be used as a model for indications of addiction disorders by comparing the measurements of an assay obtained from a genetically modified animal comprising at least one edited chromosomal sequence encoding an addiction-related protein to the measurements of the assay using a wild-type animal.
- assays used to assess for indications of an addictive disorder include behavioral assays, physiological assays, whole animal assays, tissue assays, cell assays, biomarker assays, and combinations thereof.
- the indications of addiction disorders may occur spontaneously, or may be promoted by exposure to exogenous agents such as addictive substances or addiction-related proteins. Alternatively, the indications of addiction disorders may be induced by withdrawal of an addictive substance or other compound such as an exogenously administered addiction-related protein.
- An additional aspect of the present disclosure encompasses a method of assessing the efficacy of a treatment for inhibiting addictive behaviors and/or reducing withdrawal symptoms of a genetically modified animal comprising at least one edited chromosomal sequence associated with addiction.
- Treatments for addiction that may be assessed include the administering of one or more novel candidate therapeutic compounds, a novel combination of established therapeutic compounds, a novel therapeutic method, and any combination thereof.
- Novel therapeutic methods may include various drug delivery mechanisms, nanotechnology applications in drug therapy, surgery, and combinations thereof.
- Behavioral testing of a genetically modified animal comprising at least one edited addiction-related protein and/or a wild-type animal may be used to assess the side effects of a therapeutic compound or
- the genetically modified animal and optionally a wild-type animal may be treated with the therapeutic compound or combination of therapeutic agents and subjected to behavioral testing.
- the behavioral testing may assess behaviors including but not limited to learning, memory, anxiety, depression, addiction, and sensory-motor functions.
- An additional aspect provides a method for assessing the therapeutic potential of an agent in an animal that may include contacting a genetically modified animal comprising at least one edited chromosomal sequence encoding an addiction-related protein, and comparing results of a selected parameter to results obtained from a wild-type animal with no contact with the same agent.
- Selected parameters include but are not limited to a) spontaneous behaviors; b) performance during behavioral testing; c)
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with inflammation has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with inflammation may be edited.
- An inflammation-related chromosomal sequence may typically be selected based on an experimental association of the inflammation-related sequence to an inflammation disorder.
- An inflammation-related sequence may encode an inflammation-related protein or may be an inflammation-related control sequence. For example, the production rate or circulating concentration of an inflammation-related protein may be elevated or depressed in a population having an inflammation disorder relative to a population lacking the inflammation disorder. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- Non-limiting examples of inflammation-related proteins whose chromosomal sequence may be edited include the monocyte
- MCP1 chemoattractant protein-1
- chemokine receptor type 5 CCR5 encoded by the Ccr ⁇ gene
- the IgG receptor MB FCGR2b, also termed CD32
- FCERIg Fc epsilon R1g protein encoded by the Fcerig gene
- the forkhead box N1 transcription factor FXN1 ) encoded by the FOXN1 gene
- Interferon-gamma IFN- ⁇
- IL-4 interleukin 4
- perforin-1 encoded by the PRF-1 gene perforin-1 encoded by the PRF-1 gene
- the cyclooxygenase 1 protein COX1
- COX2 cyclooxygenase 2 protein
- T-box transcription factor TBX21 protein encoded by the TBX21 gene
- SH2-B PH domain containing signaling mediator 1 protein SH2BPSM1
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of inflammation using measures commonly used in the study of inflammation.
- an animal created by a method of the invention may be used to study the effects of the mutations on the progression of a disease state or disorder associated with inflammation-related proteins using measures commonly used in the study of said disease state or disorder.
- measures include spontaneous behaviors of the genetically modified animal, performance during behavioral testing, physiological anomalies, differential responses to a
- Cardiovascular diseases generally include high blood pressure, heart attacks, heart failure, and stroke and TIA.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with cardiovascular disease has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- Any chromosomal sequence involved in cardiovascular disease or the protein encoded by any chromosomal sequence involved in cardiovascular disease may be utilized in a method of the invention.
- a cardiovascular-related sequence may typically be selected based on an experimental association of the cardiovascular-related sequence to the development of cardiovascular disease.
- a cardiovascular-related nucleic acid sequence may encode a cardiovascular-related protein or may be a
- cardiovascular-related control sequence For example, the production rate or circulating concentration of a cardiovascular-related protein may be elevated or depressed in a population having a cardiovascular disorder relative to a population lacking the cardiovascular disorder. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- the chromosomal sequence may comprise, but is not limited to, IL1 B (interleukin 1 , beta), XDH (xanthine dehydrogenase), TP53 (tumor protein p53), PTGIS (prostaglandin I2
- angiopoietin 1 ABCG8 (ATP-binding cassette, sub-family G (WHITE), member 8), CTSK (cathepsin K), PTGIR (prostaglandin I2 (prostacyclin) receptor (IP)), KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11 ), INS (insulin), CRP (C-reactive protein, pentraxin-related), PDGFRB (platelet-derived growth factor receptor, beta polypeptide), CCNA2 (cyclin A2), PDGFB (platelet- derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)), KCNJ5 (potassium inwardly-rectifying channel, subfamily J, member 5), KCNN3 (potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3), CAPN10 (calpain 10), PTGES (prostaglandin E synthase), ADRA2B
- ACE angiotensin I converting enzyme peptidyl- dipeptidase A 1
- TNF tumor necrosis factor
- IL6 interleukin 6 (interferon, beta 2)
- STN statin
- SERPINE1 serotonin peptidase inhibitor
- clade E nonin, plasminogen activator inhibitor type 1
- member 1 member 1
- ALB albumin
- ADIPOQ adiponectin, C1 Q and collagen domain containing
- APOB apolipoprotein B (including Ag(x) antigen)
- APOE apolipoprotein E
- LEP laeptin
- MTHFR 5,10-methylenetetrahydrofolate reductase (NADPH)
- APOA1 apolipoprotein A-I
- EDN 1 endothelin 1
- NPPB natriuretic peptide precursor B
- NOS3 nitric oxide synthas
- coagulation factor Il thrombin
- ICAM1 intercellular adhesion molecule 1
- TGFB1 transforming growth factor, beta 1
- NPPA natriuretic peptide precursor A
- IL10 interleukin 10
- EPO erythropoietin
- SOD1 superoxide dismutase 1 , soluble
- VCAM1 vascular cell adhesion molecule 1
- IFNG interferon, gamma
- LPA lipoprotein, Lp(a)
- MPO myeloperoxidase
- ESR1 esterogen receptor 1
- MAPK1 mitogen-activated protein kinase 1
- HP haptoglobin
- F3 coagulation factor III (thromboplastin, tissue factor)
- CST3 cystatin C
- COG2 component of oligomeric golgi complex 2
- MMP9 matrix metallopeptidase 9
- gelatinase B 92kDa ge
- NOS1 nitric oxide synthase 1 (neuronal)
- NR3C1 nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
- FGB finogen beta chain
- HGF hepatocyte growth factor
- hepapoietin A scatter factor
- IL1A interleukin 1 , alpha
- RETN resistin
- AKT1 v-akt murine thymoma viral oncogene homolog 1
- LIPC lipase, hepatic
- HSPD1 heat shock 6OkDa protein 1 (chaperonin)
- MAPK14 mitogen-activated protein kinase 14
- SPP1 secreted phosphoprotein 1
- ITGB3 integhn, beta 3 (platelet glycoprotein Ilia, antigen CD61 )
- CAT catalase
- UTS2 urotensin 2
- THBD thrombomodulin
- F10 coagulation factor X
- CP ceruloplasmin
- TNFRSF11 B tumor necrosis factor receptor superfamily, member 11 b
- EDNRA endothelin receptor type A
- EGFR epidermal growth factor receptor
- MMP2 matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)
- PLG plasma metallopeptidase 2
- NPY neuropeptide Y
- RHOD ras homolog gene family, member D
- MAPK8 mitogen-activated protein kinase 8
- MYC v-myc myelocytomatosis viral oncogene homolog (avian)
- FN 1 fibronectin 1
- CMA1 chymase 1 , mast cell
- PLAU plasminogen activator, urokinase
- GNB3 guan
- VDR vitamin D (1 ,25- dihydroxyvitamin D3) receptor
- ALOX5 arachidonate 5-lipoxygenase
- HLA-DRB1 major structural protein
- progelatinase progelatinase
- ELN elastin
- USF1 upstream transcription factor 1
- CFH complement factor H
- HSPA4 heat shock 7OkDa protein 4
- MMP12 matrix metallopeptidase 12 (macrophage elastase)
- MME membrane metallo- endopeptidase
- F2R coagulation factor Il (thrombin) receptor
- SELL selectin L
- CTSB cathepsin B
- ANXA5 annexin A5)
- ADRB1 adrenergic, beta-1 -, receptor
- CYBA cytochrome b-245, alpha polypeptide
- FGA farnesogen alpha chain
- GGT1 gamma-glutamyltransferase 1
- LIPG lipase, endothelial
- HIF1A hypooxia inducible factor 1 , alpha subunit (basic helix-loop-he
- lymphotoxin alpha TNF superfamily, member 1
- GDF15 growth differentiation factor 15
- BDNF brain-derived neurotrophic factor
- CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6
- NGF nerve growth factor (beta polypeptide)
- SP1 Sp1 transcription factor
- TGIF1 TGFB-induced factor homeobox 1
- SRC v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)
- EGF epidermal growth factor (beta-urogastrone)
- PIK3CG phosphoinositide-3-kinase, catalytic, gamma polypeptide
- HLA-A major histocompatibility complex, class I, A
- KCNQ1 potassium voltage-gated channel, KQT-like subfamily, member 1
- CNR1 cannabinoid receptor 1 (brain)
- FBN
- PRKAB1 protein kinase, AMP-activated, beta 1 non-catalytic subunit
- TPO thyroid peroxidase
- ALDH7A1 aldehyde
- dehydrogenase 7 family member A1
- CX3CR1 chemokine (C-X3-C motif) receptor 1
- TH tyrosine hydroxylase
- F9 coagulation factor IX
- GH1 growth hormone 1
- TF transferrin
- HFE hemochromatosis
- IL17A interleukin 17A
- PTEN phosphatase and tensin homolog
- GSTM 1 (glutathione S-transferase mu 1 ), DMD (dystrophin), GATA4 (GATA binding protein 4), F13A1 (coagulation factor XIII, A1 polypeptide), TTR (transthyretin), FABP4 (fatty acid binding protein 4, adipocyte), PON3 (paraoxonase 3), APOC1 (apolipoprotein C-I), INSR (insulin receptor), TNFRSF1 B (tumor necrosis factor receptor superfamily, member 1 B), HTR2A (5-hydroxy
- THBS1 THBS1
- KDR kinase insert domain receptor (a type III receptor tyrosine kinase)
- PLA2G2A phospholipase A2, group MA (platelets, synovial fluid)
- B2M beta-2-microglobulin
- THBS1 THBS1
- TCF7L2 TCF7L2
- T-cell specific, HMG-box transcription factor 7-like 2
- BDKRB2 bradykinin receptor B2
- NFE2L2 nuclear factor (erythroid-derived 2)-like 2)
- NOTCH1 Notch homolog 1 , translocation-associated (Drosophila)
- UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1
- IFNA1 interferon, alpha 1
- PPARD peroxisome proliferator-activated receptor delta
- SIRT1 sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)
- GNRH1 GNRH1
- cytochrome P450 family 1 , subfamily A, polypeptide 2
- HNF4A hepatocyte nuclear factor 4, alpha
- SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4
- PLA2G6 phospholipase A2, group Vl (cytosolic, calcium-independent)
- TNFSF11 tumor necrosis factor (ligand) superfamily, member 11
- SLC8A1 solute carrier family 8 (sodium/calcium exchanger), member 1
- F2RL1 coagulation factor Il (thrombin) receptor-like 1
- AKR1A1 aldo-keto reductase family 1 , member A1 (aldehyde reductase)
- ALDH9A1 aldehyde dehydrogenase 9 family, member A1
- BGLAP bone gamma-carboxyglutamate (gla) protein
- MTTP microsomal triglyceride transfer
- metallopeptidase 13 (collagenase 3)), TIMP2 (TIMP metallopeptidase inhibitor 2)
- CYP19A1 cytochrome P450, family 19, subfamily A, polypeptide 1
- CYP21A2 cytochrome P450, family 21 , subfamily A, polypeptide 2
- PTPN22 protein tyrosine phosphatase, non-receptor type 22 (lymphoid)
- MYH14 myosin, heavy chain 14, non-muscle
- MBL2 mannose-binding lectin (protein C) 2, soluble (opsonic defect)
- SELPLG selectivein P ligand
- AOC3 amine oxidase, copper containing 3 (vascular adhesion protein 1 )
- CTSL1 cathepsin L1
- PCNA metallopeptidase inhibitor 2
- IGF2 insulin-like growth factor 2
- ITGB1 insulin receptor, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12)
- CAST calpastatin
- KCNE1 immunoglobulin heavy constant epsilon
- KCNE1 potassium voltage-gated channel, Isk-related family, member 1
- TFRC transferrin receptor (p90, CD71 )
- COL1A1 collagen, type I, alpha 1
- COL1A2 collagen, type I, alpha 2
- IL2RB interleukin 2 receptor, beta
- PLA2G10 phospholipase A2, group X
- ANGPT2 angiopoietin 2
- PROCR protein C receptor, endothelial (EPCR)
- NOX4 immunoglobulin heavy constant epsilon
- KCNE1 potassium voltage-gated channel, Isk-related family, member 1
- TFRC transferrin receptor (p90, CD71 )
- COL1A1 collagen, type I, alpha 1
- COL1A2 collagen, type I, alpha 2
- IL2RB interleukin 2 receptor
- NADPH oxidase 4 HAMP (hepcidin antimicrobial peptide), PTPN11 (protein tyrosine phosphatase, non-receptor type 11 ), SLC2A1 (solute carrier family 2 (facilitated glucose transporter), member 1 ), IL2RA (interleukin 2 receptor, alpha), CCL5 (chemokine (C-C motif) ligand 5), IRF1 (interferon regulatory factor 1 ), CFLAR (CASP8 and FADD-like apoptosis regulator), CALCA (calcitonin- related polypeptide alpha), EIF4E (eukaryotic translation initiation factor 4E), GSTP1 (glutathione S-transferase pi 1 ), JAK2 (Janus kinase 2), CYP3A5
- cytochrome P450 family 3, subfamily A, polypeptide 5
- HSPG2 heparan sulfate proteoglycan 2
- CCL3 chemokine (C-C motif) ligand 3
- MYD88 myeloid differentiation primary response gene (88)
- VIP vaactive intestinal peptide
- SOAT1 sterol O-acyltransferase 1
- ADRBK1 adrenergic, beta, receptor kinase 1
- NR4A2 nuclear receptor subfamily 4, group A, member 2
- MMP8 matrix metallopeptidase 8 (neutrophil collagenase)
- NPR2 natriuretic peptide receptor B/guanylate cyclase B (athonathuretic peptide receptor B)
- GCH 1 GTP cyclohydrolase 1
- EPRS glutamyl-prolyl-tRNA synthetase
- PPARGC1A glutamyl-prolyl-
- ZC3H12A zinc finger CCCH-type containing 12A
- AKR1 B1 aldo-keto reductase family 1 , member B1 (aldose reductase)
- DES desmin
- MMP7 matrix metallopeptidase 7 (mathlysin, uterine)
- AHR aryl hydrocarbon receptor
- CSF1 colony stimulating factor 1 (macrophage)
- HDAC9 histone deacetylase 9
- CTGF connective tissue growth factor
- KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1
- UGT1A UDP glucuronosyltransferase 1 family, polypeptide A complex locus
- PRKCA protein kinase C, alpha
- COMT catechol-O-methyltransferase
- S100B S100 calcium binding protein B
- EGR1 early growth response 1
- PRL prolactin
- CD16a (CD16a)), LEPR (leptin receptor), ENG (endoglin), GPX1 (glutathione peroxidase 1 ), GOT2 (glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)), HRH1 (histamine receptor H1 ), NR112 (nuclear receptor subfamily 1 , group I, member 2), CRH (corticotropin releasing hormone), HTR1A (5-hydroxytryptamine (serotonin) receptor 1A), VDAC1 (voltage-dependent anion channel 1 ), HPSE (heparanase), SFTPD (surfactant protein D), TAP2
- transcription factor AP-2 alpha activating enhancer binding protein 2 alpha
- C4BPA complement component 4 binding protein, alpha
- SERPINF2 serpin peptidase inhibitor
- clade F alpha-2 antiplasmin, pigment epithelium derived factor
- member 2 transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)
- C4BPA complement component 4 binding protein, alpha
- SERPINF2 serpin peptidase inhibitor
- clade F alpha-2 antiplasmin, pigment epithelium derived factor
- member 2 member 2
- TYMP thymidine phosphorylase
- ALPP alkaline
- CXCR2 chemokine (C-X-C motif) receptor 2
- SLC39A3 solute carrier family 39 (zinc transporter), member 3
- ABCG2 ATP-binding cassette, sub-family G (WHITE), member 2)
- ADA ADA
- vascular endothelial growth factor B vascular endothelial growth factor B
- MEF2C myocyte enhancer factor 2C
- MAPKAPK2 mitogen-activated protein kinase-activated protein kinase 2
- TNFRSF11A tumor necrosis factor receptor superfamily, member 11 a, NFKB activator
- HSPA9 heat shock 7OkDa protein 9 (mortalin)
- CYSLTR1 cystyl leukotriene receptor 1
- MAT1A methionine adenosyltransferase I, alpha
- OPRL1 opiate receptor-like 1
- IMPA1 inositol(myo)-1 (or 4)-monophosphatase 1
- CLCN2 chloride channel 2)
- DLD dihydrolipoamide dehydrogenase
- PSMA6 proteasome (prosome, macropain) subunit, alpha type, 6
- PSMB8 proteasome (prosome, macropai
- EDN2 endothelin 2
- CCR6 chemokine (C-C motif) receptor 6
- GJB3 gap junction protein, beta 3, 31 kDa
- IL1 RL1 interleukin 1 receptor-like 1
- ENTPD1 ectonucleoside triphosphate diphosphohydrolase 1
- BBS4 Bardet-Biedl syndrome 4
- CELSR2 cadherin, EGF LAG seven-pass G- type receptor 2 (flamingo homolog, Drosophila)
- F11 R F 11 receptor
- RAPGEF3 Ras guanine nucleotide exchange factor (GEF) 3
- HYAL1 hyaluronoglucosaminidase 1
- ZNF259 zinc finger protein 259
- ATOX1 ATX1 antioxidant protein 1 homolog (yeast)
- ATF6 activating transcription factor 6
- KHK ketohexokinase (fructokinase)
- SAT1 spermidine/spermine N1- acetyltransferase 1
- GGH gamma-glutamyl hydrolase
- TIMP4 TIMP metallopeptidase inhibitor 4
- SLC4A4 solute carrier family 4, sodium bicarbonate cotransporter, member 4
- PDE2A phosphodiesterase 2A, cGMP-stimulated
- PDE3B phosphodiesterase 3B, cGMP-inhibited
- FADS1 fatty acid desaturase 1
- FADS2 fatty acid desaturase 2
- TMSB4X thymosin beta 4, X-linked
- TXNIP thioredoxin interacting protein
- LIMS1 LIM and senescent cell antigen-like domains 1
- RHOB ras homolog gene family, member B
- LY96 lymphocyte antigen 96
- FOXO1 forkhead box 01
- PNPLA2 patatin-like phospholipase domain containing 2
- TRH thyrotropin-releasing hormone
- GJC1 gap junction protein, gammase inhibitor 4
- GGT2 gamma-glutamyltransferase 2
- MT-CO1 mitochondrially encoded cytochrome c oxidase I
- UOX urate oxidase, pseudogene
- the chromosomal sequence may further be selected from Pon1 (paraoxonase 1 ), LDLR (LDL receptor), ApoE (Apolipoprotein E), Apo B-100 (Apolipoprotein B-100), ApoA (Apolipoprotein(a)), ApoA1 (Apolipoprotein A1 ), CBS (Cystathione B-synthase), Glycoprotein llb/llb, MTHRF (5,10-methylenetetrahydrofolate reductase (NADPH), and combinations thereof.
- Pon1 paraoxonase 1
- LDLR LDL receptor
- ApoE Apolipoprotein E
- Apo B-100 Apolipoprotein B-100
- ApoA Apolipoprotein(a)
- ApoA1 Adpolipoprotein A1
- CBS Cystathione B-synthase
- Glycoprotein llb/llb Glycoprotein llb/llb
- the chromosomal sequences and proteins encoded by chromosomal sequences involved in cardiovascular disease may be chosen from Cacnai C, Sod1 , Pten, Ppar(alpha), Apo E, Leptin, and combinations thereof.
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of cardiovascular disease using measures commonly used in the study of cardiovascular disease.
- suitable disease measures may include behavioral, electrophysiological, neurochemical, biochemical, or cellular dysfunctions which can be evaluated using any of a number of well-known diagnostic tests or assays.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with Alheimer's disease (AD) has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- one or more chromosomal sequences associated with AD may be edited.
- the AD-related nucleic acid sequence may typically be selected based on an experimental association of the AD-related nucleic acid sequence to an AD disorder.
- An AD-related nucleic acid sequence may encode an AD-related protein or may be an AD-related control sequence.
- the production rate or circulating concentration of an AD-related protein may be elevated or depressed in a population having an AD disorder relative to a population lacking the AD disorder. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- proteins associated with AD include but are not limited to the very low density lipoprotein receptor protein (VLDLR) encoded by the VLDLR gene, the ubiquitin-like modifier activating enzyme 1 (UBA1 ) encoded by the UBA1 gene, the NEDD8-activating enzyme E1 catalytic subunit protein (UBE1 C) encoded by the UBA3 gene, the aquaporin 1 protein (AQP1 ) encoded by the AQP1 gene, the ubiquitin carboxyl-terminal esterase L1 protein (UCHL1 ) encoded by the UCHL1 gene, the ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3) encoded by the UCHL3 gene, the ubiquitin B protein (UBB) encoded by the UBB gene, the microtubule- associated protein tau (MAPT) encoded by the MAPT gene, the protein tyrosine phosphatase receptor type A protein (PTPRA) encode
- VLDLR very low density lipoprotein
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of AD using measures commonly used in the study of AD.
- measures commonly used in the study of AD include without limit, learning and memory, anxiety, depression, addiction, and sensory-motor functions, as well as functional, pathological, metabolic, or biochemical assays.
- Those of skill in the art are familiar with other suitable measures or indicators of AD. In general, such measures may be made in comparison to wild type littermates.
- Other measures of behavior may include assessments of spontaneous behavior.
- Spontaneous behavior may be assessed using any one or more methods of spontaneous behavioral observations known in the art.
- any spontaneous behavior within a known behavioral repertoire of an animal may be observed, including movement, posture, social interaction, rearing, sleeping, blinking, eating, drinking, urinating, defecating, mating, and aggression.
- An extensive battery of observations for quantifying the spontaneous behavior may be assessed using any one or more methods of spontaneous behavioral observations known in the art.
- any spontaneous behavior within a known behavioral repertoire of an animal may be observed, including movement, posture, social interaction, rearing, sleeping, blinking, eating, drinking, urinating, defecating, mating, and aggression.
- mice and rats spontaneous behavior of mice and rats is well-known in the art, including but not limited to home-cage observations such as body position, respiration, tonic involuntary movement, unusual motor behavior such as pacing or rocking, catatonic behavior, vocalization, palpebral closure, mating frequency, running wheel behavior, nest building, and frequency of aggressive interactions.
- home-cage observations such as body position, respiration, tonic involuntary movement, unusual motor behavior such as pacing or rocking, catatonic behavior, vocalization, palpebral closure, mating frequency, running wheel behavior, nest building, and frequency of aggressive interactions.
- the animals of the invention may be used to study the effects of the mutations on the progression of a disease state or disorder other than AD, but which is also associated with AD-related proteins, using measures commonly used in the study of said disease state or disorder.
- disease states or disorders other than AD that may be associated with AD-related proteins include dementia, congenital cerebellar ataxia, mental retardation such as learning and memory defects, lissencephaly, tauopathy or fibrilization, amyloidosis, neurodegeneration, Parkinsonism, progressive supranuclear palsy, Pick disease, male infertility, prostate and breast cancer, squamous cell carcinoma, lymphoma, leukemia, and atherosclerosis.
- Yet another aspect encompasses a method for assessing the efficacy of a potential gene therapy strategy. That is, a chromosomal sequence encoding a protein associated with AD may be modified such that the genetically modified animal may have an altered response to the development and/or progression of AD as compared to a non treated animal. Stated another way, a mutated gene that predisposes an animal to AD may be "corrected" through gene therapy.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with autism spectrum disorder (ASD) has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with ASD may be edited.
- associated protein or control sequence may typically be selected based on an experimental association of the protein or control sequence to an incidence or indication of an ASD. For example, the production rate or circulating
- concentration of a protein associated with ASD may be elevated or depressed in a population having an ASD relative to a population lacking the ASD.
- Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- the proteins associated with ASD whose chromosomal sequence is edited can and will vary.
- the proteins associated with ASD whose chromosomal sequence is edited may be the benzodiazapine receptor (peripheral) associated protein 1 (BZRAP1 ) encoded by the BZRAP1 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 (FXR1 ) encoded by the FXR1 gene, the fragile X mental retardation autosomal homolog 2 protein (FXR2) encoded by the FXR2 gene, the MAM domain containing glycosylphosphatidylinositol anchor 2 protein (MDGA2) encoded by the MDGA2 gene, the methyl CpG binding protein 2 (MECP2) encoded by the MECP2 gene, the metabotropic glutamate receptor 5 (MGLUR5) encoded by the
- BZRAP1 benz
- the edited or integrated chromosomal sequence may be modified to encode an altered protein associated with ASD.
- mutations in proteins associated with ASD include the L18Q mutation in neurexin 1 where the leucine at position 18 is replaced with a glutamine, the R451 C mutation in neuroligin 3 where the arginine at position 451 is replaced with a cysteine, the R87W mutation in neuroligin 4 where the arginine at position 87 is replaced with a tryptophan, and the 1425V mutation in serotonin transporter where the isoleucine at position 425 is replaced with a valine.
