JP2018518165A - C9orf72遺伝子座における破壊を有する非ヒト動物 - Google Patents
C9orf72遺伝子座における破壊を有する非ヒト動物 Download PDFInfo
- Publication number
- JP2018518165A JP2018518165A JP2017561678A JP2017561678A JP2018518165A JP 2018518165 A JP2018518165 A JP 2018518165A JP 2017561678 A JP2017561678 A JP 2017561678A JP 2017561678 A JP2017561678 A JP 2017561678A JP 2018518165 A JP2018518165 A JP 2018518165A
- Authority
- JP
- Japan
- Prior art keywords
- c9orf72
- weeks
- mice
- rodent
- cells
- 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.)
- Granted
Links
- 241001465754 Metazoa Species 0.000 title claims description 75
- 241000282414 Homo sapiens Species 0.000 claims abstract description 288
- 238000000034 method Methods 0.000 claims abstract description 89
- 238000012217 deletion Methods 0.000 claims abstract description 65
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 63
- 230000037430 deletion Effects 0.000 claims abstract description 63
- 108091026890 Coding region Proteins 0.000 claims abstract description 53
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 39
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 35
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 34
- 206010018364 Glomerulonephritis Diseases 0.000 claims abstract description 25
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 20
- 201000011240 Frontotemporal dementia Diseases 0.000 claims abstract description 13
- 206010061218 Inflammation Diseases 0.000 claims abstract description 11
- 230000004054 inflammatory process Effects 0.000 claims abstract description 11
- 101150014718 C9orf72 gene Proteins 0.000 claims description 327
- 102000043334 C9orf72 Human genes 0.000 claims description 323
- 108700030955 C9orf72 Proteins 0.000 claims description 323
- 210000004027 cell Anatomy 0.000 claims description 262
- 230000014509 gene expression Effects 0.000 claims description 85
- 150000007523 nucleic acids Chemical group 0.000 claims description 84
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 83
- 210000001165 lymph node Anatomy 0.000 claims description 83
- 210000000952 spleen Anatomy 0.000 claims description 79
- 241000283984 Rodentia Species 0.000 claims description 77
- 108700008625 Reporter Genes Proteins 0.000 claims description 68
- 201000010099 disease Diseases 0.000 claims description 55
- 210000001519 tissue Anatomy 0.000 claims description 55
- 210000002161 motor neuron Anatomy 0.000 claims description 51
- 210000004369 blood Anatomy 0.000 claims description 45
- 239000008280 blood Substances 0.000 claims description 45