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of ASD using measures commonly used in the study of ASD.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with macular degeneration (MD) has been edited.
- MD macular degeneration
- chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with MD may be edited.
- a MD-associated protein or control sequence may typically be selected based on an experimental association of the protein associated with MD to an MD disorder. For example, the production rate or circulating concentration of a protein associated with MD may be elevated or depressed in a population having an MD disorder relative to a population lacking the MD disorder. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- the proteins associated with MD whose chromosomal sequence is edited can and will vary.
- the proteins associated with MD whose chromosomal sequence is edited may be the ATP-binding cassette, sub-family A (ABC1 ) member 4 protein (ABCA4) encoded by the ABCR gene, the apolipoprotein E protein (APOE) encoded by the APOE gene, the chemokine (C-C motif) Ligand 2 protein (CCL2) encoded by the CCL2 gene, the chemokine (C-C motif) receptor 2 protein (CCR2) encoded by the CCR2 gene, the ceruloplasmin protein (CP) encoded by the CP gene, the cathepsin D protein (CTSD) encoded by the CTSD gene, or the
- TIMP3 metalloproteinase inhibitor 3 protein
- a genetically modified animal created by a method of the invention may be used to study the effects of mutations on the progression of MD using measures commonly used in the study of MD.
- the genetically modified animals of the invention may be used to study the effects of the mutations on the progression of a disease state or disorder associated with proteins associated with MD using measures commonly used in the study of said disease state or disorder.
- measures include drusen accumulation, lipofuscin accumulation, thickening of Bruch's membrane, retinal degeneration, choroidal neovascularization, differential responses to a compound, abnormalities in tissues or cells, biochemical or molecular differences between genetically modified animals and wild type animals or a combination thereof.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with schizophrenia has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with schizophrenia may be edited.
- a schizophrenia-associated protein or control sequence may typically be selected based on an experimental association of the protein associated with
- schizophrenia to the development or progression of schizophrenia.
- the production rate or circulating concentration of a protein associated with schizophrenia may be elevated or depressed in a population having
- chromosomal sequences associated with schizophrenia include NRG1 , ErbB4, CPLX1 , TPH1 , TPH2, NRXN1 , GSK3A, BDNF, DISCI , GSK3B, and combinations thereof, each of which is described in more detail below.
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of MD using measures commonly used in the study of MD.
- the incidence or indication of the schizophrenia or related disorder may occur spontaneously in the genetically modified animal.
- the incidence or indication of the schizophrenia or related disorder may be promoted by exposure to a disruptive agent.
- disruptive agents include a protein associated with schizophrenia such as any of those described above, a drug, a toxin, a chemical, an activated retrovirus, and an environmental stress.
- environmental stresses include forced swimming, cold swimming, platform shaker stimuli, loud noises, and immobilization stress.
- Tumor suppression genes are genes whose protein products protect a cell from one step on the path to cancer.
- a mutation in a tumor suppressor gene may cause a loss or reduction in the protective function of its protein product, thereby increasing the probability that a tumor will form, leading to cancer, usually in combination with other genetic changes.
- the proteins encoded by tumor suppressor genes have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes both.
- Tumor suppressor proteins are involved in the repression of genes essential for the continuing cell cycle; coupling the cell cycle to DNA damage so that the cell cycle can continue; initiating apoptosis in the cell if the damage cannot be repaired; and cell adhesion to prevent tumors from dispersing, blocking a loss of contact inhibition, and inhibiting metastasis.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with tumor suppresion has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with tumor suppression may be edited.
- a tumor suppression-associated protein or control sequence may typically selected based on an experimental association of the protein of interest with a cancer. For example, the production rate or circulating concentration of a protein associated with tumor suppression may be elevated or depressed in a population having cancer relative to a population not having cancer. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- proteins involved in tumor suppression may comprise, but are not limited to, TNF (tumor necrosis factor (TNF)
- TNF tumor necrosis factor
- TP53 tumor protein p53
- ERBB2 v-erb-b2
- erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian)
- FN1 fibronectin 1
- TSC1 tuberous sclerosis 1
- PTGS2 prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)
- PTEN phosphatase and tensin homolog
- CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
- CDKN1A cyclin-dependent kinase inhibitor 1A (p21 , Cip1 )
- CCND1 cyclin D1
- AKT1 v-akt murine thymoma viral oncogene homolog 1
- MYC v-myc
- myelocytomatosis viral oncogene homolog (avian)), CTNNB1 (catenin (cadherin- associated protein), beta 1 , 88kDa), MDM2 (Mdm2 p53 binding protein homolog (mouse)), SERPINB5 (serpin peptidase inhibitor, clade B (ovalbumin), member 5), EGF (epidermal growth factor (beta-urogastrone)), FOS (FBJ murine osteosarcoma viral oncogene homolog), NOS2 (nitric oxide synthase 2, inducible), CDK4 (cyclin-dependent kinase 4), SOD2 (superoxide dismutase 2, mitochondrial), SMAD3 (SMAD family member 3), CDKN1 B (cyclin-dependent kinase inhibitor 1 B (p27, Kip1 )), SOD1 (superoxide dismutase 1 , soluble), CCNA2 (cyclin A2), LO
- telangiectasia mutated telangiectasia mutated
- STAT3 signal transducer and activator of transcription 3 (acute-phase response factor)
- HIF1A hyperoxia inducible factor 1 , alpha subunit (basic helix-loop-helix transcription factor)
- IGF1 R insulin-like growth factor 1 receptor
- MTOR mechanistic target of rapamycin (serine/threonine kinase)
- TSC2 tuberous sclerosis 2)
- CDC42 cell division cycle 42 (GTP binding protein, 25kDa)
- ODC1 ornithine decarboxylase 1
- SPARC secreted protein, acidic, cysteine-rich (osteonectin)
- HDAC1 histone deacetylase 1
- CDK2 cyclin- dependent kinase 2
- BARD1 BRCA1 associated RING domain 1
- CDH1 cadhehn 1 , type 1 , E-cadher
- EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2
- GJA1 gap junction protein, alpha 1 , 43kDa
- MYD88 myeloid differentiation primary response gene (88)
- IFI27 interferon, alpha-inducible protein 27
- RBMX RNA binding motif protein, X-linked
- EPHA1 EPH receptor A1
- TWSG1 twisted gastrulation homolog 1 (Drosophila)
- H2AFX H2A histone family, member X
- LGALS3 lectin, galactoside-binding, soluble, 3
- MUC3A mucin 3A, cell surface associated
- ILK integratedin-linked kinase
- APAF1 apoptotic peptidase activating factor 1
- MAOA monoamine oxidase A
- ERBB3 v-erb-b2
- EIF2S1 eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa
- PER2 period homolog 2 (Drosophila)
- IGFBP7 insulin-like growth factor binding protein 7
- KDM5B lysine (K)-specific demethylase 5B
- SMARCA4 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
- NME1 non-metastatic cells 1 , protein (NM23A) expressed in
- F2RL1 non-metastatic cells 1 , protein (NM23A) expressed in
- coagulation factor Il thrombin receptor-like 1
- ZFP36 zinc finger protein 36, C3H type, homolog (mouse)
- HSPA8 heat shock 7OkDa protein 8
- WNT5A wingless-type MMTV integration site family, member 5A
- ITGB4 integhn, beta 4
- RARB retinoic acid receptor, beta
- VEGFC vascular endothelial growth factor C
- CCL20 chemokine (C-C motif) ligand 20
- EPHB2 EPH receptor B2
- CSNK2A1 casein kinase 2, alpha 1 polypeptide
- PSMD9 proteasome
- SERPINB2 serotonin peptidase inhibitor, clade B (ovalbumin), member 2), RHOB (ras homolog gene family, member B), DUSP6 (dual specificity phosphatase 6), CDKN1C (cyclin- dependent kinase inhibitor 1 C (p57, Kip2)), SLIT2 (slit homolog 2 (Drosophila)), CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein)), UBC (ubiquitin C), STS (steroid sulfatase (microsomal), isozyme S), FST (follistatin), KRT1 (keratin 1 ), EIF6 (eukaryotic translation initiation factor 6), JUP (junction plakoglobin), HDAC4 (histone deacetylase 4), NEDD4 (neural precursor cell expressed, development
- BTRC beta-transducin repeat containing
- NKX3-1 NK3 homeobox 1
- GPC3 glypican 3
- CREB3 cAMP responsive element binding protein 3
- PLCB3 phospholipase C, beta 3 (phosphatidylinositol-specific)
- DMPK distrophia myotonica-protein kinase
- BLNK B-cell linker
- PPIA peptidylprolyl isomerase A (cyclophilin A)
- DAB2 disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila)
- KLF4 Kruppel-like factor 4 (gut)
- RUNX3 runt-related
- transcription factor 3 FLG (filaggrin), IVL (involuchn), CCT5 (chaperonin containing TCP1 , subunit 5 (epsilon)), LRPAP1 (low density lipoprotein receptor- related protein associated protein 1 ), IGF2R (insulin-like growth factor 2 receptor), PER1 (period homolog 1 (Drosophila)), BIK (BCL2-interacting killer (apoptosis-inducing)), PSMC4 (proteasome (prosome, macropain) 26S subunit, ATPase, 4), USF2 (upstream transcription factor 2, c-fos interacting), GAS1 (growth arrest-specific 1 ), LAMP2 (lysosomal-associated membrane protein 2), PSMD10 (proteasome (prosome, macropain) 26S subunit, non-ATPase, 10), IL24 (interleukin 24), GADD45G (growth arrest and DNA-damage-inducible, gamma), ARHGAP
- EIF4G2 eukaryotic translation initiation factor 4 gamma, 2), LOXL2 (lysyl oxidase-like 2), PSMD13 (proteasome (prosome, macropain) 26S subunit, non-ATPase, 13), ANP32A (acidic (leucine-rich) nuclear phosphoprotein 32 family, member A), COL4A3 (collagen, type IV, alpha 3 (Goodpasture antigen)), SCGB1A1 (secretoglobin, family 1A, member 1 (uteroglobin)), BNIP3L (BCL2/adenovirus E1 B 19kDa interacting protein 3-like), MCC (mutated in colorectal cancers), EFNB3 (ephrin- B3), RBBP8 (retinoblastoma binding protein 8), PALB2 (partner and localizer of BRCA2), HBP1
- tumor suppression proteins 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 erythroblastic leukemia viral oncogene homolog 3
- ERBB4 v-erb-b2
- erythroblastic leukemia viral oncogene homolog 4 Notch 1 , Notch2, Notch 3, Notch 4, ATK1 (v-akt murine thymoma viral oncogene homolog 1 ), ATK2 (v-akt murine thymoma viral oncogene homolog 2), ATK3 (v-akt murine thymoma viral oncogene homolog 3), HIFI a (hypoxia-inducible factor 1 a), HIF3a (hypoxia- inducible factor 1 a), Met (met pronto-oncogene), HRG (histidine-hch
- Bd 2 PPAR(alpha) (peroxisome proliferator-activated receptor alpha), Ppar(gamma) (peroxisome proliferator-activated receptor gamma), WT1 (Wilmus Tumor 1 ), FGF1 R(fibroblast growth factor 1 receptor) , FGF2R
- fibroblast growth factor 1 receptor fibroblast growth factor 1 receptor
- FGF3R fibroblast growth factor 3 receptor
- FGF4R fibroblast growth factor 4 receptor
- FGF5R fibroblast growth factor 5 receptor
- CDKN2a cyclin-dependent kinase inhibitor 2A
- APC adenomatous polyposis coli
- Rb1 retinoblastoma 1
- MEN1 multiple endocrine neoplasial
- VHL von-Hippel-Lindau tumor suppressor
- BRCA1 breast cancer 1
- BRCA2 breast cancer 2
- AR androgen receptor
- TSG101 tumor susceptibility gene 101
- Igf1 insulin-like growth factor 1
- Igf2 insulin-like growth factor 2
- lgf 1 R insulin-like growth factor 1 receptor
- lgf 2R insulin-like growth factor 2 receptor
- CASP 7 (Caspase 7) , CASP 8 (Caspase 8), CASP 9 (Caspase 9), CASP 12 (Caspase 12), Kras (v-Ki-ras2 Kirsten rate sarcoma viral oncogene homolog), PTEN (phosphate and tensin homolog), BCRP (breast cancer receptor protein), p53, and combinations thereof.
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and on tumor suppression using measures commonly used in the study of tumor suppression.
- a genetically modified animal comprising an inactivated chromosomal sequence involved with tumor suppression may be used to determine susceptibility to developing tumors.
- the method comprises exposing the genetically modified animal comprising an inactivated tumor suppressor sequence and a wild-type animal to a carcinogenic agent, and then monitoring the development of tumors.
- the animal comprising the inactivated tumor suppressor sequence may have an increased risk for tumor formation.
- an animal homozygous for the inactivated tumor suppressor sequence may have increased risk relative to an animal heterozygous for the same inactivated sequence, which in turn may have increased risk relative to a wild- type animal.
- a similar method may be used to screen for spontaneous tumors, wherein the animals described above are not exposed to a carcinogenic agent.
- an animal comprising an inactivated chromosomal sequence associated with tumor suppression may be used to evaluate the carcinogenic potential of a test agent.
- the method comprises contacting the genetically modified animal comprising an inactivated tumor suppressor sequence and a wild-type animal to the test agent, and then monitoring the development of tumors. If the animal comprising an inactivated tumor suppressor sequence has an increased incidence of tumors relative to the wild-type animal, the test agent may be carcinogenic.
- Secretases make up a diverse set of proteins that affect susceptibility for numerous disorders, the presence of a disorder, the severity of a disorder, or any combination thereof.
- Secretases are enzymes that clip off smaller pieces of another transmembrane protein.
- Secretases are implicated in many disorders including, for example, Alzheimer's disease.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with secretase associated disorders has been edited. Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with a secretase associated disorder may be edited.
- a secretase associated disorder-associated protein or control sequence may typically be selected based on an experimental association of the secretase-related proteins with the development of a secretase disorder. For example, the production rate or circulating concentration of a protein associated with a secretase disorder may be elevated or depressed in a population with a secretase disorder relative to a population without a secretase disorder.
- Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- proteins associated with a secretase disorder include PSENEN (presenilin enhancer 2 homolog (C.
- CTSB cathepsin B
- PSEN1 presenilin 1
- APP amphide precursor protein
- APH 1 B anterior pharynx defective 1 homolog B (C.
- apolipoprotein E apolipoprotein E
- ACE angiotensin I converting enzyme (peptidyl-dipeptidase A) 1
- STN statin
- TP53 tumor protein p53
- IL6 interleukin 6 (interferon, beta 2)
- NGFR nerve growth factor receptor (TNFR superfamily, member 16)
- IL1 B interleukin 1 , beta
- ACHE acetylcholinesterase (Yt blood group)
- CTNNB1 catenin (cadhehn-associated protein), beta 1 , 88kDa), IGF1 (insulin-like growth factor 1 (somatomedin C)), IFNG (interferon, gamma), NRG1 (neuregulin 1 ), CASP3 (caspase 3, apoptosis-related cysteine peptidase), MAPK1 (mitogen- activated protein kinase 1 ), CDH1 (cadherin 1 , type 1
- metallopeptidase 12 microphage elastase
- JAG1 jagged 1 (Alagille syndrome)
- CD40LG CD40 ligand
- PPARG peroxisome proliferator-activated receptor gamma
- FGF2 fibroblast growth factor 2 (basic)
- IL3 interleukin 3 (colony-stimulating factor, multiple)
- LRP1 low density lipoprotein receptor- related protein 1
- NOTCH4 Notch homolog 4 ⁇ Drosophila
- MAPK8 mitogen- activated protein kinase 8
- PREP prolyl endopeptidase
- NOTCH3 Notch homolog 3 ⁇ Drosophila
- PRNP prion protein
- CTSG cathepsin G
- EGF epidermal growth factor (beta-urogastrone)
- REN renin
- CD44 CD44 molecule (Indian blood group)
- SELP selectin P (granule membrane protein 14
- IL1 R1 interleukin 1 receptor, type I
- PROK1 prokineticin 1
- MAPK3 mitogen-activated protein kinase 3
- NTRK1 neurotrophic tyrosine kinase, receptor, type 1
- MME membrane metallo-endopeptidase
- TKT transketolase
- CXCR2 chemokine (C-X-C motif) receptor 2
- IGF1 R insulin-like growth factor 1 receptor
- RARA retinoic acid receptor, alpha
- CREBBP CREB binding protein
- PTGS1 prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)
- GALT galactose-1 -phosphate
- CHRM1 Cholinergic receptor, muscarinic 1 ), ATXN1 (ataxin 1 ), PAWR (PRKC, apoptosis, WT1 , regulator), NOTCH2 (Notch homolog 2 (Drosophila)), M6PR (mannose-6-phosphate receptor (cation dependent)), CYP46A1 (cytochrome P450, family 46, subfamily A, polypeptide 1 ), CSNK1 D (casein kinase 1 , delta), MAPK14 (mitogen-activated protein kinase 14), PRG2 (proteoglycan 2, bone marrow (natural killer cell activator, eosinophil granule major basic protein)), PRKCA (protein kinase C, alpha), L1 CAM (L1 cell adhesion molecule), CD40 (CD40 molecule, TNF receptor superfamily member 5), NR112 (nuclear receptor subfamily 1 , group I,
- ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)
- CAV1 caveolin 1 , caveolae protein, 22kDa
- MMP7 matrix metallopeptidase 7 (matrilysin, uterine)
- TGFA transforming growth factor, alpha
- RXRA retinoid X receptor, alpha
- STX1A syntaxin 1A (brain)
- PSMC4 proteasome (prosome, macropain) 26S subunit, ATPase, 4
- P2RY2 puhnergic receptor P2Y, G-protein coupled, 2), TNFRSF21 (tumor necrosis factor receptor superfamily, member 21 ), DLG1 (discs, large homolog 1 (Drosophila)), NUMBL (numb homolog (Drosophila
- HES5 hairy and enhancer of split 5 (Drosophila)
- GCC1 GRIP and coiled-coil domain containing 1
- Preferred proteins associated with a secretase disorder include APH-1 A (anterior pharynx-defective 1 , alpha), APH-1 B (anterior pharynx- defective 1 , beta), PSEN-1 (presenilin-1 ), NCSTN (nicastrin), PEN-2 (presenilin enhancer 2), and any combination thereof.
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of a secretase associated disorder using measures commonly used in the study of secretase disorders.
- the incidence or indication of a secretase disorder may occur spontaneously in the genetically modified animal.
- the incidence or indication of the secretase disorder may be promoted by exposure to a disruptive agent.
- disruptive agents include a protein associated with a secretase disorder such as any of those described above, a drug, a toxin, a chemical, an activated retrovirus, and an environmental stress.
- environmental stresses include forced swimming, cold swimming, platform shaker stimuli, loud noises, and
- nucleic acid sequences and the proteins encoded by them, are associated with motor neuron disorders. These sequences make up a diverse set of sequences that affect susceptibility for developing a motor neuron disorder, the presence of the motor neuron disorder, the severity of the motor neuron disorder or any combination thereof.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with a specific motor neuron disorder, amyotrophic lateral sclerosis (ALS), has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with ALS may be edited.
- a chromosomal sequence associated with ALS may typically be selected based on an
- An ALS-related nucleic acid sequence may encode an ALS-related protein or may be an ALS- related control sequence.
- the production rate or circulating concentration of a protein associated with ALS may be elevated or depressed in a population with ALS relative to a population without ALS. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- ALS include but are not limited to SOD1 (superoxide dismutase 1 ), ALS2
- VAGFA vascular endothelial growth factor A
- VAGFB vascular endothelial growth factor B
- VAGFC vascular endothelial growth factor C
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of ALS using measures commonly used in the study of ALS.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with a prion disease has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences encoding a protein or control sequence associated with prion disorders may be edited.
- a prion disorder-related nucleic acid sequence may typically be selected based on an experimental association of the prion disorder-related nucleic acid sequence to a prion disorder.
- a prion disorder- related nucleic acid sequence may encode a prion disorder-related protein or isoform thereof, or may be a prion disorder-related control sequence. For example, the production rate or circulating concentration of a prion disorder- related protein or isoform may be elevated or depressed in a population having a prion disorder relative to a population lacking the prion disorder.
- Differences in protein or certain isoform levels may be assessed using proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry.
- proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry.
- the prion disorder-related proteins may be identified by obtaining gene expression profiles of the genes encoding the proteins using genomic techniques including but not limited to DNA microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (Q-PCR).
- Non-limiting examples of prion disorder-related proteins include PrP c and its isoforms, PrP Sc and its isoforms, HECTD2 (e3-ubipuitin ligase protein), STM (stress inducible protein 1 ), DPL (residue Doppel protein, encoded by Prnd), APOA1 (Apolipoprotein A1 ), BCL-2 (B-cell lymphoma 2), HSP60 (Heat shock 6OkDa protein), BAX- inhibiting peptide (Bcl-2-associated X protein inhibitor), NRF2 (nuclear respiratory factor 2), NCAMs (neural cell- adhesion molecules), heparin, laminin and laminin receptor.
- HECTD2 e3-ubipuitin ligase protein
- STM stress inducible protein 1
- DPL desidue Doppel protein, encoded by Prnd
- APOA1 Apolipoprotein A1
- BCL-2 B-cell lymphoma 2
- genes that may be related to neurodegenerative conditions in prion disorders 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), ADRA1 D (Alpha-1 D adrenergic receptor for Alpha-1 D adrenoreceptor), AHSG (Alpha-2- HS-glycoprotein), AIF1 (Allograft inflammatory factor 1 ), ALAS2 (Delta- aminolevulinate synthase 2), AMBP (Alpha-1 -microglobulin/bikunin precursor), ANK3 (Ankryn 3), ANXA3 (Annexin A3), APCS (Amyloid P component serum), APOA1 (Apolios), APOA1 (Apoli
- B4GALNT1 Beta-M-N-acetyl-galactosaminyl transferase 1
- BAX Bcl-2-associated X protein
- BCAT Branched chain amino-acid
- BCKDHA Branched chain keto acid dehydrogenase E1 alpha
- BCKDK Branched chain alpha-ketoacid dehydrogenase kinase
- BCL2 B-cell lymphoma 2
- BCL2L1 BCL2-like 1
- BDNF Brain-derived neurotrophic factor
- BHLHE40 Class E basic helix-loop-helix protein 40
- BHLHE41 Class E basic helix-loop-helix protein 41
- BMP2 Bone
- BTC morphogenetic protein 2A
- BMP3 Bone morphogenetic protein 3
- BMP5 Bone morphogenetic protein 5
- BRD1 Bromodomain containing 1
- BTC Bromodomain containing 1
- CCAAT/enhancer-binding protein beta CEBPD (CCAAT/enhancer-binding protein delta), CEBPG (CCAAT/enhancer-binding protein gamma), CENPB (Centromere protein B), CGA (Glycoprotein hormone alpha chain), CGGBP1 (CGG triplet repeat-binding protein 1 ), CHGA (Chromogranin A), CHGB
- IFNAR2 Interferon alpha/beta/omega receptor 2
- IGF1 Insulin-like growth factor 1
- IGF2 Insulin-like growth factor 2
- IGFBP2 Insulin-like growth factor binding protein 2, 36kDa
- IGFBP7 Insulin-like growth factor binding protein 7
- IL10 Interleukin 10
- IL10RA Interleukin 10 receptor alpha
- IL11 Interleukin 11
- IL11 RA Interleukin 11 receptor alpha
- IL11 RB Interleukin 11 receptor beta
- IL13 Interleukin 13
- IL15 Interleukin 15
- IL17A Interleukin 17A
- IL17RB Interleukin 17 receptor B
- IL18 Interleukin 18
- IL18RAP Interleukin 18 receptor accessory protein
- IL1 R2 Interleukin 1 receptor type II
- IL1 RN Interleukin 1 receptor type II
- MAOB Mantonidase alpha class 1A member 1
- MAOB Monoamine oxidase B
- MAP3K1 Mitogen-activated protein kinase kinase kinase 1
- MAPK1 Mitogen- activated protein kinase 1
- MAPK3 Mitogen-activated protein kinase 3
- MAPRE2 Microtubule-associated protein RP/EB family member 2
- MARCKS Myristoylated alanine-hch protein kinase C substrate
- MAS1 MAS1 oncogene
- MASL1 MAS1 oncogene-like
- MBP Myelin basic protein
- MCL1 Myeloid cell leukemia sequence 1
- MDMX MDM2-like p53-binding protein
- MECP2 Metal CpG binding protein 2
- MFGE8 Milk fat globule-EGF factor 8 protein
- MIF Macrophage migration inhibitory factor
- MMP2 Mestrix metallopeptidase 2
- MOBP Myelin-associated oligodendrocyte basic protein
- MUC16 Cancer antigen 125
- MX2 Myxovirus (influenza virus) resistance 2
- MYBBP1A MYB binding protein 1 a
- NCOA2 Nuclear receptor coactivator 2
- NEDD9 Neuronal precursor cell expressed developmentally down-regulated 9
- NFATC1 Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1
- NFE2L2 Nuclear factor erythroid-derived 2-like 2
- NFIC Nuclear factor I/C
- NFKBIA Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha
- NGFR Neve growth factor receptor
- NIACR2 neuron receptor 2
- NLGN3 Neuroroligin 3
- NPFFR2 neuropeptide FF receptor 2
- NPY Neuropeptide Y
- NR3C2 Nuclear receptor subfamily 3 group C member 2
- NRAS Neuroroblastoma RAS viral (v-ras) oncogene homolog
- NRCAM Neuroonal cell adhesion molecule
- NRG1 Neuroregulin 1
- POU2AF1 POU domain class 2 associating factor 1
- PRKAA1 5'-AMP-activated protein kinase catalytic subunit alpha-1
- PRL Prolactin
- PSCDBP Cytohesin 1 interacting protein
- PSPN Persephin
- PTAFR Platinum-activating factor receptor
- PTGS2 Prostaglandin-endoperoxide synthase 2
- PTN Pleiotrophin
- PTPN11 Protein tyrosine phosphatase non-receptor type 11
- PYY Peptide YY
- RAB6A RAB6A member RAS oncogene family
- RAD17 RAD17 homolog
- RAF1 RAF proto-oncogene sehne/threonine-protein kinase
- RANBP2 RAN binding protein 2
- RAP1A RAP1 A member of RAS oncogene family
- RB1 Retinoblastoma 1
- RBL2 Retinoblastoma-like 2 (p130)
- RCVRN Recoverin
- REM2 RS/RAD/GEM-like GTP binding 2
- RFRP RFamide-related peptide
- RPS6KA3 Rosulft-related protein S6 kinase 9OkDa polypeptide 3
- RTN4 Reticulon 4
- RUNX1 Runt-related transcription factor 1
- S100A4 S100 calcium binding protein A4
- S1 PR1 Sphingosine-1 -phosphate receptor 1
- TGFA Transforming growth factor alpha
- TGFB1 Transforming growth factor beta 1
- TGFB2 Transforming growth factor beta 2
- TGFB3 Transforming growth factor beta 3
- TGFBR1 Transforming growth factor beta receptor I
- TGM2 Transglutaminase 2
- THPO Thrombopoietin
- TIMP1 TIMP metallopeptidase inhibitor 1
- TIMP3 TIMP metallopeptidase inhibitor 3
- TMEM129 Transmembrane protein 129
- TNFRC6 TNFR/NGFR cysteine-rich region
- TNFRSF10A Tuor necrosis factor receptor superfamily member 10a
- TNFRSF10C Tuor necrosis factor receptor superfamily member 10c decoy without an intracellular domain
- TNFRSF1 A Tuor necrosis factor receptor superfamily member 1A
- TOB2 Transducer of ERBB2 2
- Exemplary prion disorder-related proteins include PrP c and isoforms thereof, PrP Sc and isoforms thereof, HECTD2 (e3-ubipuitin ligase protein), STM (stress inducible protein 1 ), DPL (residue Doppel protein, encoded by Prnd), APOA1 (Apolipoprotein A1 ), BCL-2 (B-cell lymphoma 2), HSP60 (Heat shock 6OkDa protein), BAX- inhibiting peptide (Bcl-2-associated X protein inhibitor), NRF2 (nuclear respiratory factor 2), NCAMs (neural cell-adhesion molecules), heparin, laminin and laminin receptor and any combination thereof.
- HECTD2 e3-ubipuitin ligase protein
- STM stress inducible protein 1
- DPL desidue Doppel protein, encoded by Prnd
- APOA1 Apolipoprotein A1
- BCL-2 B-cell lymphom
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of a prion disorder using measures commonly used in the study of prion disorders.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with immunodeficiency has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- immunodeficiency protein or control sequence is a protein or control sequence for which an alteration in activity is linked to an immunodeficiency, which may be the primary or a secondary symptom of an animal disease or condition, preferably a mammalian, e.g., a human, disease or condition.
- An immunodeficiency protein or control sequence is a protein or control sequence for which an alteration in activity is linked to an immunodeficiency, which may be the primary or a secondary symptom of an animal disease or condition, preferably a mammalian, e.g., a human, disease or condition.
- immunodeficiency sequence may typically be selected based on an experimental association of the immunodeficiency sequence to an immunodeficiency disease or condition, especially a mammalian, e.g., a human, disease or condition.
- an immunodeficiency disease or condition especially a mammalian, e.g., a human, disease or condition.
- the expression of an immunodeficiency protein in a particular tissue may be elevated or depressed in a population having an immunodeficiency disease or condition relative to a population lacking the disease or condition. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- Non-limiting examples of human immunodeficiency genes include A2M [alpha-2-macroglobulin]; AANAT [arylalkylamine N- acetyltransferase]; ABCA1 [ATP-binding cassette, sub-family A (ABC1 ), member 1]; ABCA2 [ATP-binding cassette, sub-family A (ABC1 ), member 2]; ABCA3
- ABC1 [ATP-binding cassette, sub-family A (ABC1 ), member 3]; ABCA4 [ATP-binding cassette, sub-family A (ABC1 ), member 4]; ABCB1 [ATP-binding cassette, subfamily B (MDR/TAP), member 1]; ABCC1 [ATP-binding cassette, sub-family C (CFTR/MRP), member 1]; ABCC2 [ATP-binding cassette, sub-family C
- ABCG1 [ATP-binding cassette, sub-family G (WHITE), member 1]; ABCG2 [ATP- binding cassette, sub-family G (WHITE), member 2]; ABCG5 [ATP-binding cassette, sub-family G (WHITE), member 5]; ABCG8 [ATP-binding cassette, subfamily G (WHITE), member 8]; ABHD2 [abhydrolase domain containing 2]; ABL1 [c-abl oncogene 1 , receptor tyrosine kinase]; ABO [ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1 -3- galactosyltransferase)]; ABP1 [amiloride binding protein 1 (amine oxidase
- ACAA1 [acetyl-Coenzyme A acyltransferase 1]; ACACA [acetyl-Coenzyme A carboxylase alpha]; ACAN [aggrecan]; ACAT1 [acetyl- Coenzyme A acetyltransferase 1]; ACAT2 [acetyl-Coenzyme A acetyltransferase 2]; ACCN5 [amiloride-sensitive cation channel 5, intestinal]; ACE [angiotensin I converting enzyme (peptidyl-dipeptidase A) 1]; ACE2 [angiotensin I converting enzyme (peptidyl-dipeptidase A) 2]; ACHE [acetylcholinesterase (Yt blood group)]; ACLY [ATP citrate lyase]; ACOT9 [acyl-CoA thioesterase 9]; ACOX1 [acyl-Coenzyme A oxid
- ACVRL1 activin A receptor type ll-like 1
- ACY1 aminoacylase 1
- ADA aminoacylase 1
- ADAM10 [ADAM metallopeptidase domain 10]; ADAM12 [ADAM metallopeptidase domain 12]; ADAM17 [ADAM metallopeptidase domain 17]; ADAM23 [ADAM metallopeptidase domain 23]; ADAM33 [ADAM
- ADAM8 ADAM metallopeptidase domain 8
- ADAM9 [ADAM metallopeptidase domain 9 (meltrin gamma)]; ADAMTS1 [ADAM metallopeptidase with thrombospondin type 1 motif, 1]; ADAMTS12 [ADAM metallopeptidase with thrombospondin type 1 motif, 12]; ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif, 13]; ADAMTS15 [ADAM metallopeptidase with thrombospondin type 1 motif, 15]; ADAMTSL1 [ADAMTS- like 1]; ADAMTSL4 [ADAMTS-like 4]; ADAR [adenosine deaminase, RNA- specific]; ADCY1 [adenylate cyclase 1 (brain)]; ADCY10 [adenylate cyclase 10 (soluble)]; ADCY3 [adenylate cyclase 3]; ADCY9 [adenylate
- ADCYAP1 [adenylate cyclase activating polypeptide 1 (pituitary)]; ADCYAP1 R1 [adenylate cyclase activating polypeptide 1 (pituitary) receptor type I]; ADD1
- ADIPOR1 [adducin 1 (alpha)]; ADH5 [alcohol dehydrogenase 5 (class III), chi polypeptide]; ADIPOQ [adiponectin, C1Q and collagen domain containing]; ADIPOR1
- ADK adenosine kinase
- ADM adrenomedullin
- ADORA1 [adenosine A1 receptor]; ADORA2A [adenosine A2a receptor]; ADORA2B [adenosine A2b receptor]; ADORA3 [adenosine A3 receptor];
- ADRA1 B [adrenergic, alpha-1 B-, receptor]; ADRA2A [adrenergic, alpha-2A-, receptor]; ADRA2B [adrenergic, alpha-2B-, receptor]; ADRB1 [adrenergic, beta- 1 -, receptor]; ADRB2 [adrenergic, beta-2-, receptor, surface]; ADSL
- Adenylosuccinate lyase [adenylosuccinate lyase]; ADSS [adenylosuccinate synthase]; AEBP1 [AE binding protein 1]; AFP [alpha-fetoprotein]; AGER [advanced glycosylation end product-specific receptor]; AGMAT [agmatine ureohydrolase (agmatinase)]; AGPS [alkylglycerone phosphate synthase]; AGRN [agrin]; AGRP [agouti related protein homolog (mouse)]; AGT [angiotensinogen (serpin peptidase inhibitor, clade A, member 8)]; AGTR1 [angiotensin Il receptor, type 1]; AGTR2
- Abelson helper integration site 1 [Abelson helper integration site 1]; AHR [aryl hydrocarbon receptor]; AHSP
- AIRE alpha hemoglobin stabilizing protein
- AICDA activation-induced cytidine deaminase
- AIDA axin interactor, dorsalization associated
- AIMP1 aminoacyl tRNA synthetase complex-interacting multifunctional protein 1]
- AIRE alpha hemoglobin stabilizing protein
- AK1 adenylate kinase 1
- AK2 adenylate kinase 2
- AKR1A1 aldo-keto reductase family 1 , member A1 (aldehyde reductase)];
- AKR1 B1 [aldo-keto reductase family 1 , member B1 (aldose reductase)]
- AKR1 C3 aldo-keto reductase family 1 , member C3 (3-alpha hydroxysteroid
- AKT1 [v-akt murine thymoma viral oncogene homolog 1]; AKT2 [v-akt murine thymoma viral oncogene homolog 2]; AKT3 [v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma)]; ALB [albumin]; ALCAM [activated leukocyte cell adhesion molecule]; ALDH1A1 [aldehyde dehydrogenase 1 family, member A1]; ALDH2 [aldehyde dehydrogenase 2 family (mitochondrial)]; ALDH3A1 [aldehyde dehydrogenase 3 family, memberAI]; ALDH7A1 [aldehyde dehydrogenase 7 family, member A1]; ALDH9A1 [aldehyde dehydrogenase 9 family, member AI]; ALG1 [v-akt murine thymom
- ALG12 asparagine- linked glycosylation 12, alpha-1 ,6-mannosyltransferase homolog (S. cerevisiae)]; ALK [anaplastic lymphoma receptor tyrosine kinase]; ALOX12 [arachidonate 12- lipoxygenase]; ALOX15 [arachidonate 15-lipoxygenase]; ALOX15B [arachidonate 15-lipoxygenase, type B]; ALOX5 [arachidonate 5-lipoxygenase]; ALOX5AP
- ALPI alkaline phosphatase, intestinal
- ALPL alkaline phosphatase, liver/bone/kidney
- ALPP alkaline phosphatase, placental (Regan isozyme)]
- AMACR alpha-methylacyl-CoA racemase
- AMBP alpha-1 -microglobulin/bikunin precursor]
- AMPD3 adenosine monophosphate deaminase 3]
- ANG angiogenin, ribonuclease, RNase A family, 5]
- ANGPT1 angiopoietin 1]
- ANGPT2 angiopoietin 2]
- ANK1 ankyrin 1 , erythrocytic]
- ANKH ankylosis, progressive homolog (mouse)]
- ANKRD1 ankyrin repeat domain 1 (cardiac muscle)]
- ANKRD1 ankyrin repeat domain 1 (cardiac muscle)];
- AOC2 [amine oxidase, copper containing 2 (retina-specific)]; AP2B1 [adaptor-related protein complex 2, beta 1 subunit]; AP3B1 [adaptor-related protein complex 3, beta 1 subunit]; APC [adenomatous polyposis coli]; APCS [amyloid P component, serum]; APEX1 [APEX nuclease (multifunctional DNA repair enzyme) 1]; APLNR [apelin receptor]; APOA1 [apolipoprotein A-I]; APOA2 [apolipoprotein A-Il]; APOA4 [apolipoprotein A-IV]; APOB [apolipoprotein B (including Ag(x) antigen)]; APOBEC1 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1]; APOBEC3G [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G];
- A4 precursor protein [apolipoprotein D]; APOE [apolipoprotein E]; APOH [apolipoprotein H (beta-2- glycoprotein I)]; APP [amyloid beta (A4) precursor protein]; APRT [adenine phosphohbosyltransferase]; APTX [aprataxin]; AQP1 [aquaporin 1 (Colton blood group)]; AQP2 [aquaporin 2 (collecting duct)]; AQP3 [aquaporin 3 (Gill blood group)]; AQP4 [aquaporin 4]; AQP5 [aquaporin 5]; AQP7 [aquaporin 7]; AQP8 [aquaporin 8]; AR [androgen receptor]; AREG [amphiregulin]; ARF6 [ADP- ribosylation factor 6]; ARG1 [arginase, liver]; ARG2 [
- ASNS argininosuccinate lyase
- ASNS asparagine synthetase
- ASPA aspartoacylase (Canavan disease)
- ASPG asparaginase homolog (S. cerevisiae)]
- ASPH argininosuccinate lyase
- ASRGL1 [aspartate beta-hydroxylase]
- ASRGL1 [asparaginase like 1]
- ASS1 [asparaginase like 1]
- ATF1 activating transcription factor 1
- ATF2 activating transcription factor 2
- ATF3 activating transcription factor 3
- ATF4 activating transcription factor 4 (tax-responsive enhancer element B67)];
- ATG16L1 [ATG16 autophagy related 16-like 1 (S. cerevisiae)]; ATM [ataxia telangiectasia mutated]; ATMIN [ATM interactor]; ATN 1 [atrophin 1]; ATOH 1 [atonal homolog 1 (Drosophila)]; ATP2A2 [ATPase, Ca++ transporting, cardiac muscle, slow twitch 2]; ATP2A3 [ATPase, Ca++ transporting, ubiquitous];
- ATP2C1 [ATPase, Ca++ transporting, type 2C, member 1]; ATP5E [ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit]; ATP7B [ATPase, Cu++ transporting, beta polypeptide]; ATP8B1 [ATPase, class I, type 8B, member 1]; ATPAF2 [ATP synthase mitochondrial F1 complex assembly factor 2]; ATR [ataxia telangiectasia and Rad3 related]; ATRIP [ATR interacting protein]; ATRN [attracting AURKA [aurora kinase A]; AURKB [aurora kinase B]; AURKC [aurora kinase C]; AVP [arginine vasopressin]; AVPR2 [arginine vasopressin receptor 2]; AXL [AXL receptor tyrosine kinase]; AZGP1 [alpha-2- glyco
- B4GALNT1 beta-1 ,4-N-acetyl-galactosaminyl transferase 1]
- B4GALT1 [UDP-GaI :betaGlcNAc beta 1 ,4- galactosyltransferase, polypeptide 1]
- BACE1 beta-site APP-cleaving enzyme 1
- BACE2 beta-site APP-cleaving enzyme 2
- BACH1 [BTB and CNC homology 1 , basic leucine zipper transcription factor 1]
- BAD BCL2-associated agonist of cell death]
- BAD BCL2-associated agonist of cell death
- BAIAP2 [BAM -associated protein 2]; BAK1 [BCL2-antagonist/killer 1]; BARX2 [BARX homeobox 2]; BAT1 [HLA-B associated transcript 1]; BAT2 [HLA-B associated transcript 2]; BAX [BCL2-associated X protein]; BBC3 [BCL2 binding component 3]; BCAR1 [breast cancer anti-estrogen resistance 1]; BCAT1
- BRCA1 [breast cancer 1 , early onset]; BRCA2 [breast cancer 2, early onset]; BRCC3 [BRCA1/BRCA2- containing complex, subunit 3]; BRD8 [bromodomain containing 8]; BRIP1 [BRCA1 interacting protein C-terminal helicase 1]; BSG [basigin (Ok blood group)]; BSN [bassoon (presynaptic cytomatrix protein)]; BSX [brain-specific homeobox]; BTD [biotinidase]; BTK [Bruton agammaglobulinemia tyrosine kinase]; BTLA [B and T lymphocyte associated]; BTNL2 [butyrophilin-like 2 (MHC class Il associated)]; BTRC [beta-transducin repeat containing]; C10orf67
- CABIN1 [calcineurin binding protein 1]; CACNA1 C [calcium channel, voltage-dependent, L type, alpha 1 C subunit]; CACNA1 S [calcium channel, voltage-dependent, L type, alpha 1 S subunit]; CAD [carbamoyl- phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase]; CALB1 [calbindin 1 , 28kDa]; CALB2 [calbindin 2]; CALCA [calcitonin-related polypeptide alpha]; CALCRL [calcitonin receptor-like]; CALD
- CASP2 caspase 2, apoptosis-related cysteine peptidase]; CASP3 [caspase 3, apoptosis-related cysteine peptidase]; CASP5 [caspase 5, apoptosis-related cysteine peptidase]; CASP6 [caspase 6, apoptosis-related cysteine peptidase]; CASP7 [caspase 7, apoptosis-related cysteine peptidase]; CASP8 [caspase 8, apoptosis-related cysteine peptidase]; CASP8AP2 [caspase 8 associated protein 2]; CASP9 [caspase 9, apoptosis-related cysteine peptidase]; CASR [calcium- sensing receptor]; CAST [calpastatin]; CAT [catalase]; CAV1 [caveolin 1 , caveolae protein, 22kDa]; CAV2 [caveolin 2
- CCDC144A [coiled-coil domain containing 144A]; CCDC144B [coiled-coil domain containing 144B]; CCDC68 [coiled-coil domain containing 68]; CCK [cholecystokinin]; CCL1 [chemokine (C-C motif) ligand 1]; CCL11 [chemokine (C- C motif) ligand 11]; CCL13 [chemokine (C-C motif) ligand 13]; CCL14
- C-C motif [chemokine (C-C motif) ligand 14]; CCL17 [chemokine (C-C motif) ligand 17]; CCL18 [chemokine (C-C motif) ligand 18 (pulmonary and activation-regulated)]; CCL19 [chemokine (C-C motif) ligand 19]; CCL2 [chemokine (C-C motif) ligand 2]; CCL20 [chemokine (C-C motif) ligand 20]; CCL21 [chemokine (C-C motif) ligand 21]; CCL22 [chemokine (C-C motif) ligand 22]; CCL24 [chemokine (C-C motif) ligand 24]; CCL25 [chemokine (C-C motif) ligand 25]; CCL26 [chemokine (C-C motif) ligand 26]; CCL27 [chemokine (C-C motif) ligand 27]; CCL28
- chemokine (C-C motif) ligand 28 [chemokine (C-C motif) ligand 28]; CCL3 [chemokine (C-C motif) ligand 3]; CCL4 [chemokine (C-C motif) ligand 4]; CCL4L1 [chemokine (C-C motif) ligand 4-like 1]; CCL5 [chemokine (C-C motif) ligand 5]; CCL7 [chemokine (C-C motif) ligand I]; CCL8 [chemokine (C-C motif) ligand 8]; CCNA1 [cyclin A1]; CCNA2 [cyclin A2]; CCNB1 [cyclin B1]; CCNB2 [cyclin B2]; CCNC [cyclin C]; CCND1 [cyclin D1]; CCND2 [cyclin D2]; CCND3 [cyclin D3]; CCNE1 [cyclin E1]; CCNG1 [cyclin G1
- chemokine (C-C motif) receptor 8 [chemokine (C-C motif) receptor 8]; CCR9 [chemokine (C-C motif) receptor 9]; CCRL1 [chemokine (C-C motif) receptor-like 1]; CD14 [CD14 molecule]; CD151 [CD151 molecule (Raph blood group)]; CD160 [CD160 molecule]; CD163
- CD274 [CD274 molecule]; CD28 [CD28 molecule]; CD2AP [CD2-associated protein]; CD300LF [CD300 molecule-like family member f]; CD34 [CD34 molecule]; CD36 [CD36 molecule (thrombospondin receptor)]; CD37 [CD37 molecule]; CD38 [CD38 molecule]; CD3E [CD3e molecule, epsilon (CD3-TCR complex)]; CD4 [CD4 molecule]; CD40 [CD40 molecule, TNF receptor
- CD40LG CD40 ligand
- CD44 CD44 molecule (Indian blood group)]
- CD46 CD46 molecule, complement regulatory protein]
- CD47 CD47 molecule
- CD48 CD48 molecule
- CD5 CD5 molecule
- CD52 CD52 molecule
- CD53 CD53 molecule
- CD55 CD55 molecule, decay accelerating factor for complement (Cromer blood group)]
- CD58 CD58 molecule
- CD79A [CD79a molecule, immunoglobulin-associated alpha]
- CD79B [CD79b molecule, immunoglobulin- associated beta]
- CD80 [CD80 molecule]; CD81 [CD81 molecule]; CD82 [CD82 molecule]; CD83 [CD83 molecule]; CD86 [CD86 molecule]; CD8A [CD8a molecule]; CD9 [CD9 molecule]; CD93 [CD93 molecule]; CD97 [CD97 molecule]; CDC20 [cell division cycle 20 homolog (S. cerevisiae)]; CDC25A [cell division cycle 25 homolog A (S.
- CDH1 [cadherin 1 , type 1 , E-cadherin (epithelial)]; CDH2 [cadherin 2, type 1 , N-cadherin (neuronal)]; CDH26 [cadherin 26]; CDH3 [cadherin 3, type 1 , P-cadherin (placental)]; CDH5 [cadherin 5, type 2 (vascular endothelium)]; CDIPT [CDP-diacylglycerol-inositol 3- phosphatidyltransferase (phosphatidylinositol synthase)]; CDK1 [cyclin- dependent kinase 1]; CDK2 [cycl in-dependent kinase 2]; CDK4 [cyclin-dependent kinase 4]; CDK5 [cyclin-dependent kinase 5]; CDK5R1 [cyclin-dependent kinase 5, regulatory subunit
- CDKN2B cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4)]
- CDKN3 cyclin-dependent kinase inhibitor 3]
- CEACAM3 Carcinoembryonic antigen-related cell adhesion molecule 3
- CEACAM5 Carcinoembryonic antigen-related cell adhesion molecule 5
- CEACAM6 Carcinoembryonic antigen-related cell adhesion molecule 6 (non-specific cross reacting antigen)]
- CEACAM7 Carcinoembryonic antigen-related cell adhesion molecule 7]
- CEBPB CCAAT/enhancer binding protein (C/EBP), beta]
- CEL carbboxyl ester lipase (bile salt-stimulated lipase)]
- CENPJ centromere protein J]
- CENPV centromere protein V]
- CEP290 CEP290
- CGA glycoprotein hormones, alpha polypeptide
- CGB chorionic gonadotropin, beta polypeptide
- CGB5 chorionic gonadotropin, beta polypeptide 5
- CHGA chromogranin A (parathyroid secretory protein 1 )]; CHGB [chromogranin B (secretogranin 1 )]; CHI3L1 [chitinase 3-like 1 (cartilage glycoprotein-39)]; CHIA [chitinase, acidic]; CHIT1 [chitinase 1 (chitothosidase)]; CHKA [choline kinase alpha]; CHML [choroideremia-like (Rab escort protein 2)]; CHRD [chordin];
- CLEC12A [C-type lectin domain family 12, member A]; CLEC16A [C-type lectin domain family 16, member A]; CLEC4A [C-type lectin domain family 4, member A]; CLEC4D [C- type lectin domain family 4, member D]; CLEC4M [C-type lectin domain family 4, member M]; CLEC7A [C-type lectin domain family 7, member A]; CLIP2 [CAP- GLY domain containing linker protein 2]; CLK2 [CDC-like kinase 2]; CLSPN
- CMKLR1 [claspin homolog (Xenopus laevis)]; CLSTN2 [calsyntenin 2]; CLTCL1 [clathrin, heavy chain-like 1]; CLU [clusterin]; CMA1 [chymase 1 , mast cell]; CMKLR1
- CNBP CCHC-type zinc finger, nucleic acid binding protein
- CNDP2 CNDP dipeptidase 2 (metallopeptidase M20 family)]
- CNN1 Calponin 1 , basic, smooth muscle]
- CNP [2',3'-cyclic nucleotide 3' phosphodiesterase]
- CNR1 cannabinoid receptor 1 (brain)]
- CNR2 cannabinoid receptor 2 (macrophage)]
- CNTF ciliary neurotrophic factor]
- CNTN2 contactin 2 (axonal)]
- COG1 component of oligomeric golgi complex 1]
- COG2 Component of oligomeric golgi complex 2]
- COIL coilin]
- COL11 A1 collagen, type Xl, alpha 1]
- COL11A2 [collagen, type Xl, alpha 2]
- COL17A1 [collagen, type X
- COL6A1 [collagen, type Vl, alpha 1]
- COL6A2 [collagen, type Vl, alpha 2]
- COL6A3 [collagen, type Vl, alpha 3]
- COL7A1 [collagen, type VII, alpha 1]
- COL8A2 [collagen, type VIII, alpha 2]
- COL9A1 [collagen, type IX, alpha 1]
- COMT catechol-O-methyltransferase
- COQ3 coenzyme Q3 homolog, methyltransferase (S. cerevisiae)]
- COQ7 coenzyme Q7 homolog, ubiquinone (yeast)]
- CORO1A coronin, actin binding protein, 1A]
- COX10 COX10 homolog, cytochrome c oxidase assembly protein, heme A: farnesyltransferase (yeast)]
- COX15 COX15 homolog, cytochrome c oxidase assembly protein (yeast)]
- COX5A [cytochrome c oxidase subunit Va]
- COX8A [cytochrome c oxidase subunit VIIIA (ubiquitous)]
- CP ceruloplasmin (ferroxidase)]
- CPN1 [carboxypeptidase N, polypeptide 1]; CPOX [coproporphyrinogen oxidase]; CPS1 [carbamoyl-phosphate synthetase 1 , mitochondrial]; CPT2 [carnitine palmitoyltransferase 2]; CR1 [complement component (3b/4b) receptor 1 (Knops blood group)]; CR2 [complement component (3d/Epstein Barr virus) receptor 2]; CRAT [carnitine O-acetyltransferase]; CRB1 [crumbs homolog 1 (Drosophila)]; CREB1 [cAMP responsive element binding protein 1]; CREBBP [CREB binding protein]; CREM [cAMP responsive element modulator]; CRH [corticotropin releasing hormone]; CRHR1 [corticotropin releasing hormone receptor 1]; CRHR2 [corticotropin releasing hormone receptor 2]; CRK [v-crk sar
- CSF2 colony stimulating factor 2
- CSF2RB colony stimulating factor 2 receptor, beta, low-affinity (granulocyte-macrophage)]
- CSF3 colony stimulating factor 3
- CTNNB1 [catenin (cadherin-associated protein), beta 1 , 88kDa]; CTNND1
- CTNS cystinosis, nephropathy
- CTRL chymotrypsin-like
- CTSB cathepsin B
- CTSC cathepsin C
- CXCL1 chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha)]
- CXCL10 chemokine (C- X-C motif) ligand 1 O]
- CXCL11 chemokine (C-X-C motif) ligand 11]
- CXCL12 chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1 )]
- CXCL13 chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha)
- CXCL10 chemokine (C- X-C motif) ligand 1 O]
- CXCL11 chemokine (C-X-C motif) ligand 11]
- CXCL12 chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1 )]
- CXCL13 chemokine (C-X-C motif) ligand 1 (mela
- CYP19A1 [cytochrome P450, family 19, subfamily A, polypeptide 1]; CYP1A1 [cytochrome P450, family 1 , subfamily A, polypeptide 1]; CYP1A2 [cytochrome P450, family 1 , subfamily A, polypeptide 2]; CYP1 B1 [cytochrome P450, family 1 , subfamily B, polypeptide 1]; CYP21A2 [cytochrome P450, family 21 , subfamily A, polypeptide 2]; CYP24A1 [cytochrome P450, family 24, subfamily A, polypeptide 1]; CYP27A1 [cytochrome P450, family 27, subfamily A, polypeptide 1];
- CYP27B1 [cytochrome P450, family 27, subfamily B, polypeptide 1]; CYP2A6 [cytochrome P450, family 2, subfamily A, polypeptide 6]; CYP2B6 [cytochrome P450, family 2, subfamily B, polypeptide 6]; CYP2C19 [cytochrome P450, family 2, subfamily C, polypeptide 19]; CYP2C8 [cytochrome P450, family 2, subfamily C, polypeptide 8]; CYP2C9 [cytochrome P450, family 2, subfamily C, polypeptide 9]; CYP2D6 [cytochrome P450, family 2, subfamily D, polypeptide 6]; CYP2E1 [cytochrome P450, family 2, subfamily E, polypeptide 1]; CYP2J2 [cytochrome P450, family 2, subfamily J, polypeptide 2]; CYP2R1 [cytochrome P450, family 2, subfamily R, polypeptide 1]; CYP3
- tautomerase (dopachrome delta-isomerase, tyrosine-related protein 2)]; DCTN2 [dynactin 2 (p50)]; DDB1 [damage-specific DNA binding protein 1 , 127kDa];
- DDB2 [damage-specific DNA binding protein 2, 48kDa]
- DDC [dopa]
- DDIT3 DNA-damage- inducible transcript 3
- DDR1 discoidin domain receptor tyrosine kinase 1
- DDX1 DEAD (Asp-Glu-Ala-Asp) box polypeptide 1]
- DDX41 DEAD (Asp-Glu-Ala-Asp) box polypeptide 41]
- DDX42 DEAD (Asp-Glu-Ala-Asp) box polypeptide 42];
- DDX58 [DEAD (Asp-Glu-Ala-Asp) box polypeptide 58]; DEFA1 [defensin, alpha 1]; DEFA5 [defensin, alpha 5, Paneth cell-specific]; DEFA6 [defensin, alpha 6, Paneth cell-specific]; DEFB1 [defensin, beta 1]; DEFB103B [defensin, beta 103B]; DEFB104A [defensin, beta 104A]; DEFB4A [defensin, beta 4A]; DEK
- DGAT1 diacylglycerol O-acyltransferase homolog 1 (mouse)]
- DGCR14 [DiGeorge syndrome critical region gene 14]; DGCR2 [DiGeorge syndrome critical region gene 2]; DGCR6 [DiGeorge syndrome critical region gene 6]; DGCR6L [DiGeorge syndrome critical region gene 6-like]; DGCR8 [DiGeorge syndrome critical region gene 8]; DGUOK [deoxyguanosine kinase]; DHFR [dihydrofolate reductase]; DHODH [dihydroorotate dehydrogenase]; DHPS [deoxyhypusine synthase]; DHRS7B [dehydrogenase/reductase (SDR family) member 7B]; DHRS9 [dehydrogenase/reductase (SDR family) member 9];
- DIAPH1 diaphanous homolog 1 (Drosophila)]; DICER1 [dicer 1 , ribonuclease type III]; DIO2 [deiodinase, iodothyronine, type M]; DKC1 [dyskeratosis congenita 1 , dyskerin]; DKK1 [dickkopf homolog 1 (Xenopus laevis)]; DLAT
- Drosophila (Drosophila)]; DLG5 [discs, large homolog 5 ⁇ Drosophila)]; DMBT1 [deleted in malignant brain tumors 1]; DMC1 [DMC1 dosage suppressor of mck1 homolog, meiosis-specific homologous recombination (yeast)]; DMD [dystrophin]; DMP1 [dentin matrix acidic phosphoprotein 1]; DMPK [dystrophia myotonica-protein kinase]; DMRT1 [doublesex and mab-3 related transcription factor 1]; DMXL2 [Dmx-like 2]; DNA2 [DNA replication helicase 2 homolog (yeast)]; DNAH1
- DPP10 Downstream of tyrosine kinase 1 )]; DOLK [dolichol kinase]; DPAGT1 [dolichyl- phosphate (UDP-N-acetylglucosamine) N-acetylglucosaminephosphotransferase 1 (GlcNAc-1 -P transferase)]; DPEP1 [dipeptidase 1 (renal)]; DPH1 [DPH1 homolog (S. cerevisiae)]; DPMI [dolichyl-phosphate mannosyltransferase polypeptide 1 , catalytic subunit]; DPP10 [dipeptidyl-peptidase 1 O]; DPP4
- EIF4G1 eukaryotic translation initiation factor 4 gamma, 1
- EIF6 eukaryotic translation initiation factor 6
- ELAC2 elaC homolog 2 (E.
- ELANE elastase, neutrophil expressed
- ELAVL1 ELAV (embryonic lethal, abnormal vision, Drosophila)- ⁇ ke 1 (Hu antigen R)]
- ELF3 E74-like factor 3 (ets domain transcription factor, epithelial-specific )]
- ELF5 E74-like factor 5 (ets domain transcription factor)]
- ELN elastin
- ELOVL4 elongation of very long chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 4]
- EMD [emerin]
- EMILIN1 elastin microfibril interfacer 1]
- EMR2 egf-like module containing, mucin-like, hormone receptor-like 2]
- EN2 engagerailed homeobox 2]
- ENG Endoglin]
- ENO1 enolase 1 , (alpha)]
- ENO2 elastase, neutrophil expressed
- EPCAM epidermal cell adhesion molecule
- EPHB6 EPH receptor B6
- EPHX1 epoxide hydrolase 1 , microsomal
- EPHX2 epoxide hydrolase 2, cytoplasmic]; EPO [erythropoietin]; EPOR [erythropoietin receptor]; EPRS [glutamyl-prolyl-tRNA synthetase]; EPX [eosinophil peroxidase]; ERBB2 [v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)]; ERBB2IP [erbb2 interacting protein]; ERBB3 [v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian)]; ERBB4 [v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)]; ERCC1 [excision repair cross-complementing rodent repair deficiency, complementation group 1 (includes overlapping antis
- ESR1 estradiosine receptor 1
- ESR2 esterogen receptor 2 (ER beta)
- ESRRA estrogen-related receptor alpha
- ETS1 [estrogen-related receptor beta]
- ETS2 [v-ets erythroblastosis virus E26 oncogene homolog 2 (avian)]
- EWSR1 Ewing sarcoma breakpoint region 1]
- TNFRSF6 TNFRSF6-associated via death domain
- FADS1 fatty acid desaturase 1
- FADS2 [fatty acid desaturase 2]; FAF1 [Fas (TNFRSF6) associated factor 1]; FAH [fumarylacetoacetate hydrolase (fumarylacetoacetase)]; FAM189B [family with sequence similarity 189, member B]; FAM92B [family with sequence similarity 92, member B]; FANCA [Fanconi anemia, complementation group A]; FANCB [Fanconi anemia, complementation group B]; FANCC [Fanconi anemia, complementation group C]; FANCD2 [Fanconi anemia, complementation group D2]; FANCE [Fanconi anemia, complementation group E]; FANCF [Fanconi anemia, complementation group F]; FANCG [Fanconi anemia, complementation group G]; FANCI [Fanconi anemia, complementation group I]; FANCL [Fanconi anemia, complementation group L]; FANCM [Fanconi anemia
- FDX1 [ferredoxin 1]; FEN1 [flap structure-specific endonuclease 1]; FERMT1 [fermitin family homolog 1 (Drosophila)]; FERMT3 [fermitin family homolog 3 (Drosophila)]; FES [feline sarcoma oncogene]; FFAR2 [free fatty acid receptor 2]; FGA [fibrinogen alpha chain]; FGB [fibrinogen beta chain]; FGF1 [fibroblast growth factor 1 (acidic)]; FGF2 [fibroblast growth factor 2 (basic)]; FGF5 [fibroblast growth factor 5]; FGF7 [fibroblast growth factor 7 (keratinocyte growth factor)]; FGF8 [fibroblast growth factor 8 (androgen-induced)]; FGFBP2 [fibroblast growth factor binding protein 2]; FGFR1 [fibroblast growth factor receptor 1];
- FKBP4 [FK506 binding protein 4, 59kDa]; FKBP5 [FK506 binding protein 5]; FLCN [folliculin]; FLG [filaggrin]; FLG2 [filaggrin family member 2]; FLNA [filamin A, alpha]; FLNB [filamin B, beta]; FLT1 [fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor)]; FLT3 [fms- related tyrosine kinase 3]; FLT3LG [fms-related tyrosine kinase 3 ligand]; FLT4 [fms-related tyrosine kinase 4]; FMN1 [formin 1]; FMOD [fibromodulin]; FMR1 [fragile X mental retardation 1]; FN1 [fibronectin 1]; FOLH1 [folate hydrolase (prostate-specific membrane anti
- FTH1 [ferritin, heavy polypeptide 1]
- FTL [ferritin, light polypeptide]
- FURIN furin (paired basic amino acid cleaving enzyme)]
- FUT1 [fucosyltransferase 1 (galactoside 2-alpha-L-fucosyltransferase, H blood group)]
- FUT2 [fucosyltransferase 2 (secretor status included)]
- FUT3 [fucosyltransferase 3 (galactoside 3(4)-L-fucosyltransferase, Lewis blood group)]
- FUT4
- GAST [phosphohbosylglycinamide formyltransferase, phosphohbosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase]; GAST [gastrin]; GATA1 [GATA binding protein 1 (globin transcription factor 1 )]; GATA2 [GATA binding protein 2]; GATA3 [GATA binding protein 3]; GATA4 [GATA binding protein 4]; GATA6 [GATA binding protein 6]; GBA [glucosidase, beta, acid]; GBA3
- GCG [glucosidase, beta, acid 3 (cytosolic)]; GBE1 [glucan (1 [4-alpha-), branching enzyme 1]; GC [group-specific component (vitamin D binding protein)]; GCG
- GCH1 GTP cyclohydrolase 1
- GCKR glucokinase (hexokinase 4) regulator
- GCLC glutamate-cysteine ligase, catalytic subunit
- GCLM glutamate-cysteine ligase, catalytic subunit
- Glutaminase [glutaminase]; GLT25D1 [glycosyltransferase 25 domain containing 1]; GLUL [glutamate-ammonia ligase (glutamine synthetase)]; GLYAT [glycine-N- acyltransferase]; GM2A [GM2 ganglioside activator]; GMDS [GDP-mannose 4 [6- dehydratase]; GNA12 [guanine nucleotide binding protein (G protein) alpha 12]; GNA13 [guanine nucleotide binding protein (G protein), alpha 13]; GNAM
- G protein [guanine nucleotide binding protein (G protein), alpha inhibiting activity
- polypeptide 1 polypeptide 1]; GNAO1 [guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O]; GNAQ [guanine nucleotide binding protein (G protein), q polypeptide]; GNAS [GNAS complex locus]; GNAZ [guanine
- G protein nucleotide binding protein
- GNB1 nucleotide binding protein (G protein), beta polypeptide 1]
- GNB1 L guanine nucleotide binding protein (G protein), beta polypeptide 1 -like]
- GNB2L1 guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1]
- GNB3 guanine nucleotide binding protein (G protein), beta polypeptide 3]
- GNE glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase]
- GNG2 guanine nucleotide binding protein (G protein), gamma 2]
- GNLY granulysin]
- GNPAT glycosamine O-acyltransferase]
- GNPDA2 glucosamine-6-phosphate deaminase 2]
- GNRH1 gonado
- GOT1 glutamic-oxaloacetic transaminase 1 , soluble (aspartate aminotransferase 1 )]
- GOT2 glutamic- oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)];
- GP1 BA [glycoprotein Ib (platelet), alpha polypeptide]; GP2 [glycoprotein 2 (zymogen granule membrane)]; GP6 [glycoprotein Vl (platelet)]; GPBAR1 [G protein-coupled bile acid receptor 1]; GPC5 [glypican 5]; GPI [glucose phosphate isomerase]; GPLD1 [glycosylphosphatidyl inositol specific phospholipase D1]; GPN1 [GPN-loop GTPase 1]; GPR1 [G protein-coupled receptor 1]; GPR12 [G protein-coupled receptor 12]; GPR123 [G protein-coupled receptor 123]; GPR143 [G protein-coupled receptor 143]; GPR15 [G protein-coupled receptor 15];
- GPR182 [G protein-coupled receptor 182]; GPR44 [G protein-coupled receptor 44]; GPR77 [G protein-coupled receptor 77]; GPRASP1 [G protein-coupled receptor associated sorting protein 1]; GPRC6A [G protein-coupled receptor, family C, group 6, member A]; GPT [glutamic-pyruvate transaminase (alanine aminotransferase)]; GPX1 [glutathione peroxidase 1]; GPX2 [glutathione peroxidase 2 (gastrointestinal)]; GPX3 [glutathione peroxidase 3 (plasma)];
- GRAP2 [GRB2-related adaptor protein 2]; GRB2 [growth factor receptor-bound protein 2]; GRIA2 [glutamate receptor, ionotropic, AMPA 2]; GRIN1 [glutamate receptor, ionotropic, N-methyl D-aspartate 1]; GRIN2A [glutamate receptor, ionotropic, N-methyl D-aspartate 2A]; GRIN2B [glutamate receptor, ionotropic, N- methyl D-aspartate 2B]; GRIN2C [glutamate receptor, ionotropic, N-methyl D- aspartate 2C]; GRIN2D [glutamate receptor, ionotropic, N-methyl D-aspartate 2D]; GRIN3A [glutamate receptor, ionotropic, N-methyl-D-aspartate 3A]; GRIN3B [glutamate receptor, ionotropic, N-methyl-D-aspartate 3
- GTF2A1 general transcription factor MA, 1 , 19/37kDa
- GTF2F1 general transcription factor MF, polypeptide 1 , 74kDa
- GTF2H2 general transcription factor MF, polypeptide 1 , 74kDa
- GULP1 [GULP, engulfment adaptor PTB domain containing 1]; GUSB
- GZMA granzyme A (granzyme 1 , cytotoxic T-lymphocyte-associated serine esterase 3)]; GZMB [granzyme B (granzyme 2, cytotoxic T-lymphocyte- associated serine esterase 1 )]; GZMK [granzyme K (granzyme 3; tryptase II)]; H1 FO [H1 histone family, member O]; H2AFX [H2A histone family, member X]; HABP2 [hyaluronan binding protein 2]; HACL1 [2-hydroxyacyl-CoA lyase 1];
- HADHA hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (thfunctional protein), alpha subunit]
- HAL histidine ammonia-lyase
- HAMP hepcidin antimicrobial peptide
- HAVCR1 hepatitis A virus cellular receptor 1
- HAVCR2 hepatitis A virus cellular receptor 2
- HAX1 HCLS1 associated protein X-1]
- HBA1 hemoglobin, alpha 1]
- HBA2 hemoglobin, alpha 2]
- HBB hemoglobin, beta
- HBE1 hemoglobin, epsilon 1
- HBEGF heparin- binding EGF-like growth factor]
- HBG2 hemoglobin, gamma G]
- HCCS heparin- binding EGF-like growth factor
- HCRTR1 hemocytochrome c synthase (cytochrome c heme-lyase)]; HCK [hemopoietic cell kinase]; HCRT [hypocretin (orexin) neuropeptide precursor]; HCRTR1
- HES1 [hypocretin (orexin) receptor 1]; HCRTR2 [hypocretin (orexin) receptor 2]; HCST [hematopoietic cell signal transducer]; HDAC1 [histone deacetylase 1]; HDAC2 [histone deacetylase 2]; HDAC6 [histone deacetylase 6]; HDAC9 [histone deacetylase 9]; HDC [histidine decarboxylase]; HERC2 [hect domain and RLD 2]; HES1 [hairy and enhancer of split 1 , (Drosophila)]; HES6 [hairy and enhancer of split 6 ⁇ Drosophila)]; HESX1 [HESX homeobox 1]; HEXA [hexosaminidase A (alpha polypeptide)]; HEXB [hexosaminidase B (beta polypeptide)]; HFE
- HGF hepatocyte growth factor (hepapoietin A; scatter factor)
- HGS hepatocyte growth factor-regulated tyrosine kinase substrate
- HGSNAT heparan-alpha-glucosaminide N-acetyltransferase
- HIF1A hypooxia inducible factor 1 , alpha subunit (basic helix-loop-helix transcription factor)];
- HINFP histone H4 transcription factor
- HINT1 histidine triad nucleotide binding protein 1
- HIPK2 homeodomain interacting protein kinase 2
- HIRA HIRA
- HIST1 H1 B histone cluster 1 , HI b]
- HIST1 H3E histone cluster 1 , H3e]
- HIST2H2AC histone cluster 2, H2ac]
- HIST2H3C histone cluster 2, H3c]
- HIST4H4 histone cluster 4, H4]
- HJURP Holliday junction recognition protein]
- HK2 [hexokinase 2]
- HLA-A major histocompatibility complex, class I, A]
- HLA-B major histocompatibility complex, class I, B]
- HLA-C major histocompatibility complex, class I, C]
- HLA-DMA major histocompatibility complex, class II, DM alpha]
- HLA-DMB major histocompatibility complex, class II, DM alpha
- HLA-DOA major histocompatibility complex, class II, DO alpha
- HLA-DOB major histocompatibility complex, class II, DO beta
- HLA-DPA1 major histocompatibility complex, class II, DP alpha 1
- HLA-DPB1 major histocompatibility complex, class II, DP beta 1
- HLA-DQA1 major histocompatibility complex, class II, DQ alpha 1
- HLA-DQA2 major histocompatibility complex, class II, DQ alpha 2]
- HLA-DQB1 major histocompatibility complex, class II, DM beta]
- HLA-DOA major histocompatibility complex, class II, DO alpha
- HLA-DOB major histocompatibility complex, class II, DO beta
- HLA-DPA1 major histocompatibility complex, class II, DP alpha 1
- HLA-DPB1 major histocompatibility complex, class II, DP beta 1
- HLA-DRB1 histocompatibility complex, class II, DR alpha
- HLA-E major histocompatibility complex, class I, E
- HLA-F major histocompatibility complex, class I, F
- HLA-G major histocompatibility complex, class I, G
- HLCS holocarboxylase synthetase (biotin-(proprionyl-Coenzyme A-carboxylase (ATP-hydrolysing)) ligase)]
- HLTF helicase-like transcription factor]
- HLX H2.0-like homeobox]
- HMBS histocompatibility complex
- HMGA1 high mobility group AT-hook 1
- HMGB1 high-mobility group box 1]; HMGCR [3-hydroxy-3-methylglutaryl- Coenzyme A reductase]; HMOX1 [heme oxygenase (decycling) 1]; HMOX2 [heme oxygenase (decycling) 2]; HNF1 A [HNF1 homeobox A]; HNF4A
- HNMT hepatocyte nuclear factor 4, alpha
- HNMT histamine N-methyltransferase
- HNRNPA1 heterogeneous nuclear ribonucleoprotein A1
- HNRNPH2 heterogeneous nuclear ribonucleoprotein H2 (H')]
- HNRNPUL1 heterogeneous nuclear ribonucleoprotein U-like 1
- HOXA13 homeobox A13
- HOXA4 homeobox A4
- HOXA9 homeobox A9
- HPXB4 homeobox B4
- HPGDS haptoglobin
- HPR hematopoietic prostaglandin D synthase
- HPR haptoglobin-related protein
- HPRT1 hyperxanthine phosphoribosyltransferase 1
- HPS1 Hermansky-Pudlak syndrome 1]
- HPS3 Hermansky-Pudlak syndrome 3
- HPS4 Hermansky-Pudlak syndrome 4]
- HPSE Heparanase]
- HPX Hepexin
- HRAS v-Ha-ras Harvey rat sarcoma viral oncogene homolog
- HRG histidine-rich glycoprotein
- HSD11 B1 hydroxysteroid (11 -beta) dehydrogenase 1]
- HSD11 B2 hydroxysteroid (11 -beta) dehydrogenase 2];
- HSD17B1 [hydroxysteroid (17-beta) dehydrogenase 1]; HSD17B4
- HSF1 heat shock transcription factor 1
- HSP90AA1 heat shock protein 9OkDa alpha (cytosolic), class A member 1
- HSP90AB1 heat shock protein 9OkDa alpha (cytosolic), class B member 1
- HSP90B1 heat shock protein 9OkDa beta (Grp94), member 1];
- HSPA14 [heat shock 7OkDa protein 14]; HSPA1A [heat shock 7OkDa protein 1A]; HSPA1 B [heat shock 7OkDa protein 1 B]; HSPA2 [heat shock 7OkDa protein 2]; HSPA4 [heat shock 7OkDa protein 4]; HSPA5 [heat shock 7OkDa protein 5 (glucose-regulated protein, 78kDa)]; HSPA8 [heat shock 7OkDa protein 8];
- HSPB1 heat shock 27kDa protein 1
- HSPB2 heat shock 27kDa protein 2
- HSPD1 heat shock 6OkDa protein 1 (chaperonin)
- HSPE1 heat shock 1 OkDa protein 1 (chaperonin 10)
- HSPG2 heparan sulfate proteoglycan 2]
- HTR1A 5-hydroxytryptamine (serotonin) receptor 1A
- HTR2A 5- hydroxytryptamine (serotonin) receptor 2A
- HTR3A 5-hydroxytryptamine
- HTRA1 HtrA serine peptidase 1]
- HTT huntingtin
- HUS1 HUS1 checkpoint homolog (S. pombe)]
- HUWE1 HECT, UBA and WE domain containing 1]
- HYAL1 hyaluronoglucosaminidase 1]
- HYLS1 HYaluronoglucosaminidase 1
- IAPP hydrolethalus syndrome 1
- IAPP islet amyloid polypeptide
- IBSP integrated protein-binding sialoprotein
- ICAM1 intercellular adhesion molecule 1]
- ICAM2 intercellular adhesion molecule 2
- intercellular adhesion molecule 2 [intercellular adhesion molecule 2]; ICAM3 [intercellular adhesion molecule 3]; ICAM4 [intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)]; ICOS [inducible T-cell co-stimulator]; ICOSLG [inducible T-cell co-stimulator ligand]; ID1 [inhibitor of DNA binding 1 , dominant negative helix-loop-helix protein]; ID2 [inhibitor of DNA binding 2, dominant negative helix-loop-helix protein]; IDO1 [indoleamine 2 [3-dioxygenase 1]; IDS [iduronate 2-sulfatase]; IDUA [iduronidase, alpha-L-]; IFI27 [interferon, alpha-inducible protein 27]; IFI30 [interferon, gamma-inducible protein 30]; IFITM1 [interferon induced
- transmembrane protein 1 (9-27)]; IFNA1 [interferon, alpha 1]; IFNA2 [interferon, alpha 2]; IFNAR1 [interferon (alpha, beta and omega) receptor 1]; IFNAR2
- IGF1 insulin growth factor 1 (somatomedin C)]; IGF1 R [insulin-like growth factor 1 receptor]; IGF2 [insulin-like growth factor 2 (somatomedin A)]; IGF2R [insulin-like growth factor 2 receptor]; IGFBP1 [insulin-like growth factor binding protein 1]; IGFBP2 [insulin-like growth factor binding protein 2, 36kDa]; IGFBP3 [insulin-like growth factor binding protein 3]; IGFBP4 [insulin-like growth factor binding protein 4]; IGFBP5 [insulin-like growth factor binding protein 5]; IGHA1 [imm
- IGHMBP2 [immunoglobulin mu binding protein 2]
- IGKC immunoglobulin kappa constant]
- IGKV2D-29 immunoglobulin kappa variable 2D-29
- IGLL1 immunoglobulin lambda-like polypeptide 1]
- IGSF1 immunoglobulin superfamily, member 1]
- IKBKAP inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein]
- IKBKB [inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta]; IKBKE [inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon]; IKBKG [inhibitor of kappa light polypeptide gene enhancer in B- cells, kinase gamma]; IKZF1 [IKAROS family zinc finger 1 (Ikaros)]; IKZF2
- IL10 interleukin 1 O
- IL10RA interleukin 10 receptor, alpha
- IL10RB interleukin 10 receptor, beta
- IL11 interleukin 11
- IL12A interleukin 12A (natural killer cell stimulatory factor 1 , cytotoxic
- lymphocyte maturation factor 1 lymphocyte maturation factor 1 , p35)]; IL12B [interleukin 12B (natural killer cell stimulatory factor 2, cytotoxic lymphocyte maturation factor 2, p40) ]; IL12RB1 [interleukin 12 receptor, beta 1]; IL12RB2 [interleukin 12 receptor, beta 2]; IL13 [interleukin 13]; IL13RA1 [interleukin 13 receptor, alpha 1]; IL13RA2 [interleukin 13 receptor, alpha 2]; IL15 [interleukin 15]; IL15RA [interleukin 15 receptor, alpha]; IL16 [interleukin 16 (lymphocyte chemoattractant factor)]; IL17A
- IL18BP interleukin 18 binding protein
- IL18R1 interleukin 18 receptor 1
- IL18RAP interleukin 18 receptor accessory protein
- IL19 interleukin 19
- IL1A interleukin 1 , alpha]
- IL1 B interleukin 1 , beta]
- IL1 F9 interleukin 1 family, member 9]
- IL1 R1 interleukin 1 receptor, type I]
- IL1 RAP interleukin 1 receptor accessory protein]
- IL1 receptor-like 1 [interleukin 1 receptor-like 1]; IL1 RN [interleukin 1 receptor antagonist]; IL2
- IL20 [interleukin 20]; IL21 [interleukin 21]; IL21 R [interleukin 21 receptor]; IL22 [interleukin 22]; IL23A [interleukin 23, alpha subunit p19]; IL23R [interleukin 23 receptor]; IL24 [interleukin 24]; IL25 [interleukin 25]; IL26
- IL27 [interleukin 27]; IL27RA [interleukin 27 receptor, alpha]; IL29 [interleukin 29 (interferon, lambda 1 )]; IL2RA [interleukin 2 receptor, alpha];
- IL2RB interleukin 2 receptor, beta
- IL2RG interleukin 2 receptor, gamma (severe combined immunodeficiency)]
- IL3 interleukin 3 (colony-stimulating factor, multiple)]
- IL31 interleukin 31]
- IL32 interleukin 32
- IL33 interleukin 33
- IL3RA interleukin 3 receptor, alpha (low affinity)]
- IL4 interleukin 4]
- IL4R interleukin 4
- IL5 interleukin 5 (colony-stimulating factor, eosinophil)]; IL5RA [interleukin 5 receptor, alpha]; IL6 [interleukin 6 (interferon, beta 2)]; IL6R [interleukin 6 receptor]; IL6ST [interleukin 6 signal transducer (gp130, oncostatin M receptor)]; IL7 [interleukin 7]; IL7R [interleukin 7 receptor]; IL8 [interleukin 8]; IL9 [interleukin 9]; IL9R [interleukin 9 receptor]; ILK [integrin-linked kinase]; IMP5 [intramembrane protease 5]; INCENP [inner centromere protein antigens
- ING1 [inhibitor of growth family, member 1]; INHA [inhibin, alpha]; INHBA [inhibin, beta A]; INPP4A [inositol polyphosphate-4-phosphatase, type I, 107kDa]; INPP5D [inositol polyphosphate-5-phosphatase, 145kDa]; INPP5E [inositol polyphosphate-5-phosphatase, 72 kDa]; INPPL1 [inositol polyphosphate phosphatase-like 1]; INS [insulin]; INSL3 [insulin-like 3 (Leydig cell)]; INSR
- IRS1 insulin receptor substrate 1
- IRS2 insulin receptor substrate 2
- IRS4 insulin receptor substrate 4
- ISG15 ISG15 ubiquitin-like modifier]
- ITCH itchy E3 ubiquitin protein ligase homolog (mouse)]
- ITFG1 integerghn alpha FG-GAP repeat containing 1]
- ITGA1 integerghn, alpha 1
- ITGA2 integratedin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)]
- ITGA2B integratedin, alpha 2b (platelet glycoprotein Mb of llb/llla complex, antigen CD41 )]
- ITGA3 integratedin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor)]
- ITGA4 integratedin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor)]
- ITGA5 integratedin, alpha 5
- ITK IL2-inducible T-cell kinase
- ITPA inosine triphosphatase (nucleoside triphosphate pyrophosphatase)]; ITPR1 [inositol 1 ,4,5-thphosphate receptor, type 1]; ITPR3 [inositol 1 ,4,5-triphosphate receptor, type 3]; IVD [isovaleryl Coenzyme A dehydrogenase]; IVL [involucrin]; IVNS1ABP [influenza virus NS1A binding protein]; JAG1 [jagged 1 (Alagille syndrome)]; JAK1 [Janus kinase 1]; JAK2 [Janus kinase 2]; JAK3 [Janus kinase 3]; JAKMIP1 [janus kinase and microtubule interacting protein 1]; JMJD6 [junnonji domain containing 6]; JPH4 [jun
- KIR2DL3 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3]
- KIR2DL5A killer cell immunoglobulin-like receptor, two domains, long
- KIR2DS1 killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1]
- KIR2DS2 killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 2]
- KIR2DS5 killer cell
- KIR3DL1 killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 1]
- KIR3DS1 killer cell immunoglobulin-like receptor, three domains, short cytoplasmic tail, 1]
- KISS1 KiSS-1 metastasis-suppressor]
- KISS1 R KISS1 receptor
- KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog]
- KITLG KIT ligand]
- KLF2 Kruppel-like factor 2 (lung)]
- KLF4 Kruppel-like factor 4 (gut)]
- KLK1 kallikrein 1]
- KLK11 kallikrein-related peptidase 11]
- KLKB1 kallikrein B, plasma (Fletcher factor) 1]
- KLRB1 killer cell lectin-like receptor subfamily B, member 1]
- KLRC1 killer cell lectin-like receptor subfamily C, member 1]
- KLRD1 killer cell lectin-like receptor subfamily D, member 1]
- KLRK1 killer cell lectin-like receptor subfamily K, member 1]
- KNG1 [kininogen 1]
- KPNA1 Karyopherin alpha 1 (importin alpha 5)]
- KPNA2 Karyopherin alpha 2 (RAG cohort 1 , importin alpha 1 )]
- KPNB1 KPNB1
- LBR lipopolysaccharide binding protein
- LBR lamin B receptor
- LBXCOR1 Longer than COR1
- LCAT lecithin-cholesterol acyltransferase
- LCK lecithin-cholesterol acyltransferase
- LCN1 lipocalin 1 (tear prealbumin)]
- LCN2 lipocalin 1 (tear prealbumin)
- LMAN1 [lectin, mannose-binding, 1]; LMLN [leishmanolysin-like (metallopeptidase M8 family)]; LMNA [lamin AZC]; LMNB1 [lamin B1]; LMNB2 [lamin B2]; LOC646627 [phospholipase inhibitor]; LOX [lysyl oxidase]; LOXHD1 [lipoxygenase homology domains 1]; LOXL1 [lysyl oxidase-like 1]; LPA
- LPCAT2 [lipoprotein, Lp(a)]; LPAR3 [lysophosphatidic acid receptor 3]; LPCAT2
- LPO lipoprotein lipase
- LRP1 low density lipoprotein receptor-related protein 1
- LRP6 low density lipoprotein receptor-related protein 6
- LRPAP1 low density lipoprotein receptor- related protein associated protein 1
- LRRC32 leucine rich repeat containing 32]
- LRRC37B leucine rich repeat containing 37B]
- LRRC8A leucine rich repeat containing 8 family, member A]
- LRRK2 leucine-rich repeat kinase 2]
- LRTOMT leucine rich transmembrane and O-methyltransferase domain containing]
- LSM1 LSM1 homolog, U6 small nuclear RNA associated (S.
- LSM2 LSM2 homolog, U6 small nuclear RNA associated (S. cerevisiae)]
- LSP1 lymphocyte-specific protein 1
- LTA lymphotoxin alpha (TNF superfamily, member 1 )];
- LTA4H leukothene A4 hydrolase]; LTB [lymphotoxin beta (TNF superfamily, member 3)]; LTB4R [leukotriene B4 receptor]; LTB4R2 [leukotriene B4 receptor 2]; LTBR [lymphotoxin beta receptor (TNFR superfamily, member 3)]; LTC4S [leukotriene C4 synthase]; LTF [lactotransferhn]; LY86 [lymphocyte antigen 86]; LY9 [lymphocyte antigen 9]; LYN [v-yes-1 Yamaguchi sarcoma viral related oncogene homolog]; LYRM4 [LYR motif containing 4]; LYST [lysosomal trafficking regulator]; LYZ [lysozyme (renal amyloidosis)]; LYZL6 [lysozyme-like 6]; LZTR1 [leucine-zipper-like transcription regulator 1]; M6
- MAP2K1 mitogen- activated protein kinase kinase 1]
- MAP2K2 mitogen-activated protein kinase kinase 2
- MAP2K3 mitogen-activated protein kinase kinase 3]
- MAP2K4 mitogen-activated protein kinase kinase 4
- MAP3K5 [mitogen-activated protein kinase kinase kinase 5]; MAP3K7 [mitogen- activated protein kinase kinase 7]; MAP3K9 [mitogen-activated protein kinase kinase kinase 9]; MAPK1 [mitogen-activated protein kinase 1]; MAPK10 [mitogen-activated protein kinase 10]; MAPK11 [mitogen-activated protein kinase 11]; MAPK12 [mitogen-activated protein kinase 12]; MAPK13 [mitogen-activated protein kinase 13]; MAPK14 [mitogen-activated protein kinase 14]; MAPK3
- MDC1 [melanocortin 4 receptor]; MCCC2 [methylcrotonoyl-Coenzyme A carboxylase 2 (beta)]; MCHR1 [melanin-concentrating hormone receptor 1]; MCL1 [myeloid cell leukemia sequence 1 (BCL2-related)]; MCM2 [minichromosonne maintenance complex component 2]; MCM4 [minichromosome maintenance complex component 4]; MCOLN1 [mucolipin 1]; MCPH1 [microcephalin 1]; MDC1
- MEN1 multiple endocrine neoplasia I]; MEPE [matrix extracellular phosphoglycoprotein]; MERTK [c-mer proto- oncogene tyrosine kinase]; MESP2 [mesoderm posterior 2 homolog (mouse)]; MET [met proto-oncogene (hepatocyte growth factor receptor)]; MGAM [maltase- glucoamylase (alpha-glucosidase)]; MGAT1 [mannosyl (alpha-1 ,3-)-glycoprotein beta-1 ,2-N-acetylglu
- MICA MHC class I polypeptide-related sequence A
- MICB MHC class I polypeptide-related sequence B
- MKI67 antigen identified by monoclonal antibody Ki-67
- MKS1 Meckel syndrome, type 1
- MLH1 mutant L homolog 1 , colon cancer, nonpolyposis type 2 (E. coli)]
- MLL myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila)]
- MLLT4 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog,
- Drosophila Drosophila
- translocated to, 4]; MLN motilin]; MLXIPL [MLX interacting protein- like]; MMAA [methylmalonic aciduria (cobalamin deficiency) cblA type]; MMAB [methylmalonic aciduria (cobalamin deficiency) cblB type]; MMACHC
- MME membrane metallo-endopeptidase
- MMP1 matrix metallopeptidase 1 (interstitial collagenase)]
- MMP10 matrix metallopeptidase 10 (stromelysin 2)]
- MMP12 matrix metallopeptidase 12 (macrophage elastase)]
- MMP13 matrix metallopeptidase 13 (collagenase 3)]
- MMP14 matrix metallopeptidase 14 (membrane-inserted)]
- MMP15 matrix metallopeptidase 15 (membrane- inserted)]
- MMP17 matrix metallopeptidase 17 (membrane-inserted)]
- MMP2 matrix metallopeptidase 2 (gelatinase
- MMP28 matrix metallopeptidase 28
- MMP3 matrix metallopeptidase 3 (stromelysin 1 , progelatinase)]
- MMP7 matrix metallopeptidase 7
- MMP8 matrix metallopeptidase 8 (neutrophil collagenase)]
- MMP9 matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)]
- MMRN1 multimerin 1]
- MNAT1 multimerin 1
- MRGPRX1 MAS-related GPR, member X1]
- MRPL28 mitochondrial ribosomal protein L28
- MRPL40 mitochondrial ribosomal protein L40
- MRPS16 mitochondrial ribosomal protein S16
- MRPS22 mitochondrial ribosomal protein S22
- MS4A1 membrane- spanning 4-domains, subfamily A, member 1]
- MS4A2 membrane-spanning 4- domains, subfamily A, member 2 (Fc fragment of IgE, high affinity I, receptor for; beta polypeptide)]
- MS4A3 membrane-spanning 4-domains, subfamily A, member 3 (hematopoietic cell-specific)]
- MSH2 mutant S homolog 2, colon cancer, nonpolyposis type 1 (E.
- MSH5 [mutS homolog 5 (E. coli)]; MSH6 [mutS homolog 6 (E. coli)]; MSLN [mesothelin]; MSN [moesin]; MSR1 [macrophage scavenger receptor 1]; MST1 [macrophage stimulating 1 (hepatocyte growth factor-like)]; MST1 R [macrophage stimulating 1 receptor (c-met-related tyrosine kinase)]; MSTN [myostatin]; MSX2 [msh homeobox 2]; MT2A [metallothionein 2A]; MTCH2 [mitochondrial carrier homolog 2 (C.
- MT-CO2 mitochondrially encoded cytochrome c oxidase II
- MTCP1 matrix T-cell proliferation 1
- MT-CYB mitochondrially encoded cytochrome b
- NADP+ dependent [methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 ,
- MTOR mechanistic target of rapamycin (serine/threonine kinase)]; MTR [5-methyltetrahydrofolate- homocysteine methyltransferase]; MTRR [5-methyltetrahydrofolate-homocysteine methyltransferase reductase]; MTTP [microsomal triglyceride transfer protein]; MTX1 [metaxin 1]; MUC1 [mucin 1 , cell surface associated]; MUC12 [mucin 12, cell surface associated]; MUC16 [mucin 16, cell surface associated]; MUC19 [mucin 19, oligomehc]; MUC2 [mucin 2, oligomehc mucus/gel-forming]; MUC3A [mucin 3A, cell surface associated]; MUC3B [mucin 3B, cell surface associated]; MUC4
- MVP major vault protein
- MX1 myxovirus (influenza virus) resistance 1 , interferon-inducible protein p78 (mouse)]
- MYB v-myb
- MYBPH myosin binding protein H
- MYC v-myc myelocytomatosis viral oncogene homolog (avian)]
- MYCN v- myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian)]
- MYD88 myeloid differentiation primary response gene (88)]
- MYH1 myosin, heavy chain 1 , skeletal muscle, adult]
- MYH10 myosin, heavy chain 10, non- muscle]
- MYH11 myosin, heavy chain 11 , smooth muscle]
- MYH14 myosin, heavy chain 14, non-muscle
- MYH2 myosin, heavy chain 2, skeletal muscle, adult]
- MYH3 myosin, heavy chain 3, skeletal muscle, embryonic]
- MYH6 myosin, heavy chain 6, cardiac muscle, alpha];
- NAT2 N-acetyltransferase 2 (arylamine N- acetyltransferase)]
- NAT9 N-acetyltransferase 9 (GCN5-related, putative)];
- NBEA neurorobeachin
- NBN nobrin
- NCAM1 noural cell adhesion molecule 1
- NCF1 neurotrophil cytosolic factor 1
- NCF2 neutral cell adhesion molecule 2
- NCF4 neutral cell cytosolic factor 4, 4OkDa]
- NCK1 NCK adaptor protein 1]
- NCL nucleophilicity factor 1
- nucleolin [nucleolin]; NCOA1 [nuclear receptor coactivator 1]; NCOA2 [nuclear receptor coactivator 2]; NCOR1 [nuclear receptor co-repressor 1]; NCR3 [natural cytotoxicity triggering receptor 3]; NDUFA13 [NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13]; NDUFAB1 [NADH dehydrogenase (ubiquinone) 1 , alpha/beta subcomplex, 1 , 8kDa]; NDUFAF2 [NADH dehydrogenase
- NEDD4 nerve growth factor 4
- NEFL neuroofilament, light polypeptide
- NEFM neuroofilament, medium polypeptide
- NEGRI neuroal growth regulator 1
- NEK6 NIMA (never in mitosis gene a)-related kinase 6]
- NELF neuronic LHRH factor
- NELL1 NELL1 [NEL-like 1 (chicken)]
- NEU1 sialidase 1 (lysosomal sialidase)]; NEUROD1 [neurogenic differentiation 1]; NF1 [neurofibromin 1]; NF2 [neurofibromin 2 (merlin)]; NFAT5 [nuclear factor of activated T-cells 5, tonicity-responsive]; NFATC1 [nuclear factor of activated T-cells, cytoplasmic, calcineuhn-dependent 1]; NFATC2 [nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2]; NFATC4
- NFE2L2 nuclear factor (erythroid-dehved 2)-like 2
- NFKB1 nuclear factor of kappa light polypeptide gene enhancer in B-cells 1
- NFKB2 nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (p49/p100)
- NFKBIA nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha
- NFKBIB nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, beta
- NFKBIL1 nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 1
- NFU1 NFU1 iron-sulfur cluster scaffold homolog (S. cerevisiae)]
- NGF nerve growth factor (beta polypeptide)]
- NGFR nerve growth factor receptor (TNFR superfamily, member 16)]
- NID1 nonhomologous end-joining factor 1
- NKAP NFkB activating protein
- NKX2-1 ,NK2 homeobox 1
- NKX2-3 NK2 transcription factor related, locus 3 (Drosophila)]
- NLRP3 NLR family, pyrin domain containing 3]
- NMB nonhomologous end-joining factor 1
- NID1 nonhomologous end-joining factor 1
- NKAP NFkB activating protein
- NKX2-1 ,NK2 homeobox 1
- NKX2-3 NK2 transcription factor related, locus 3 (Drosophila)]
- NLRP3 NLR family, pyrin domain containing 3]
- NMB nonhomologous end-joining factor 1
- NME1 [non-metastatic cells 1 , protein (NM23A) expressed in]; NME2 [non-metastatic cells 2, protein (NM23B) expressed in]; NMU [neuromedin U]; NNAT [neuronatin]; NOD1 [nucleotide-binding oligomerization domain containing 1]; NOD2 [nucleotide-binding oligomerization domain containing 2]; NONO [non-POU domain containing, octamer-binding]; NOS1 [nitric oxide synthase 1 (neuronal)]; NOS2 [nitric oxide synthase 2, inducible]; NOS3 [nitric oxide synthase 3 (endothelial cell)]; NOTCH1 [Notch homolog 1 , translocation- associated ⁇ Drosophila)]; NOTCH2 [Notch homolog 2 ⁇ Drosophila)]; NOTCH3 [Notch homolog 3
- NPHS2 nephrosis 2, idiopathic, steroid-resistant (podocin)
- NPLOC4 nuclear protein localization 4 homolog
- NPM1 [nucleophosmin (nucleolar phosphoprotein B23, numatrin)]; NPPA [natriuretic peptide precursor A]; NPPB [natriuretic peptide precursor B]; NPPC [natriuretic peptide precursor C]; NPR1 [natriuretic peptide receptor A/guanylate cyclase A (atrionatriuretic peptide receptor A)]; NPR3 [natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C)]; NPS [neuropeptide S]; NPSR1 [neuropeptide S receptor 1]; NPY [neuropeptide Y]; NPY2R [neuropeptide Y receptor Y2]; NQO1 [NAD(P)H dehydrogenase, quinone 1]; NR0B1 [nuclear
- nuclear receptor subfamily 1 group I, member 3
- NR2F2 nuclear receptor subfamily 2, group F, member 2
- NR3C1 nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)]
- NR3C2 nuclear receptor subfamily 3, group C, member 2
- NR4A1 nuclear receptor subfamily 4, group A, member 1];
- NR4A3 [nuclear receptor subfamily 4, group A, member 3]; NR5A1 [nuclear receptor subfamily 5, group A, member 1]; NRF1 [nuclear respiratory factor 1]; NRG1 [neuregulin 1]; NRIP1 [nuclear receptor interacting protein 1]; NRIP2
- NTF3 [nuclear receptor interacting protein 2]; NRP1 [neuropilin 1]; NSD1 [nuclear receptor binding SET domain protein 1]; NSDHL [NAD(P) dependent steroid dehydrogenase-like]; NSF [N-ethylmaleimide-sensitive factor]; NT5E [5'- nucleotidase, ecto (CD73)]; NTAN1 [N-terminal asparagine amidase]; NTF3
- NTF4 neurotrophin 4
- NTN1 [netrin 1]
- NTRK1 neurotrophic tyrosine kinase, receptor, type 1]
- NTRK2 neurotrophic tyrosine kinase, receptor, type 2]
- NTRK3 neurotrophic tyrosine kinase, receptor, type 3]
- NTS neurorotensin
- NUCB2 [nucleobindin 2]
- NUDT1 [nudix (nucleoside diphosphate linked moiety X)-type motif 1]
- NUDT2 [nudix (nucleoside diphosphate linked moiety X)-type motif 2]
- NUDT6 nuudix (nucleoside diphosphate linked moiety X)- type motif 6]
- NUFIP2 nuclear fragile X mental retardation protein interacting protein 2]
- NUP98 [nucleoporin 98
- decarboxylase 1 oral-facial-digital syndrome 1]; OGDH [oxoglutarate (alpha-ketoglutarate) dehydrogenase (lipoamide)]; OGG1 [8-oxoguanine DNA glycosylase]; OGT [O-linked N-acetylglucosamine (GIcNAc) transferase (UDP-N- acetylglucosamine:polypeptide-N-acetylglucosaminyl transferase)]; OLR1
- OSBP oxysterol binding protein
- OSGIN2 oxidative stress induced growth inhibitor family member 2
- OSM oncostatin M
- OTC ornithine carbamoyltransferase
- OTOP2 otopethn 2
- OTOP3 otopetrin 3
- OTUD1 OTU domain containing 1]
- OXA1 L oxidase (cytochrome c) assembly 1 -like]
- OXER1 oxoeicosanoid (OXE) receptor 1]
- OXT oxytocin, prepropeptide]
- OXTR oxidative stress induced growth inhibitor family member 2
- OTC ornithine carbamoyltransferase
- OTOP2 otopethn 2
- OTOP3 otopetrin 3
- OTUD1 OTU domain containing 1]
- OXA1 L oxidase (cytochrome c) assembly 1 -like
- acetylhydrolase 1 b regulatory subunit 1 (45kDa)]; PAH [phenylalanine hydroxylase]; PAK1 [p21 protein (Cdc42/Rac)-activated kinase 1]; PAK2 [p21 protein (Cdc42/Rac)-activated kinase 2]; PAK3 [p21 protein (Cdc42/Rac)- activated kinase 3]; PAM [peptidylglycine alpha-amidating monooxygenase]; PAPPA [pregnancy-associated plasma protein A, pappalysin 1]; PARG [poly (ADP-ribose) glycohydrolase]; PARK2 [Parkinson disease (autosomal recessive, juvenile) 2, parkin]; PARP1 [poly (ADP-ribose) polymerase 1]; PAWR [PRKC, apoptosis, WT1 , regulator]; PAX
- PCM1 phosphoenolpyruvate carboxykinase 1 (soluble)]
- PCM1 pericentriolar material 1
- PCNA proliferating cell nuclear antigen
- PCNT peripheral antigen
- PCSK6 proprotein convertase subtilisin/kexin type 6
- PCSK7 proprotein convertase subtilisin/kexin type 7
- PCYT1A phosphate cytidylyltransferase 1 , choline, alpha
- PCYT2 phosphate cytidylyltransferase 2, ethanolamine
- PDCD1 programmeed cell death 1]
- PDCD1 LG2 [programmed cell death 1 ligand 2]; PDCD6 [programmed cell death 6]; PDE3B [phosphodiesterase 3B, cGMP-inhibited]; PDE4A [phosphodiesterase 4A, cAMP-specific (phosphodiesterase E2 dunce homolog, Drosophila)]; PDE4B [phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 dunce homolog, Drosophila)]; PDE4D [phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila)]; PDE7A [phosphodiesterase 7A]; PDGFA
- PDGFB platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)]
- PDGFRA platelet-derived growth factor receptor, alpha polypeptide
- PDGFRB platelet-derived growth factor receptor, beta polypeptide
- PDIA2 protein disulfide isomerase family A, member 2]
- PDIA3 protein disulfide isomerase family A, member 3]
- PDK1 pyruvate dehydrogenase kinase, isozyme 1];
- PDLIM1 [PDZ and LIM domain 1]; PDLIM5 [PDZ and LIM domain 5]; PDLIM7 [PDZ and LIM domain 7 (enigma)]; PDP1 [pyruvate dehyrogenase phosphatase catalytic subunit 1]; PDX1 [pancreatic and duodenal homeobox 1]; PDXK
- PEMT phosphatidylethanolamine N-methyltransferase
- PENK proenkephalin
- PEPD peptidase D
- PER1 period homolog 1 (Drosophila)]
- PEX1 peroxisomal biogenesis factor 1]
- PEX10 peroxisomal biogenesis factor 1
- PEX12 [peroxisomal biogenesis factor 12]; PEX13 [peroxisomal biogenesis factor 13]; PEX14 [peroxisomal biogenesis factor 14]; PEX16 [peroxisomal biogenesis factor 16]; PEX19 [peroxisomal biogenesis factor 19]; PEX2 [peroxisomal biogenesis factor 2]; PEX26
- PHB [phosphohbosylformylglycinamidine synthase]; PFDN4 [prefoldin subunit 4]; PFN1 [profilin 1]; PGC [progastricsin (pepsinogen C)]; PGD [phosphogluconate dehydrogenase]; PGF [placental growth factor]; PGK1 [phosphoglycerate kinase 1]; PGM1 [phosphoglucomutase 1]; PGR [progesterone receptor]; PHB
- PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide
- PIK3CB phosphoinositide-3-kinase, catalytic, beta polypeptide
- PIK3CD phosphoinositide-3-kinase, catalytic, delta polypeptide]
- PIK3CG phosphoinositide-3-kinase, catalytic, gamma polypeptide]
- PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha)]
- PIK3R2 phosphoinositide-3-kinase, regulatory subunit 2 (beta)]
- PIN1 peptidylprolyl cis/trans isomerase, NIMA-interacting 1
- PINK1 PTEN induced putative kinase 1
- PIP prolactin-induced protein
- PIP5KL1 phosphatidylinositol-4-phosphate 5-kinase- like 1
- PITPNM1 phosphatidylinositol transfer protein, membrane-associated 1
- PITRM1 pitrilysin metallopeptidase 1]
- PITX2 paired-like homeodomain 2]
- PKD2 polycystic kidney disease 2 (autosomal dominant)]
- PKLR pyruvate kinase, liver and RBC]
- PKM2 pyruvate kinase, muscle]
- PKN1 protein kinase N1]
- PL-5283 PL-5283 protein]
- PLA2 phosphoinositide kinase, FYVE finger containing
- PLA2G2A phospholipase A2, group MA (platelets, synovial fluid)]
- PLA2G2D phospholipase A2, group MD]
- PLA2G4A phospholipase A2, group IVA (cytosolic, calcium-dependent)]
- PLA2G6 phospholipase A2, group Vl (cytosolic, calcium-independent)]
- PLA2G7 [phospholipase A2, group VII
- PLA2R1 phospholipase A2 receptor 1 , 18OkDa
- PLAT plasminogen activator, tissue]
- PLAU plasminogen activator, urokinase
- PLAUR plasminogen activator, urokinase receptor
- PLCB1 phospholipase C, beta 1 (phosphoinositide-specific)]
- PLCB2 phospholipase C, beta 2]
- PLCB4 phospholipase C, beta 4]
- PLCD1 phospholipase C, delta 1]
- PLCG1 phospholipase C, gamma 1]
- PLCG2 phospholipase C, gamma 2 (phosphatidylinositol-specific)]
- PLD1 phospholipase D1 , phosphatidylcholine- specific]
- PLEC phosphatidylinositol-specific
- PMAIP1 phorbol-12-myristate-13-acetate- induced protein 1
- PMCH pro-melanin-concentrating hormone
- RNA Rimerase (RNA) Il (DNA directed) polypeptide D
- POLR2E polymerase (RNA) Il (DNA directed) polypeptide E, 25kDa]
- POLR2F polymerase (RNA) Il (DNA directed) polypeptide F]
- POLR2G polymerase (RNA) Il (DNA directed) polypeptide G]
- POLR2H polymerase (RNA) Il (DNA directed) polypeptide H]
- POLR2I polymerase (RNA) Il (DNA directed) polypeptide I, 14.5kDa]
- POLR2J polymerase (RNA) Il (DNA directed) polypeptide J, 13.3kDa]
- POLR2K polymerase (RNA) Il (DNA directed) polypeptide J
- PPARD peroxisome proliferator-activated receptor delta
- PPARG peroxisome proliferator-activated receptor gamma
- PPARGC1A peroxisome proliferator-activated receptor gamma, coactivator 1 alpha
- PPAT phosphoribosyl pyrophosphate
- amidotransferase amidotransferase
- PPBP pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)
- PPFIA1 protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 1]
- PPIA protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 1
- PPIA peptidylprolyl isomerase A (cyclophilin A)]
- PPIB peptidylprolyl isomerase B (cyclophilin B)]
- PPIG protein tyrosine phosphatase, receptor type, f polypeptide
- PPIA protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 1]
- PPIA peptidylprolyl isome
- PRKAR2A protein kinase, cAMP-dependent, regulatory, type II, alpha
- PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta
- PRKCA protein kinase C, alpha
- PRKCB protein kinase C, beta]
- PRKCD protein kinase C, beta
- PTPRE protein tyrosine phosphatase, receptor type, E
- PTPRJ protein tyrosine phosphatase, receptor type, J
- PTPRN protein tyrosine phosphatase, receptor type, N
- PTPRT protein tyrosine phosphatase, receptor type, T]
- PTPRU protein tyrosine phosphatase, receptor type, T
- PXK PX domain containing serine/threonine kinase]; PXN [paxillin]; PYCR1 [pyrrol ine-5-carboxylate reductase 1]; PYCR2 [pyrrol ine-5-carboxylate reductase family, member 2]; PYGB [phosphorylase, glycogen; brain]; PYGM [phosphorylase, glycogen, muscle]; PYY [peptide YY]; PZP [pregnancy-zone protein]; QDPR [quinoid dihydropteridine reductase];
- RAB11A [RAB11A, member RAS oncogene family]; RAB11 FIP1 [RAB11 family interacting protein 1 (class I)]; RAB27A [RAB27A, member RAS oncogene family]; RAB37 [RAB37, member RAS oncogene family]; RAB39 [RAB39, member RAS oncogene family]; RAB7A [RAB7A, member RAS oncogene family]; RAB9A [RAB9A, member RAS oncogene family]; RAC1 [ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1 )]; RAC2 [ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)]; RAD17 [RAD17 homolog (S.
- RAD50 [RAD50 homolog (S. cerevisiae)]; RAD51 [RAD51 homolog (RecA homolog, E. coli) (S. cerevisiae)]; RAD51 C [RAD51 homolog C (S. cerevisiae)]] RAD51 L1 [RAD51-like 1 (S.
- RAF 1 [v-raf-1 murine leukemia viral oncogene homolog 1]; RAG1 [recombination activating gene 1]; RAG2 [recombination activating gene 2]; RAN [RAN, member RAS oncogene family]; RANBP1 [RAN binding protein 1]; RAP1A [RAP1A, member of RAS oncogene family]; RAPGEF4 [Rap guanine nucleotide exchange factor (GEF) 4]; RARA [retinoic acid receptor, alpha]; RARB [retinoic acid receptor, beta]; RARG [retinoic acid receptor, gamma]; RARRES2 [retinoic acid receptor responder (tazarotene induced) 2]; RARS [arginyl-tRNA synthetase]; RASA1 [RAS p21 protein activator (GTPase activating protein) 1]; RASGRP1 [RAS guanyl
- RNASE1 Ribonuclease, RNase A family, 1 (pancreatic)]
- RNASE2 Ribonuclease, RNase A family, 2 (liver, eosinophil- derived neurotoxin)]
- RNASE3 Ribonuclease, RNase A family, 3 (eosinophil cationic protein)]
- RNASEH1 Ribonuclease H1]
- RNASEH2A Riclease H2, subunit A]
- RNASEL ribonuclease L (2' [5'-oligoisoadenylate synthetase- dependent)]
- RNASEN Rionuclease type III, nuclear]
- RNF123 Ring finger protein 123]
- RNF13 Ring finger protein 13]
- RNF135 Ring finger protein 135
- RNF138 Ring finger protein 138
- RNF4 Ring finger protein 4]
- RNH1 Ribonuclease type III, nuclear]
- RNA-binding region RNP1 , RRM
- RNPEP arginyl aminopeptidase (aminopeptidase B)]
- ROCK1 Rho-associated, coiled-coil containing protein kinase 1]
- ROM1 Retinal outer segment membrane protein 1]
- ROR2 Receptor tyrosine kinase-like orphan receptor 2]
- RORA RORA [RAR-related orphan receptor A]
- RPA1 replication protein A1 , 7OkDa]
- RPA2 [replication protein A2, 32kDa]
- RPGRIP1 L RGRIP1 -like]
- RPLP1 Ribonuclease/angiogenin inhibitor 1
- RNPEP RNA-binding region (RNP1 , RRM) containing 3]
- RNPEP arginyl aminopeptidase (aminopeptidase B)]
- ROCK1 Rho-associated, coiled-
- RUNX1 [runt-related transcription factor 1]; RUNX3 [runt-related transcription factor 3]; RXRA [retinoid X receptor, alpha]; RXRB [retinoid X receptor, beta]; RYR1 [ryanodine receptor 1 (skeletal)]; RYR3 [ryanodine receptor 3]; S100A1 [S100 calcium binding protein A1]; S100A12 [S100 calcium binding protein A12]; S100A4 [S100 calcium binding protein A4]; S100A7 [S100 calcium binding protein A7]; S100A8 [S100 calcium binding protein A8]; S100A9 [S100 calcium binding protein A9]; S100B [S100 calcium binding protein B]; S100G [S100 calcium binding protein G]; S1 PR1 [sphingosine-1 -phosphate receptor 1]; SAA1 [serum amyloid A1]; SAA4 [serum amyloid A4, constitutive]; SAFB [scaffold attachment factor
- SCAMP3 secretory carrier membrane protein 3
- SCAP SREBF chaperone
- SCARB1 scavenger receptor class B, member 1
- SCD stearoyl-CoA
- SCG2 secretogranin M
- SCG3 secretogranin III
- SCG5 secretogranin V (7B2 protein)
- SCGB1A1 secretoglobin, family 1A, member 1 (uteroglobin)
- SCGB3A2 secretoglobin, family 3A, member 2];
- SCN4A sodium channel, voltage-gated, type IV, alpha subunit
- SDC2 [syndecan 2]; SDC4 [syndecan 4]; SDHB [succinate dehydrogenase complex, subunit B, iron sulfur (Ip)]; SDHD [succinate dehydrogenase complex, subunit D, integral membrane protein]; SEC14L2 [SEC14-like 2 (S. cerevisiae)]; SEC16A [SEC16 homolog A (S. cerevisiae)]; SEC23B [Sec23 homolog B (S.
- SERPINE1 mRNA binding protein 1 SERPINA1 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1]; SERPINA2 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 2]; SERPINA3 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3]; SERPINA5 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 5]; SERPINA6 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 6]; SERPINA7 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 7]; SERPINB1 [serpin
- SERPINB2 serotonin-1 [serpin peptidase inhibitor, clade B (ovalbumin), member 2];
- SERPINB3 serotonin peptidase inhibitor, clade B (ovalbumin), member 3
- SERPINB4 serpin peptidase inhibitor, clade B (ovalbumin), member 4
- SERPINB5 serpin peptidase inhibitor, clade B (ovalbumin), member 5
- SERPINB6 serpin peptidase inhibitor, clade B (ovalbumin), member 6
- SERPINB9 serotonin peptidase inhibitor, clade B (ovalbumin), member 9
- SERPINC1 serpin peptidase inhibitor, clade C (antithrombin), member 1
- SERPIND1 [serpin peptidase inhibitor, clade D (heparin cofactor), member 1]; SERPINE1 [serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1 ), member 1]; SERPINE2 [serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1 ), member 2]; SERPINF2 [serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 2]; SERPING1 [serpin peptidase inhibitor, clade G (C1 inhibitor), member 1]; SERPINH1 [serpin peptidase inhibitor, clade H (heat shock protein 47), member 1 , (collagen binding protein 1 )]; SET [SET nuclear oncogene]; SETDB2 [SET domain, bifurcated 2]; SETX [senataxin]
- SGCB sarcoglycan, beta (43kDa dystroph in-associated
- SLP2 S-phase kinase- associated protein 2 (p45)]; SLAMF1 [signaling lymphocytic activation molecule family member 1]; SLAMF6 [SLAM family member 6]; SLC11A1 [solute carrier family 11 (proton-coupled divalent metal ion transporters), member 1]; SLC11A2 [solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2]; SLC12A1 [solute carrier family 12 (sodium/potassium/chloride transporters), member 1]; SLC12A2 [solute carrier family 12 (sodium/potassium/chloride transporters), member 2]; SLC14A1 [solute carrier family 14 (urea transporter), member 1 (Kidd blood group)]; SLC15A1 [solute carrier family 15 (oligopeptide transporter), member 1]; SLC16
- SLC17A6 solute carrier family 17 (sodium- dependent inorganic phosphate cotransporter), member 6]; SLC17A7 [solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 7]; SLC19A1 [solute carrier family 19 (folate transporter), member 1]; SLC1A1 [solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1]; SLC1A2 [solute carrier family 1 (glial high affinity glutamate transporter), member 2]; SLC1 A4 [solute carrier family 1 (glutamate/neutral amino acid transporter), member 4]; SLC22A12 [solute carrier family 22 (organic anion/urate transporter), member 12]; SLC22A2 [solute carrier family 22 (organic cation transporter), member 2]; SLC22A23 [solute carrier family 22, member 23]; SLC22A12 [solute carrier family 17 (sodium
- SLC25A3 [solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3]; SLC25A32 [solute carrier family 25, member 32]; SLC25A33 [solute carrier family 25, member 33]; SLC25A4 [solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4]; SLC26A4 [solute carrier family 26, member 4]; SLC27A4 [solute carrier family 27 (fatty acid transporter), member 4]; SLC28A1 [solute carrier family 28 (sodium-coupled nucleoside transporter), member 1]; SLC2A1 [solute carrier family 2 (facilitated glucose transporter), member 1]; SLC2A13 [solute carrier family 2 (facilitated glucose transporter), member 13]; SLC2A3 [solute carrier family 2 (facilitated glucose transporter), member 3]; SLC2A4 [solute carrier family 2 (facilitated glucose transporter), member 4]; SLC30A1 [solute carrier family 30
- SLC7A4 solute carrier family 7 (cationic amino acid transporter, y+ system), member 4]; SLC7A5 [solute carrier family 7 (cationic amino acid transporter, y+ system), member 5]; SLC8A1 [solute carrier family 8 (sodium/calcium exchanger), member 1]; SLC9A1 [solute carrier family 9 (sodium/hydrogen exchanger), member 1]; SLC9A3R1 [solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 1]; SLCO1A2 [solute carrier organic anion transporter family, member 1 A2]; SLCO1 B1 [solute carrier organic anion transporter family, member 1 B1]; SLCO1 B3 [solute carrier organic anion transporter family, member 1 B3]; SLPI [secretory leukocyte peptidase inhibitor]; SMAD1 [SMAD family member 1]; SMAD2
- SMPD1 structural maintenance of chromosomes 1A
- SMC3 structural maintenance of chromosomes 3
- SMG1 SMG1 homolog, phosphatidylinositol 3-kinase-related kinase (C. elegans)]
- SMN1 survival of motor neuron 1 , telomeric]
- SMPD1 structural maintenance of chromosomes 1A
- SMC3 structural maintenance of chromosomes 3
- SMG1 SMG1 homolog, phosphatidylinositol 3-kinase-related kinase (C. elegans)]
- SMN1 survival of motor neuron 1 , telomeric]
- SMPD2 sphingomyelin phosphodiesterase 2, neutral membrane (neutral sphingomyelinase)]; SMTN [smoothelin]; SNAI2 [snail homolog 2 (Drosophila)]; SNAP25 [synaptosomal- associated protein, 25kDa]; SNCA [synuclein, alpha (non A4 component of amyloid precursor)]; SNCG [synuclein, gamma (breast cancer-specific protein 1 )]; SNURF [SNRPN upstream reading frame]; SNW1 [SNW domain containing 1]; SNX9 [sorting nexin 9]; SOAT1 [sterol O-acyltransferase 1]; SOCS1
- SPARC secreted protein, acidic, cysteine-rich
- SPRED1 prouty-related, EVH 1 domain containing 1]; SPRR2A [small proline- rich protein 2A]; SPRR2B [small proline-rich protein 2B]; SPTB [spectrin, beta, erythrocytic]; SRC [v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)]; SRD5A1 [steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1 )]; SREBF1 [sterol regulatory element binding transcription factor 1]; SREBF2 [sterol regulatory element binding transcription factor 2]; SRF [serum response factor (c-fos serum response element-binding transcription factor)]; SRGN [serglycin]; SRP9 [signal recognition particle 9kDa]; SRP9 [signal recognition particle 9kDa]; SRP9 [
- TAP1 transporter 1 , ATP-binding cassette, sub-family B (MDR/TAP)]; TAP2 [transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)]; TARDBP [TAR DNA binding protein]; TARP [TCR gamma alternate reading frame protein]; TAT [tyrosine aminotransferase]; TBK1 [TANK- binding kinase 1]; TBP [TATA box binding protein]; TBX1 [T-box 1]; TBX2 [T-box 2]; TBX21 [T-box 21]; TBX3 [T-box 3]; TBX5 [T-box 5]; TBXA2R [thromboxane A2 receptor]; TBXAS1
- TCEAL1 transcription elongation factor A (Sll)-like 1]
- TCF4 transcription factor 4]
- TCF7L2 transcription factor 7-like 2 (T-cell specific, HMG-box)]
- TCL1A T-cell leukemia/lymphoma 1A]
- TCL1 B T- cell leukemia/lymphoma 1 B
- TCN1 transcobalamin I (vitamin B12 binding protein, R binder family)]
- TCN2 transcobalamin II; macrocytic anemia]
- TDP1 tyrosyl-DNA phosphodiesterase 1]
- TEC detect protein tyrosine kinase]
- TECTA tectorin alpha]
- TEK TEK tyrosine kinase, endothelial
- TERF1 telomehc repeat binding factor (NIMA-interacting) 1]
- TERF2 telomehc repeat binding factor (NIMA-interacting) 1]
- TGFBR1 transformed growth factor, beta receptor 1
- TGFBR2 transformed growth factor, beta receptor Il (70/8OkDa)]
- TGIF1 TGFB-induced factor homeobox 1]
- TGM1 transglutaminase 1 (K polypeptide epidermal type I, protein-glutamine-gamma-glutamyltransferase)]
- TGM2 transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase)]
- TGM3 transglutaminase 3 (E polypeptide, protein-glutamine-gannnna- glutamyltransferase)]
- TH tyrosine hydroxylase]
- THAP1 THAP domain containing, apoptosis associated protein 1]
- THBD thrombomodulin
- THBS1 thrombospondin
- TIRAP toll-interleukin 1 receptor (TIR) domain containing adaptor protein]
- TJP1 tight junction protein 1 (zona occludens 1 )]
- TK1 thymidine kinase 1 , soluble]
- TK2 thymidine kinase 2, mitochondrial]
- TKT transketolase
- TLE4 transducin-like enhancer of split 4 (E(sp1 ) homolog, Drosophila)]
- TLR1 toll-like receptor 1]
- TLR10 toll-like receptor 10]
- TLR2 toll- like receptor 2]
- TLR3 toll-like receptor 3]
- TLR4 toll-like receptor 4]
- TLR5 toll- like receptor 5]
- TLR6 toll-like receptor 6]
- TLR7 toll-like receptor I]
- TLR8 toll-like receptor 8]
- TLR9 toll-like receptor
- TMPRSS15 transmembrane protease, serine 15
- TMSB4X thymosin beta 4, X- linked
- TNC tenascin C
- TNF tumor necrosis factor (TNF superfamily, member 2)
- TNFAIP1 tumor necrosis factor, alpha-induced protein 1 (endothelial)]
- TNFAIP3 tumor necrosis factor, alpha-induced protein 3
- TNFAIP6 tumor necrosis factor, alpha-induced protein 6
- TNFRSF10A tumor necrosis factor receptor superfamily, member 1 Oa
- TNFRSF10B tumor necrosis factor receptor superfamily, member 1 Ob
- TNFRSF10C tumor necrosis factor receptor superfamily, member 10c, decoy without an intracellular domain
- TNFRSF10D [tumor necrosis factor receptor superfamily, member 10d, decoy with truncated death domain]
- TNFRSF11A [tumor necrosis factor receptor superfamily, member 11 a, NFKB activator]
- TNFRSF11 B tumorumor necrosis factor receptor superfamily, member 11 b]
- TNFRSF13B tumorumor necrosis factor receptor superfamily, member 13B]
- TNFRSF13C tumor necrosis factor receptor superfamily, member 13
- TNFRSF25 tumor necrosis factor receptor
- TNFRSF4 tumor necrosis factor receptor superfamily, member 4
- TNFRSF6B tumor necrosis factor receptor superfamily, member 6b, decoy
- TNFRSF8 tumor necrosis factor receptor superfamily, member 8]
- TNFRSF9 tumor necrosis factor receptor superfamily, member 9]; TNFSF10 [tumor necrosis factor (ligand) superfamily, member 10]; TNFSF11 [tumor necrosis factor (ligand) superfamily, member 11]; TNFSF12 [tumor necrosis factor (ligand) superfamily, member 12]; TNFSF13 [tumor necrosis factor (ligand) superfamily, member 13]; TNFSF13B [tumor necrosis factor (ligand) superfamily, member 13b]; TNFSF14 [tumor necrosis factor (ligand) superfamily, member 14]; TNFSF15 [tumor necrosis factor (ligand) superfamily, member 15]; TNFSF18 [tumor necrosis factor (ligand) superfamily, member 18]; TNFSF4 [tumor necrosis factor (ligand) superfamily, member 4]; TNFSF8 [tumor necrosis factor (ligand) superfamily, member 8]; TNFSF10
- TNNI3 troponin I type 3 (cardiac)]
- TNNT3 troponin T type 3 (skeletal, fast)]
- TNPO1 transportin 1]
- TNS1 tensin 1
- TNXB tenascin XB
- TOM1 L2 target of myb1 -like 2 (chicken)]
- TOP1 topoisomerase (DNA) I];
- TOP1 MT topoisomerase (DNA) I, mitochondrial
- TOP2A topoisomerase (DNA) Il alpha 17OkDa
- TOP2B topoisomerase (DNA) Il beta 18OkDa]
- TOP3A topoisomerase (DNA) I, mitochondrial
- TRAF1 [TNF receptor-associated factor 1]; TRAF2 [TNF receptor-associated factor 2]; TRAF3IP2 [TRAF3 interacting protein 2]; TRAF6 [TNF receptor-associated factor 6]; TRAIP [TRAF interacting protein]; TRAPPC10 [trafficking protein particle complex 10]; TRDN [triadin]; TREX1 [three prime repair exonuclease 1]; TRH [thyrotropin-releasing hormone]; TRIB1 [tribbles homolog 1 (Drosophila)]; TRIM21 [tripartite motif- containing 21]; TRIM22 [tripartite motif-containing 22]; TRIM26 [tripartite motif- containing 26]; TRIM28 [tripartite motif-containing 28]; TRIM29 [tripartite motif-containing 29]; TRIM68 [tripartite motif-containing 68]; TRPA1 [transient receptor potential cation
- thyroid stimulating hormone receptor [thyroid stimulating hormone receptor]; TSLP [thymic stromal lymphopoietin]; TSPAN7 [tetraspanin I]; TSPO [translocator protein (18kDa)]; TSSK2 [testis- specific serine kinase 2]; TSTA3 [tissue specific transplantation antigen P35B]; TTF2 [transcription termination factor, RNA polymerase II]; TTN [titin]; TTPA
- TYMS thymidylate synthetase
- TYR tyrosinase
- TYRO3 TYRO3 protein tyrosine kinase
- TYROBP TYRO protein tyrosine kinase binding protein
- TYRP1 tyrosinase- related protein 1
- UBB ubiquitin B
- UBC ubiquitin C
- UBE2C ubiquitin- conjugating enzyme E2C
- UBE2N ubiquitin-conjugating enzyme E2N (UBC13 homolog, yeast)]
- UBE2U ubiquitin-conjugating enzyme E2U (putative)]
- UBE3A ubiquitin protein ligase E3A]
- UBE4A ubiquitination factor E4A (UFD2 homolog, yeast)]
- UCHL1 ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)]
- UCN urocortin]
- UCN2 urocortin 2
- UCP1 uncoupling protein 1 (mitochondrial, proton carrier)]
- UCP2 uncoupling protein
- glycosyltransferase 8 glycosyltransferase 8]; UIMC1 [ubiquitin interaction motif containing 1]; ULBP1 [UL16 binding protein 1]; ULK2 [unc-51-like kinase 2 (C. elegans)]; UMOD
- UMPS uridine monophosphate synthetase
- UNCI 3D unc-13 homolog D (C. elegans)]
- UNC93B1 unc-93 homolog B1 (C. elegans)]
- UNG uracil-DNA glycosylase
- UQCRFS1 ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1]
- UROD uroporphyrinogen decarboxylase
- upstream transcription factor 1 [upstream transcription factor 1]; USF2 [upstream transcription factor 2, c-fos interacting]; USP18 [ubiquitin specific peptidase 18]; USP34 [ubiquitin specific peptidase 34]; UTRN [utrophin]; UTS2 [urotensin 2]; VAMP8 [vesicle-associated membrane protein 8 (endobrevin)]; VAPA [VAMP (vesicle-associated membrane protein)-associated protein A, 33kDa]; VASP [vasodilator-stimulated
- VAV1 vav 1 guanine nucleotide exchange factor
- VA V3 vav 3 guanine nucleotide exchange factor
- VCAM 1 vascular cell adhesion molecule 1]
- VCAN versican]
- VCL vinculin
- VDAC1 voltage-dependent anion channel 1]
- VDR vitamin D (1 [25- dihydroxyvitamin D3) receptor
- VEGFA vascular endothelial growth factor A]
- VEGFC vascular endothelial growth factor C]
- VHL von Hippel-Lindau tumor suppressor]
- VIL1 villin 1]
- VIM vimentin]
- VRR1 vasoactive intestinal peptide receptor 1
- VIPR2 vasoactive intestinal peptide receptor 2
- VLDLR very low density lipoprotein receptor
- VMAC vimentin-type intermediate filament associated coiled-coil protein
- VPREB1 pre-B lymphocyte 1
- VPS39 vacuum protein sorting 39 homolog
- VTN vitronectin
- VWF von Willebrand factor
- WARS tryptophanyl-tRNA synthetase
- WAS WAS [Wiskott-Aldrich syndrome (eczema-thrombocytopenia)]
- WASF1 WAS protein family, member 1]
- WASF2 WAS protein family, member 2]
- WASL WASL [Wiskott-Aldrich syndrome-like]
- WDFY3 WD repeat and FYVE domain containing 3]
- WDR36 WD repeat domain 36]
- WEE1 WEE1 homolog (S. pombe)]
- WIF1 WNT inhibitory factor 1]
- WIPF1 WIPF1
- WNK1 [WNK lysine deficient protein kinase 1]; WNT5A [wingless-type MMTV integration site family, member 5A]; WRN [Werner syndrome, RecQ helicase-like]; WT1 [Wilms tumor 1]; XBP1 [X-box binding protein 1]; XCL1 [chemokine (C motif) ligand 1]; XDH [xanthine dehydrogenase]; XIAP [X-linked inhibitor of apoptosis]; XPA [xeroderma pigmentosum, complementation group A]; XPC [xeroderma pigmentosum, complementation group C]; XPO5 [exportin 5]; XRCC1 [X-ray repair
- YBX1 Y box binding protein 1]; YES1 [v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1]; YPEL1 [yippee-like 1 ⁇ Drosophila)]; YPEL2 [yippee- like 2 (Drosophila)]; YWHAB [tyrosine 3-monooxygenase/tryptophan 5- monooxygenase activation protein, beta polypeptide]; YWHAQ [tyrosine 3- monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide]; YWHAZ [tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide]; YY1 [YY1 transcription factor]; ZAP70 [zeta- chain (TCR) associated protein kinase 7OkDa]; ZB
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and development and/or progression of an immunodeficiency using measures commonly used in the study of immunodeficiencies.
- the genetically modified animals e.g., knock-out and transgenic animals created by a method of the invention may include genes altered singly or in combination, including alteration to any one or more of Rag1 , Rag2, FoxN1 , and DNAPK. Accordingly, for example, animals including a single, double or triple gene knock-out are contemplated. Any of these may be used in various methods in which alteration of one or more immunodeficiency genes may be useful.
- genetically modified animals as described herein may be used in studies of hematopoietic cells, such as in the identification of progenitor cells including lymphoid progenitors and pluripotential stem cells; in the identification of new cytokines which play a role in the growth and differentiation of hematopoietic cells; in the analysis of the effect of known cytokines; and in the analysis of drugs effects on hematopoietic cells.
- Such animals can also be used in studies on pathogenetic mechanisms in disease caused by viral infections such as but not limited to influenza, West Nile virus, herpesviruses, picornaviruses, neurotropic coronavirus, Varicella-zoster (chicken pox), respiratory syncytial virus, cowpox, hepatitis B, rabies, and Dengue virus, and lymphotropic viruses including human immunodeficiency virus (HIV), human T lymphotropic virus (HTLV-1 ), and Epstein Barr virus (EBV), and also a virus that specifically infects rats but models the effects of a human-specific virus on its host, for example the rat-adapted influenza virus (see, e.g., H. Lebrec and G. R. Burleson (1994) Toxicology. JuI 1 ;91 (2):179-88).
- viral infections such as but not limited to influenza, West Nile virus, herpesviruses, picornaviruses, neurotropic coronavirus, Varicella-zo
- a genetically modified animal created by a method of the invention may also be useful in studies of defense
- genetically modified animals such as for example knock-out rats can be subjects for pre-clinical evaluation of a specific "gene therapy".
- genes may be introduced into hematopoietic progenitor cells, preferably into pluripotential stem cells with self-renewal capacity from patients with inherited genetic defects, or into pluripotential stem cells with self- renewal capacity from rat models of inherited genetic defects, and the cells reintroduced into the genetically modified rats for the purpose of determining therapeutic usefulness of the modified cells.
- Genetically modified animals may also be useful for studying the biological mechanisms underlying
- immunodeficiency diseases and conditions caused by or linked to a mutation in an immunodeficiency gene such as Rag1 , Rag2, FoxN1 , or DNAPK.
- a genetically modified animal created by a method of the invention may be used to develop a diagnostic assay for an immunodeficiency disorder including but not limited to a leukemia, in which the animal, either untreated or previously treated with a therapeutic agent, is assessed for the presence of one or more biomarkers relative to a non-affected control animal.
- Such a genetically modified animal may be used in a method of screening a candidate therapy or therapeutic compound for treating an immunodeficiency disorder such as a leukemia, using a genetically modified animal in which one or more immunodeficiency genes including but not limited to Rag1 , Rag2, FoxN1 , or DNAPK are knocked out, and the animal, either untreated or previously treated with another therapeutic agent which may be a drug, microbe, transplanted cells, or other agent, is then treated with the candidate therapy or candidate therapeutic agent, a biological sample is obtained from the animal, and the biological sample evaluated relative to a sample from a non-affected wild-type control sample, or a sample from a genetically modified animal not subjected to the candidate therapy or therapeutic agent.
- an immunodeficiency disorder such as a leukemia
- a genetically modified animal in which one or more immunodeficiency genes including but not limited to Rag1 , Rag2, FoxN1 , or DNAPK are knocked out
- another therapeutic agent which may be a drug
- a method for modeling an autoimmune disease may involve the adoptive transfer of B cells reacting to an antigen for an autoimmune disease, or T cells activated for an autoimmune disease.
- the appropriate non-human mammal with the antigen target of the autoimmune disease can be immunized as follows.
- Immune cells may be prepared from the immunized animal and may be then transplanted to a genetically modified animal as described herein such as a Rag1 , Rag2, FoxN1 , or DNAPK knock-out rat, or a rat with any combination of these genes knocked out.
- a genetically modified animal as described herein such as a Rag1 , Rag2, FoxN1 , or DNAPK knock-out rat, or a rat with any combination of these genes knocked out.
- the development of autoimmune phenotypes in the recipient knock-out animal may then evaluated as compared to either a non-transplanted knock-out animal, or as compared to a knock-out animal transplanted with non-pathologic immune cells that lack auto-reactivity, or as compared to a wild type animal transplanted with immune cells as described above.
- a method for creating a combined immunodeficiency syndrome model may include providing a genetically modified animal such as a rat wherein Rag1 , Rag2, FoxN1 , or DNAPK are knocked out as described herein, and the knock-out animal may be further rendered deficient for natural killer (NK) cells by any one of several possible methods.
- a genetically modified animal such as a rat wherein Rag1 , Rag2, FoxN1 , or DNAPK are knocked out as described herein, and the knock-out animal may be further rendered deficient for natural killer (NK) cells by any one of several possible methods.
- Non-limiting examples of methods of rendering the knock-out animal deficient for NK include i) disruption of the Lyst gene; or ii) treatment of FoxN1 mutant animals with a compound that inhibits NK cell activity including but not limited to NSAIDs (nonsteroidal anti-inflammatory drugs), statins, allostehc LFA-1 inhibitors, vinblastine, paclitaxel, docetaxel, cladhbine, chlorambucil, bortezomib, or MG-132.
- NSAIDs nonsteroidal anti-inflammatory drugs
- Trinucleotide repeat expansion disorders are divided into two categories determined by the type of repeat.
- the most common repeat is the triplet CAG, which, when present in the coding region of a gene, codes for the amino acid glutamine (Q). Therefore, these disorders are referred to as the polyglutamine (polyQ) disorders and may include Huntington Disease (HD);
- SBMA Spinobulbar Muscular Atrophy
- SCA types 1 , 2, 3, 6, 7, and 17 Spinocerebellar Ataxias
- DPLA Dentatorubro-Pallidoluysian Atrophy
- Other trinucleotide repeat expansion disorders either do not involve the CAG triplet, or the CAG triplet is not in the coding region of the gene and are referred to as the non-polyglutamine disorders.
- Non-polyglutamine disorders may include Fragile X Syndrome (FRAXA); Fragile XE Mental Retardation (FRAXE); Friedreich Ataxia (FRDA); Myotonic Dystrophy (DM); and Spinocerebellar Ataxias (SCA types 8, and 12).
- a method of the invention may be used to create a genetically modified animal or cell in which at least one chromosomal sequence associated with a trinucleotide repeat disorder has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with a trinucleotide repeat disorder may be edited.
- a trinucleotide repeat disorder associated protein or control sequence may typically be selected based on an experimental association of the protein or sequence to a trinucleotide repeat expansion disorder.
- Trinucleotide repeat expansion proteins may include proteins associated with susceptibility for developing a trinucleotide repeat expansion disorder, the presence of a trinucleotide repeat expansion disorder, the severity of a trinucleotide repeat expansion disorder or any combination thereof.
- the production rate or circulating concentration of a protein associated with a trinucleotide repeat expansion disorder may be elevated or depressed in a population having a trinucleotide repeat expansion disorder relative to a population lacking the trinucleotide repeat expansion disorder. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- trinucleotide repeat expansion disorders include AR (androgen receptor), FMR1 (fragile X mental retardation 1 ), HTT (huntingtin), DMPK (dystrophia myotonica- protein kinase), FXN (frataxin), ATXN2 (ataxin 2), ATN1 (atrophin 1 ), FEN1 (flap structure-specific endonuclease 1 ), TNRC6A (trinucleotide repeat containing 6A), PABPN1 (poly(A) binding protein, nuclear 1 ), JPH3 (junctophilin 3), MED15 (mediator complex subunit 15), ATXN1 (ataxin 1 ), ATXN3 (ataxin 3), TBP (TATA box binding protein), CACNA1A (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit), ATXN8OS (ATXN8 opposite strand (non-protein coding)), PPP2R2B (protein
- G protein guanine nucleotide binding protein
- beta polypeptide 2 ribosomal protein L14
- ATXN8 ataxin 8
- INSR insulin receptor
- TTR transthyretin
- EP400 E1A binding protein p400
- GIGYF2 GYF protein 2
- MAGUK family calcium/calmodulin-dependent serine protein kinase
- MAPT microtubule-associated protein tau
- SP1 Sp1 transcription factor
- POLG polymerase (DNA directed), gamma
- AFF2 AF4/FMR2 family, member 2
- THBS1 thrombospondin 1
- TP53 tumor protein p53
- ESR1 esterogen receptor 1
- CGGBP1 CGG triplet repeat binding protein 1
- ABT1 activator of basal transcription 1
- KLK3 kallikrein-related peptidase 3
- PRNP prion protein
- JUN jun oncogene
- KCNN3 potassium intermediate/small conductance calcium- activated channel, subfamily N, member 3
- BAX BCL2-associated X protein
- FRAXA fragmentile site, folic acid type, rare, fra(X)(q27.3) A (macroorchidism, mental retardation)
- KBTBD10 KBTBD10
- coli (S. cerevisiae)
- NCOA3 nuclear receptor coactivator 3
- ERDA1 expanded repeat domain, CAG/CTG 1
- TSC1 tuberous sclerosis 1
- COMP cartilage oligomeric matrix protein
- GCLC glycolutamate-cysteine ligase, catalytic subunit
- RRAD Ras-related associated with diabetes
- MSH3 mutant S homolog 3
- DRD2 dopamine receptor D2
- CD44 CD44 molecule (Indian blood group)
- CTCF CCCTC-binding factor (zinc finger protein)
- CCND1 cyclin D1
- CLSPN claspin homolog (Xenopus laevis)
- MEF2A MEF2A
- TRIM22 myocyte enhancer factor 2A
- PTPRU protein tyrosine phosphatase, receptor type, U
- GAPDH glycosyl transfer protein dehydrogenase
- TMEM158 meencephalic astrocyte-derived neurotrophic factor
- transmembrane protein 158 (gene/pseudogene)
- ENSG00000078687 transmembrane protein 158 (gene/pseudogene)
- Exemplary proteins associated with trinucleotide repeat expansion disorders include HTT (Huntingtin), AR (androgen receptor), FXN (frataxin), Atxn3 (ataxin), Atxni (ataxin), Atxn2 (ataxin), Atxn7 (ataxin), Atxni O (ataxin), DMPK (dystrophia myotonica-protein kinase), Atn1 (atrophin 1 ), CBP (creb binding protein), VLDLR (very low density lipoprotein receptor), and any combination thereof.
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and the development and/or progression of a trinucleotide repeat disorder using measures commonly used in the study of a trinucleotide repeat disorder.
- Non-limiting examples of a neurotransmission disorder include amylotropic lateral sclerosis (ALS), spinocerebellar ataxias (SCA) including SCA2, Alzheimer's; autism, mental retardation, Rett's syndrome, fragile X syndrome, depression, schizophrenia, bi-polar disorders, disorders of learning, memory or behavior, anxiety, brain injury, seizure disorders, Huntington's disease (chorea), mania, neuroleptic malignant syndrome, pain, Parkinsonism, Parkinson's disease, tardive dyskinesia, myasthenia gravis, episodic ataxias, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, Lambert-Eaton syndrome, paramyotonia congenita, Rasmussen's encephalitis, startle disease (hyperexplexia, stiff baby syndrome), and the effects of poisoning such as botulism, mushroom poisoning, organophosphates, snake venom such as from Bungarus multicinctus (Taiwanese band
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with a neurotransmission disorder has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- chromosomal sequences associated with a neurotransmission disorder may be edited.
- a neurotransmission disorder associated protein or control sequence may typically be selected based on an experimental association of the protein to a neurotransmission disorder.
- Neurotransmission disorder-related proteins include proteins associated with the susceptibility for developing a neurotransmission disorder, the presence of a neurotransmission disorder, the severity of a neurotransmission disorder or any combination thereof. For example, the production rate or circulating concentration of a neurotransmission disorder- related protein may be elevated or depressed in a population having a
- neurotransmission disorder relative to a population lacking the neurotransmission disorder. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- Non-limiting examples of neurotransmission disorder-related proteins include SST (somatostatin), NOS1 (nitric oxide synthase 1 (neuronal)), ADRA2A (adrenergic, alpha-2A-, receptor), ADRA2C (adrenergic, alpha-2C-, receptor), TACR1 (tachykinin receptor 1 ), HTR2C (5-hydroxytryptamine
- GABA gamma-aminobutyric acid
- CACNA1 B calcium channel, voltage- dependent, N type, alpha 1 B subunit
- NOS2 nitric oxide synthase 2, inducible
- SLC6A5 excute carrier family 6 (neurotransmitter transporter, glycine), member 5
- GABRG1 gamma-aminobutyric acid (GABA) A receptor, gamma 1
- NOS3 nitric oxide synthase 3 (endothelial cell)
- GRM3 glutamate receptor
- HTR6 (5-hydroxytryptamine (serotonin) receptor 6
- SLC1A3 (solute carrier family 1 (glial high affinity glutamate transporter), member 3
- GRM7 (glutamate receptor, metabotropic 7)
- HRH1 histamine receptor H1
- SLC1A1 (solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 )
- GRM4 (glutamate receptor, metabotropic 4
- GLUD2 (glutamate dehydrogenase 2)
- ADRA2B adrenergic, alpha-2B-, receptor
- SLC1A6 (solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6
- GRM6 (glutamate receptor, metabotropic 6)
- SLC1A7 (solute carrier family 1 (glutamate transporter), member 7
- SLC6A11 (solute carrier family 6 (neurotransmitter transporter,
- CACNA1 H (calcium channel, voltage- dependent, T type, alpha 1 H subunit), GRM8 (glutamate receptor, metabotropic 8), CHRNA3 (cholinergic receptor, nicotinic, alpha 3), P2RY2 (puhnergic receptor P2Y, G-protein coupled, 2), TRPV6 (transient receptor potential cation channel, subfamily V, member 6), CACNA1 E (calcium channel, voltage-dependent, R type, alpha 1 E subunit), ACCN1 (amiloride-sensitive cation channel 1 , neuronal), CACNA1 I (calcium channel, voltage-dependent, T type, alpha 11 subunit), GABARAP (GABA (A) receptor-associated protein), P2RY1 (purinergic receptor P2Y, G-protein coupled, 1 ), P2RY6 (pyrimidinergic receptor P2Y, G-protein coupled, 6), RPH3A (rabphilin 3A homolog (mouse)), HDC
- P2RY14 purinergic receptor P2Y, G-protein coupled, 14
- P2RY4 pyrimidinergic receptor P2Y, G-protein coupled, 4
- P2RY10 purinergic receptor P2Y, G-protein coupled, 10
- SLC28A3 synthetic carrier family 28
- HTR3A (5- hydroxytryptamine (serotonin) receptor 3A), DRD2 (dopamine receptor D2), HTR2A (5-hydroxytryptamine (serotonin) receptor 2A), TH (tyrosine
- CN R1 cannabinoid receptor 1 (brain)
- VIP vasoactive intestinal peptide
- NPY neuropeptide Y
- GAL galanin prepropeptide
- TAC1 tachykinin, precursor 1
- SYP serophysin
- SLC6A4 solute carrier family 6
- GABA gamma-aminobutyric acid A receptor, alpha 1 ), GCH1 (GTP
- DDC dopa decarboxylase (aromatic L-amino acid
- MAOB monoamine oxidase B
- DRD5 dopamine receptor D5
- GABRE gamma-aminobutyric acid (GABA) A receptor, epsilon
- SLC6A2 solute carrier family 6 (neurotransmitter transporter, noradrenalin), member 2)
- GABRR2 gamma-aminobutyric acid (GABA) receptor, rho 2), SV2A (synaptic vesicle glycoprotein 2A), GABRR1 (gamma-aminobutyric acid (GABA) receptor, rho 1 ), GHRH (growth hormone releasing hormone), CCK (cholecystokinin), PDYN (prodynorphin), SLC6A9 (solute carrier family 6 (neurotransmitter transporter, glycine), member 9), KCND1 (potassium voltage-gated channel, Shal-related subfamily, member 1 ), SRR (serine racemase), DYT10 (dystonia 10), MAPT (microtubule-associated protein tau), APP (amyloid beta (A4) precursor protein), CTSB (cathepsin B), ADA (adenosine deaminase), AKT1 (v- akt murine thymoma
- decarboxylase 1 (brain, 67kDa)), NSF (N-ethylmaleimide-sensitive factor), GRIN2D (glutamate receptor, ionotropic, N-methyl D-aspartate 2D), ADORA1 (adenosine A1 receptor), GABRA2 (gamma-aminobutyric acid (GABA) A receptor, alpha 2), GLRA1 (glycine receptor, alpha 1 ), CHRM3 (cholinergic receptor, muscarinic 3), CHAT (choline acetyltransferase), KNG1 (kininogen 1 ), HMOX2 (heme oxygenase (decycling) 2), DRD4 (dopamine receptor D4), MAOA (monoamine oxidase A), CHRM2 (cholinergic receptor, muscarinic 2), ADORA2A (adenosine A2a receptor), STXBP1 (syntaxin binding protein 1 ), GABRA3 (gam
- epidermal growth factor (beta-urogastrone)), GRIA3 (glutamate receptor, ionotrophic, AMPA 3), NCAM1 (neural cell adhesion molecule 1 ), CDKN1A (cyclin-dependent kinase inhibitor 1A (p21 , Cip1 )), BCL2L1 (BCL2-like 1 ), TP53 (tumor protein p53), CASP9 (caspase 9, apoptosis-related cysteine peptidase), CCKBR (cholecystokinin B receptor), PARK2 (Parkinson's disease (autosomal recessive, juvenile) 2, parkin), ADRA1 B (adrenergic, alpha-1 B-, receptor), CASP3 (caspase 3, apoptosis-related cysteine peptidase), PRNP (prion protein), CRHR1 (corticotropin releasing hormone receptor 1 ), L1 CAM (L1 cell adhesion molecule),
- AGT angiotensinogen (serpin peptidase inhibitor, clade A, member 8)
- AGTR1 angiotensin Il receptor, type 1
- CDK5 cyclin-dependent kinase 5
- LRP1 low density lipoprotein receptor-related protein 1
- ARRB2 arrestin, beta 2
- PLD2 phospholipase D2
- OPRD1 opioid receptor, delta 1
- GNB3 guanine nucleotide binding protein (G protein), beta polypeptide 3
- PIK3CG phosphoinositide-3-kinase, catalytic, gamma polypeptide
- APAF1 apoptotic peptidase activating factor 1
- SSTR2 somatostatin receptor 2
- IL2 interleukin 2
- ADORA3 adenosine A3 receptor
- ADRA1A adrenergic, alpha-1
- serotonin receptor 7 (adenylate cyclase-coupled)), ADRBK2 (adrenergic, beta, receptor kinase 2), ALOX5 (arachidonate 5-lipoxygenase), NPR1 (natriuretic peptide receptor A/guanylate cyclase A (athonathuretic peptide receptor A)), AVPR1A (arginine vasopressin receptor 1A), CHRNB1 (cholinergic receptor, nicotinic, beta 1 (muscle)), SET (SET nuclear oncogene), PAH (phenylalanine hydroxylase), POMC (proopiomelanocortin), LEPR (leptin receptor), SDC2 (syndecan 2), VIPR1 (vasoactive intestinal peptide receptor 1 ), DBI (diazepam binding inhibitor (GABA receptor modulator, acyl-Coenzyme A binding protein)), NPY1 R (neuropeptide Y receptor Y
- B/guanylate cyclase B (athonathuretic peptide receptor B)), CNR2 (cannabinoid receptor 2 (macrophage)), LEP (leptin), CCKAR (cholecystokinin A receptor), GLRB (glycine receptor, beta), KCNQ2 (potassium voltage-gated channel, KQT- like subfamily, member 2), CHRNA2 (cholinergic receptor, nicotinic, alpha 2 (neuronal)), BDKRB2 (bradykinin receptor B2), CHRNA1 (cholinergic receptor, nicotinic, alpha 1 (muscle)), CHRND (cholinergic receptor, nicotinic, delta), CHRNA7 (cholinergic receptor, nicotinic, alpha 7), PLD1 (phospholipase D1 , phosphatidylcholine-specific), NRXN1 (neurexin 1 ), NRP1 (neuropilin 1 ), DLG3 (
- Glutamate receptor (glutamate receptor, ionotropic, kainate 3), NPY2R (neuropeptide Y receptor Y2), GRIK5 (glutamate receptor, ionotropic, kainate 5), GRIA4 (glutamate receptor, ionotrophic, AMPA 4), EDN1 (endothelin 1 ), PRLR (prolactin receptor), GABRB1 (gamma-aminobutyhc acid (GABA) A receptor, beta 1 ), GARS (glycyl-tRNA synthetase), GRIK2 (glutamate receptor, ionotropic, kainate 2), ALOX12
- PLCD1 phospholipase C, delta 1
- NTF3 neurotrophin 3
- NFE2L2 neuroar factor (erythroid-dehved 2)-like 2)
- PLCB4 phospholipase C, beta 4
- GNRHR gonadotropin-releasing hormone receptor
- NLGN1 neuroligin 1
- PPP2R4 protein phosphatase 2A activator, regulatory subunit 4
- SSTR3 somatostatin receptor 3
- CRHR2 corticotropin releasing hormone receptor 2
- NGF nerve growth factor (beta polypeptide)
- NRCAM neuroonal cell adhesion molecule
- NRXN3 neuroexin 3
- GNRH1 gonadotropin- releasing hormone 1 (luteinizing-releasing hormone)
- TRHR thyrotropin- releasing hormone
- GABRP gamma-aminobutyric acid
- GABA gamma-aminobutyric acid
- pi GLRA2
- PRKG2 protein kinase, cGMP-dependent, type II
- GLS glutaminase
- TACR3 tachykinin receptor 3
- ALDH7A1 aldehyde dehydrogenase 7 family, member A1
- GABBR2 gamma-aminobutyric acid (GABA) B receptor, 2)
- GDNF glial cell derived neurotrophic factor
- CNTFR ciliary neurotrophic factor receptor
- CNTN2 contactin 2 (axonal)
- TOR1 A torsin family 1 , member A (torsin A)
- CNTN1 contactin 1
- CAMK1 CAMK1
- somatostatin receptor 4 somatostatin receptor 4
- NPPA neuropeptide precursor A
- SNAP23 serotonin 23kDa
- AKAP9 A kinase (PRKA) anchor protein (yotiao) 9
- NRXN2 neuroexin 2
- FHL2 four and a half LIM domains 2
- TJP1 tight junction protein 1 (zona occludens 1 )
- NRG1 neutralregulin 1
- CAMK4 calcium/calmodulin-dependent protein kinase IV
- CAV3 caveolin 3
- VAMP2 vesicle-associated membrane protein 2 (synaptobrevin 2)
- GALR1 galanin receptor 1
- GHRHR growth hormone releasing hormone receptor
- HTR1 E (5- hydroxytryptamine (serotonin) receptor 1 E
- PENK proenkephalin
- ENTPD1 ectonucleoside triphosphate diphosphohydrolase 1
- GRIP1 Glutamate receptor interacting protein 1
- GRP Gastrin-releasing peptide
- NCAM2 Neural cell adhesion molecule 2
- SSTR1 somatostatin receptor 1
- CLTB clathhn, light chain (Lcb)
- DAO D-amino-acid oxidase
- QDPR quinoid dihydropteridine reductase
- PYY peptide YY
- NTSR1 neuropeptide receptor 1 (high affinity)
- NTS neurorotensin
- HCRT hypercretin (orexin) neuropeptide precursor
- SNAP29 serotosomal-associated protein, 29kDa
- SNAP91 serotosomal- associated protein, 91 kDa homolog (mouse)
- MADD MAP-kinase activating death domain
- IDO1 indoleamine 2,3-dioxygenase 1
- TPH2 tryptophan hydroxylase 2
- TAC3 tachykinin 3
- GRIN3A glycolutamate receptor, ionotropic, N- methyl-D-aspartate 3A
- REN renin
- GALR3 galanin receptor 3
- MAGI2 membrane associated guanylate kinase, WW and PDZ domain containing 2
- KCNJ9 potassium in
- DPEP1 dipeptidase 1 (renal)
- SLC1A4 synthetic carrier family 1 (glutamate/neutral amino acid transporter), member 4
- DNM3 dynamin 3
- SLC6A12 synthetic carrier family 6 (neurotransmitter transporter, betaine/GABA), member 12
- SLC6A6 synthetic carrier family 6 (neurotransmitter transporter, taurine), member 6
- YME1 L1 YME1 -like 1 (S.
- SLC17A7 solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 7), HOMER2 (homer homolog 2 (Drosophila)), SYT7 (synaptotagmin VII), TFIP11 (tuftelin interacting protein 11 ), GMFB (glia maturation factor, beta), PREB (prolactin regulatory element binding), NTSR2 (neurotensin receptor 2), NTF4 (neurotrophin 4), PPP1 R9B (protein phosphatase 1 , regulatory (inhibitor) subunit 9B), DISC1 (disrupted in schizophrenia 1 ), NRG3 (neuregulin 3), OXT (oxytocin, prepropeptide), TRH (thyrotropin-releasing hormone), NISCH (nischarin), CRHBP (corticotropin releasing hormone binding protein), SLC6A13 (solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 7),
- SLC17A6 (solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6), GABRR3 (gamma-aminobutyric acid (GABA) receptor, rho 3), DAOA (D-amino acid oxidase activator), ENSG00000123384, nd NOS2P1 (nitric oxide synthase 2 pseudogene 1 ).
- Exemplary neurotransmission-related proteins include 5-HTT
- an animal created by a method of the invention may be used to study the effects of mutations on the animal and on the development and/or progression of a neurotransmission disorder using measures commoningly used in the study of a neurotransmission disorder. / ' / ' . pharmacological models
- a method of the invention may be used to create an animal or cell that may be used as a pharmacological model.
- a pharmacological model may be a model for pharmacokinetics or a model for pharmacodynamics.
- a method of the invention may be used to create an animal or cell that comprises a chromosomal edit in one or more nucleic acid sequences associated with the metabolism of a pharmaceutically active compound.
- Such an animal or cell may be used to study the effect of the nucleic acid sequence on the pharmaceutical compound.
- a method of the invention may be used to create an animal or cell that comprises a chromosomal edit in a disease associated sequence.
- Such an animal or cell may be used for assessing the effect(s) of a therapeutic agent in the development or progression of the disease.
- the effect(s) of a therapeutic agent may be measured in a
- the method comprises contacting a genetically modified animal comprising at least one edited
- chromosomal sequence encoding a protein associated with the disease with the therapeutic agent, and comparing results of a selected parameter to results obtained from contacting a wild-type animal with the same agent.
- suitable diseases include those listed in section ll(a)i.
- the role of a particular protein associated with a disease in the metabolism of a particular agent may be determined using such methods.
- substrate specificity and pharmacokinetic parameters may be readily determined using such methods.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with toxicology has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above. Any chromosomal sequence or protein involved in absorption, distribution,
- ADME metabolism, and excretion
- toxicology may be utilized for purposes of the present invention.
- the ADME and toxicology-related proteins are typically selected based on an experimental association of the protein to an ADME and toxicology-related disorder. For example, the production rate or circulating concentration of an ADME and toxicology-related protein may be elevated or depressed in a population having an ADME and toxicology disorder relative to a population lacking the ADME and toxicology disorder. Differences in protein levels may be assessed using proteomic or genomic analysis techniques known in the art.
- Exemplary non-limiting examples of the chromosomal sequence or protein involved in ADME and toxicology may be chosen from Oct 1 , Oct 2, Hfe2, Ppar(alpha) MDRI a (ABC Transporter ABCBI a), MDRI b
- BCRP BCRP
- MRP1 ABCG2
- MRP2 ABCC2, cMOAT
- a further aspect of the present disclosure encompasses a method for assessing the effect(s) of an agent.
- Suitable agents include without limit pharmaceutically active ingredients, drugs, food additives, pesticides, herbicides, toxins, industrial chemicals, household chemicals, and other environmental chemicals.
- the effect(s) of an agent may be measured in a "humanized" genetically modified animal, such that the information gained therefrom may be used to predict the effect of the agent in a human.
- the method comprises contacting a genetically modified animal comprising at least one inactivated chromosomal sequence involved in ADME and toxicology and at least one chromosomally integrated sequence encoding an orthologous human protein involved in ADME and toxicology with the agent, and comparing results of a selected parameter to results obtained from contacting a wild-type animal with the same agent.
- Selected parameters include but are not limited to (a) rate of elimination of the agent or its metabolite(s); (b) circulatory levels of the agent or its metabolite(s); (c)bioavailability of the agent or its metabolite(s); (d) rate of metabolism of the agent or its metabolite(s); (e) rate of clearance of the agent or its metabolite(s); (f) toxicity of the agent or its metabolite(s); (g) efficacy of the agent or its metabolite(s); (h) disposition of the agent or its metabolite(s); and (i) extrahepatic contribution to metabolic rate and clearance of the agent or its metabolite(s).
- methods to assess the effect(s) of an agent in an isolated cell comprising at least one edited chromosomal sequence involved in ADME and toxicology as well as methods of using lysates of such cells (or cells derived from a genetically modified animal disclosed herein) to assess the effect(s) of an agent.
- the role of a particular protein involved in ADME and toxicology in the metabolism of a particular agent may be determined using such methods.
- pharmacokinetic parameters may be readily determined using such methods. Those of skill in the art are familiar with suitable tests and/or procedures.
- ADME and toxicology are the ABC transporters, also known as efflux transport proteins.
- the genetically modified animals as described herein containing an edited chromosomal sequences encoding an ABC transporter can be useful for screening biologically active agents including drugs and for investigating their distribution, efficacy, metabolism and/or toxicity. These screening methods are of particular use for assessing with improved
- a candidate therapeutic agent i.e, a candidate drug can be
- the knock-out or knock-in gene is associated with at least one aspect of the drug ADME profile or toxicology, and/or metabolism, and may be derived from a mouse, rat, or human genome.
- a method of screening for the target of a test compound can make use of a genetically modified animal in which any one or more of an ABC transporter such as Mdr1 a, MdM b, PXR, BCRP, MRP1 , or MRP2 are knocked out, thus inhibiting or eliminating transmembrane transport mediated by the knocked out protein(s).
- an animal can be exposed to a test compound suspected of inhibiting transporter activity of the knocked-out protein(s).
- Inhibition of transport by the compound in the genetically modified animal can be determined using any of a number of routine laboratory tests and techniques, and the inhibition of transport may be compared to that observed in a wild-type animal treated with the same test compound.
- a difference in the effect of the test compound in the two animals can be indicative of the target of the test compound.
- inhibition of one or more ABC transporter proteins such as Mdri a, MdM b, PXR, BCRP, MRP1 , or MRP2
- Mdri a, MdM b, PXR, BCRP, MRP1 , or MRP2 may improve certain ADME characteristics of a candidate therapeutic agent.
- the absorption or efficacy of a candidate therapeutic compound may be improved by knock-ing out expression of one or more ABC transporter proteins such as Mdri a, MdM b, PXR, BCRP, MRP1 , or MRP2, in a particular tissue.
- genetically modified animals and cells as described herein for example genetically modified animals and cells including a genetic modification of one or more ABC transporter proteins, can be used advantageously in many methods that evaluate the ADME and toxicology characteristics of a candidate therapeutic compound, to identify targets of a test compound, or to identify ways in which the ADME characteristics and toxicology of a candidate compound may be improved.
- the overwhelming need to accurately predict how drugs and environmental chemicals may affect large populations can be readily.
- genetically modified animals, embryos, cells and cell lines described herein can be used to analyze how various compounds may interact with biological systems.
- Genetically modified cells and cell lines can be used, for example, to control many of the known complexities in biological systems to improve the predictive ability of cell-based assay systems, such as those used to evaluate new molecular entities and possible drug-drug interactions. More specifically, it is recognized that biological systems typically include multiple components that respond to exposure to new, potentially harmful compounds.
- the "ADMET system” has been described as including five components.
- the first component are those biological systems that when disrupted signal the drug metabolism system to turn on, and may include stress response and DNA repair pathways.
- xenosensors surveil for exogenous molecules that need removal. Detection of an exogenous molecule by the xenosensors then activates a cascade of gene inductions that up-regulate the enzymes responsible for metabolizing exogenous molecules into forms for easier removal.
- the enzymes of the third ADMET component include Phase I enzymes that include at least three classes of oxidases, of which the best known class is the cytochrome P450 s class.
- Cytochrome 450 enzymes typically add reactive hydroxyl moieties to potential toxins to inactivate and render the toxins more polar (soluble).
- the fourth component of the ADMET system includes at least seven classes of enzymes that further alter the products of Phase I enzymatic modification.
- these enzymes are conjugating enzymes that add hydrophilic moieties to make the now oxidized xenobiotics even more water soluble ADMET, and readily collected and excreted through urine or bile.
- the last component is the transporter system involving transporter proteins, such as the ABC transporters, that function as molecular pumps to facilitate the movement of the xenobiotics from one tissue to another.
- transporter proteins are responsible for moving drugs into a cell, out of a cell, or through a cell.
- Each component of the ADMET system has its own set of substrate structural specificities, which must be taken into account by any assay. Making predictability an even larger challenge is that, for critical members of each of the five component classes, a constellation of genetic polymorphisms exists in the population and these can dramatically affect activity towards specific xenobiotic chemical structures. The growing field of pharmacogenomics addresses the challenges created by such genetic variation. In addition, gender differences in how the different components of the xenobiotic system respond are also known to play a role in variations in drug metabolism.
- cell-based assays can be created that are representative of the target tissue where metabolism or toxicity of a drug compound is likely to occur.
- standard assays are usually run in transformed cell lines that are derived from the target tissue and have some concordant functional properties.
- genetically modified and differentiated pluripotent cells could be used to replace the immortalized cell components.
- genetically modified cell lines can be used in more highly predictive cell-based assays suitable for high-throughput, high-content compound screening.
- the present disclosure contemplates ZFN- mediated genetic modifications of genes relevant to each part of the xenobiotic metabolism machinery.
- Such modifications include knock-outs, knock-ins of reporter tags, the introduction of specific mutations known to affect activity, or combinations of these.
- the genetically modified cells and cell lines can be used to create tissue-specific, gender-specific, and/or population- reflective transporter panels; cell-based xenosenor assay panels that are tissue- specific and functionally reflective of the population; and induction assays that measure the genetic activation of different drug metabolism components and overt toxicological responses such as genotoxicity, cardiotoxicity, and apoptosis.
- tissue-specific lines can be established that have been modified to isolate specific transporter activities and predict the reaction of populations to individual chemical entities.
- ZFNs can be used to create transporter gene knock-outs in enterocyte cell lines, such as to introduce important, common polymorphisms into
- enterocyte cell lines and in cell lines representative of liver, blood-brain-barrier (brain micro-vasculature endothelial cells), kidney and any relevant tissue- specific cell lines.
- Panels of cell lines can include enterocytes (Caco2 or BBeI ) with knock-outs of individual transporter proteins (e.g. MDR-1 , MRP1 , 2, 3, 4, 6, BCRP), knock-out combinations to isolate effects of individual transporters (e.g. BCRP and MRP2, MDR-1 and MRP2, MRP-3 and MRP1 ), and a transporter null line (i.e. all 7 transporters knocked out).
- Panels of enterocytes may include knock-outs of OATP-2B1 , PEPT-1 , and OCT-N2. Panels of enterocytes may be created which include prevalent polymorphisms in the major transporter genes that affect drug transport and are of concern to pharmaceutical researchers.
- the three xenosensors in humans are known to have overlapping specificities in response to xenobiotics. Knowing which xenosensors are activated and to what extent by any particular chemical compound is also an important consideration for understanding drug responses, and drug-drug interactions. Creating panels of cells that report induction by the xenosensors can delineate the specificities. Further modifying the cells to address functionally important polymorphisms in the xenosensors would permit population predictions.
- ZFNs can be used to create knock-out cell lines analogous to transporter knockout cell lines as described above, and to create reporter cell lines that express different fluorescent proteins upon induction of different xenosensors.
- cell lines can be created in which green FP is expressed if PXR is induced, red FP if CAR activity is induced, blue FP if AhR is induced. All lines may be constructed in the relevant tissue-type cell lines, i.e. intestine, liver, kidney, brain, and heart. Panels of cells can be created that represent the tissues most involved with drug toxicity and metabolism, and in which each xenosensor (CAR, PXR, AhR) is knocked out. Cell lines can also be produced that produce fluorescent proteins upon the activation of each of the three xenosensors.
- ZFNs can be used to create genetically modified cell lines as described herein that can provide the basis for assays that can measure the up/down regulation of key Phase I and Phase Il enzymes, along with genes involved in a toxicological response.
- ZFNs can be used to build lines that have a reporter gene (e.g. encoding fluorescent protein or luciferase) inserted proximal to the promoter of the gene being measured.
- Tissue-specific panels of cells can also be created, which report on the activation of genes encoding either the Phase I or Phase Il enzymes, the transporters, or toxicity response pathways (e.g., genotoxicity or apoptosis).
- a method of the invention may be used to create an animal or cell that may be used as a developmental model. Such a model may be used to study embryogenesis, organ development, organ system development, or the like. For instance, in one embodiment, a method of the invention may be used to create an animal or cell that comprises a chromosomal edit in one or more nucleic acid sequences associated with the development of an organ or organ system.
- Non-limiting examples of organs include the brain, eyes, nose, ears, throat, mouth (including teeth, tongue, lips, gums), spinal cord, bones, heart, blood vessels, lungs, liver, pancreas, gall bladder, spleen, esophagus, stomach, small intestines, large intestines, appendix, rectum, bladder, organs of the reproductive system, organs of the immune system (including thyroid, lymph nodes, lymph vessels), and organs of the endocrine system.
- organ systems include the nervous system, the circulatory system, the digestive system, the respiratory system, the skeletal system, the lymphatic system, the reproductive system, the muscular system, the integumentary system, the excretory system, and the endocrine system.
- a method of the invention may be used to create an animal or cell in which at least one chromosomal sequence associated with neurodevelopment has been edited.
- Suitable chromosomal edits may include, but are not limited to, the type of edits detailed in section l(f) above.
- a chromosomal sequence associated with neurodevelopment may be a protein coding sequence or a control sequence. In certain embodiments, a
- neurodevelopmental sequence may be associated with a neurodevelopmental disorder, with biochemical pathways associated with a neurodevelopmental disorder, or associated with a disorder such as phenylketonuria that is closely associated with neurodevelopmental disorders.
- Non-limiting examples of neurodevelopmental-associated sequences include A2BP1 [ataxin 2-binding protein 1], AADAT [aminoadipate aminotransferase], AANAT [arylalkylamine N-acetyltransferase], ABAT [4- aminobutyrate aminotransferase], ABCA1 [ATP-binding cassette, sub-family A (ABC1 ), member 1], ABCA13 [ATP-binding cassette, sub-family A (ABC1 ), member 13], ABCA2 [ATP-binding cassette, sub-family A (ABC1 ), member 2], ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1], ABCB11 [ATP-binding cassette, sub-family B (MDR/TAP), member 11], ABCB4 [ATP- binding cassette, sub-family B (MDR/TAP), member 4], ABCB6 [ATP-binding cassette, sub-family B (MDR/TAP), member 6], ABCB7 [
- ADAM11 [ADAM metallopeptidase domain 11]
- ADAM12 [ADAM metallopeptidase domain 12]
- ADAM15 [ADAM
- ADAM17 [ADAM metallopeptidase domain 17]
- ADAM18 [ADAM metallopeptidase domain 18]
- ADAM19 [ADAM
- ADAM2 [ADAM metallopeptidase domain 2]
- ADAM20 [ADAM metallopeptidase domain 20]
- ADAM21 [ADAM metallopeptidase domain 21]
- ADAM22 [ADAM metallopeptidase domain 22]
- ADAM23 [ADAM metallopeptidase domain 23]
- ADAM28 [ADAM
- ADAM metallopeptidase domain 28 ADAM29 [ADAM metallopeptidase domain 29], ADAM30 [ADAM metallopeptidase domain 30], ADAM8 [ADAM metallopeptidase domain 8], ADAM9 [ADAM metallopeptidase domain 9 (meltrin gamma)], ADAMTS1 [ADAM metallopeptidase with thrombospondin type 1 motif, 1], ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif, 13], ADAMTS4 [ADAM metallopeptidase with thrombospondin type 1 motif, 4], ADAMTS5 [ADAM metallopeptidase with thrombospondin type 1 motif, 5], ADAP2 [ArfGAP with dual PH domains 2], ADAR [adenosine deaminase, RNA- specific], ADARB1 [adenosine deaminase, RNA-
- dehydrogenase 1A (class I), alpha polypeptide], ADIPOQ [adiponectin, C1Q and collagen domain containing], ADK [adenosine kinase], ADM [adrenomedullin], ADNP [activity-dependent neuroprotector homeobox], ADORA1 [adenosine A1 receptor], ADORA2A [adenosine A2a receptor], ADORA2B [adenosine A2b receptor], ADORA3 [adenosine A3 receptor], ADRA1 B [adrenergic, alpha-1 B-, receptor], ADRA2A [adrenergic, alpha-2A-, receptor], ADRA2B [adrenergic, alpha-2B-, receptor], ADRA2C [adrenergic, alpha-2C-, receptor], ADRB1
- ADRB2 [adrenergic, beta-1 -, receptor], ADRB2 [adrenergic, beta-2-, receptor, surface], ADRB3 [adrenergic, beta-3-, receptor], ADRBK2 [adrenergic, beta, receptor kinase 2], ADSL [adenylosuccinate lyase], AFF2 [AF4/FMR2 family, member 2], AFM [afamin], AFP [alpha-fetoprotein], AGAP1 [ArfGAP with GTPase domain, ankyrin repeat and PH domain 1], AGER [advanced glycosylation end product- specific receptor], AGFG1 [ArfGAP with FG repeats 1], AGPS [alkylglycerone phosphate synthase], AGRN [agrin], AGRP [agouti related protein homolog (mouse)], AGT [angiotensinogen (serpin peptidase inhibitor, clade A, member 8)], AG
- AIFM1 [activation-induced cytidine deaminase], AIFM1 [apoptosis-inducing factor, mitochondrion-associated, 1], AIRE [autoimmune regulator], AKAP12 [A kinase (PRKA) anchor protein 12], AKAP9 [A kinase (PRKA) anchor protein (yotiao) 9], AKR1A1 [aldo-keto reductase family 1 , member A1 (aldehyde reductase)], AKR1 B1 [aldo-keto reductase family 1 , member B1 (aldose reductase)], AKR1 C3 [aldo-keto reductase family 1 , member C3 (3-alpha hydroxysteroid
- AKT1 [v-akt murine thymoma viral oncogene homolog 1]
- AKT2 [v-akt murine thymoma viral oncogene homolog 2]
- AKT3 [v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma)]
- ALAD v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma)]
- ANK1 [ankyrin 1 , erythrocytic], ANK3 [ankyrin 3, node of Ranvier (ankyrin G)], ANKRD1 [ankyrin repeat domain 1 (cardiac muscle)], ANP32E [acidic (leucine-rich) nuclear phosphoprotein 32 family, member E], ANPEP [alanyl (membrane) aminopeptidase], ANXA1
- AP1 [annexin A1], ANXA2 [annexin A2], ANXA5 [annexin A5], AP1 S1 [adaptor-related protein complex 1 , sigma 1 subunit], AP1 S2 [adaptor-related protein complex 1 , sigma 2 subunit], AP2A1 [adaptor-related protein complex 2, alpha 1 subunit], AP2B1 [adaptor-related protein complex 2, beta 1 subunit], APAF1 [apoptotic peptidase activating factor 1], APBA1 [amyloid beta (A4) precursor protein- binding, family A, member 1], APBA2 [amyloid beta (A4) precursor protein- binding, family A, member 2], APBB1 [amyloid beta (A4) precursor protein- binding, family B, member 1 (Fe65)], APBB2 [amyloid beta (A4) precursor protein-binding, family B, member 2], APC [adenomatous polyposis coli], APCS [amyloid P component
- APLP1 [amyloid beta (A4) precursor-like protein 1], APOA1 [apolipoprotein A-I], APOA5 [apolipoprotein A-V], APOB [apolipoprotein B (including Ag(x) antigen)], APOC2 [apolipoprotein C-Il], APOD [apolipoprotein D], APOE [apolipoprotein E], APOM [apolipoprotein M], APP [amyloid beta (A4) precursor protein], APPL1 [adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1], APRT [adenine phosphohbosyltransferase], APTX [aprataxin], AQP1 [aquaporin 1 (Colton blood group)], AQP2 [aquapohn 2 (collecting duct)], AQP3 [aquaporin 3 (Gill blood group)], AQP4 [aquaporin
- ARFGEF2 [ADP-ribosylation factor guanine nucleotide-exchange factor 2 (brefeldin A-inhibited)], ARG1 [arginase, liver], ARHGAP1 [Rho GTPase activating protein 1], ARHGAP32 [Rho GTPase activating protein 32], ARHGAP4 [Rho GTPase activating protein 4], ARHGAP5 [Rho GTPase activating protein 5], ARHGDIA [Rho GDP dissociation inhibitor (GDI) alpha], ARHGEF1 [Rho guanine nucleotide exchange factor (GEF) 1], ARHGEF10 [Rho guanine nucleotide exchange factor (GEF) 10], ARHGEF11 [Rho guanine nucleotide exchange factor (GEF) 11], ARHGEF12 [Rho guanine nucleotide exchange factor (GEF) 12], ARHGEF15 [Rh
- ARHGEF16 Rho guanine nucleotide exchange factor (GEF) 16
- GEF2 Rho guanine nucleotide exchange factor (GEF) 16
- ARPC1A [actin related protein 2/3 complex, subunit 1A, 41 kDa]
- ARPC1 B [actin related protein 2/3 complex, subunit 1 B, 41 kDa]
- ARPC2 [actin related protein 2/3 complex, subunit 2, 34kDa]
- ARPC3 [actin related protein 2/3 complex, subunit 3, 21 kDa]
- ARPC4 [actin related protein 2/3 complex, subunit 4, 2OkDa]
- ARPC5 [actin related protein 2/3 complex, subunit 5, 16kDa]
- ARPC5L [actin related protein 2/3 complex, subunit 5-like]
- ARPP19 [cAMP-regulated phosphoprotein, 19kDa]
- ARR3 arrestin 3, retinal (X-arrestin)]
- ARRB2 [arrestin, beta 2]
- ARSA arylsulfatase A
- ATP2B4 [ATPase, Ca++ transporting, plasma membrane 4], ATP5O [ATP synthase, H+ transporting, mitochondrial F1 complex, O subunit], ATP6AP1 [ATPase, H+ transporting, lysosomal accessory protein 1], ATP6V0C [ATPase, H+ transporting, lysosomal 16kDa, VO subunit c], ATP7A [ATPase, Cu++ transporting, alpha polypeptide], ATP8A1 [ATPase, aminophospholipid transporter (APLT), class I, type 8A, member 1], ATR [ataxia telangiectasia and Rad3 related], ATRN [attractin], ATRX [alpha
- CACNA2D1 [calcium channel, voltage-dependent, T type, alpha 1 H subunit]
- CADM1 cell adhesion molecule 1]
- CADPS2 [Ca++-dependent secretion activator 2]
- CALB2 [calbindin 2]
- CALCA calcium-dependent polypeptide alpha]
- CALCR calcium-dependent receptor
- CALM3 calcium-driven receptor for CALR
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Applications Claiming Priority (41)
Application Number | Priority Date | Filing Date | Title |
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US22841909P | 2009-07-24 | 2009-07-24 | |
US23262009P | 2009-08-10 | 2009-08-10 | |
US24587709P | 2009-09-25 | 2009-09-25 | |
US26369609P | 2009-11-23 | 2009-11-23 | |
US26390409P | 2009-11-24 | 2009-11-24 | |
US33600010P | 2010-01-14 | 2010-01-14 | |
US30808910P | 2010-02-25 | 2010-02-25 | |
US30972910P | 2010-03-02 | 2010-03-02 | |
US32369810P | 2010-04-13 | 2010-04-13 | |
US32371910P | 2010-04-13 | 2010-04-13 | |
US32370210P | 2010-04-13 | 2010-04-13 | |
US34328710P | 2010-04-26 | 2010-04-26 | |
PCT/US2010/043167 WO2011011767A1 (en) | 2009-07-24 | 2010-07-23 | Method for genome editing |
US12/842,886 US20110023157A1 (en) | 2008-12-04 | 2010-07-23 | Equine genome editing with zinc finger nucleases |
US12/842,980 US20110023150A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of genes associated with schizophrenia in animals |
US12/842,897 US20110023148A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of addiction-related genes in animals |
US12/842,982 US20110023151A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of abc transporters |
US12/842,198 US20110023139A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved in cardiovascular disease |
US12/842,893 US20110016546A1 (en) | 2008-12-04 | 2010-07-23 | Porcine genome editing with zinc finger nucleases |
US12/842,219 US20110023156A1 (en) | 2008-12-04 | 2010-07-23 | Feline genome editing with zinc finger nucleases |
US12/842,666 US20110023144A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved in amyotrophyic lateral sclerosis disease |
US12/842,994 US20110030072A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of immunodeficiency genes in animals |
US12/842,839 US20110016542A1 (en) | 2008-12-04 | 2010-07-23 | Canine genome editing with zinc finger nucleases |
US12/842,188 US20110023158A1 (en) | 2008-12-04 | 2010-07-23 | Bovine genome editing with zinc finger nucleases |
US12/842,204 US20110023159A1 (en) | 2008-12-04 | 2010-07-23 | Ovine genome editing with zinc finger nucleases |
US12/842,719 US20110016541A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of sensory-related genes in animals |
US12/842,269 US20110023154A1 (en) | 2008-12-04 | 2010-07-23 | Silkworm genome editing with zinc finger nucleases |
US12/842,713 US20110023147A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of prion disorder-related genes in animals |
US12/842,620 US20110016539A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of neurotransmission-related genes in animals |
US12/842,578 US20110023143A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of neurodevelopmental genes in animals |
US12/843,000 US20120159654A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of genes involved in adme and toxicology in animals |
US12/842,217 US20110023141A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved with parkinson's disease |
US12/842,999 US20110016543A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved in inflammation |
US12/842,694 US20110023146A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved in secretase-associated disorders |
US12/842,678 US20110023145A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved in autism spectrum disorders |
US12/842,991 US20110023152A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of cognition related genes in animals |
US12/842,208 US20110023140A1 (en) | 2008-12-04 | 2010-07-23 | Rabbit genome editing with zinc finger nucleases |
US12/842,993 US20110023153A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved in alzheimer's disease |
US12/842,708 US20110016540A1 (en) | 2008-12-04 | 2010-07-23 | Genome editing of genes associated with trinucleotide repeat expansion disorders in animals |
US12/842,976 US20120159653A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved in macular degeneration |
US12/842,978 US20110023149A1 (en) | 2008-12-04 | 2010-07-23 | Genomic editing of genes involved in tumor suppression in animals |
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KR (1) | KR20120097483A (de) |
AU (1) | AU2010275432A1 (de) |
CA (1) | CA2767377A1 (de) |
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EP2456877A4 (de) | 2012-05-30 |
CA2767377A1 (en) | 2011-01-27 |
IL217409A0 (en) | 2012-02-29 |
JP2013500018A (ja) | 2013-01-07 |
AU2010275432A1 (en) | 2012-02-02 |
WO2011011767A1 (en) | 2011-01-27 |
KR20120097483A (ko) | 2012-09-04 |
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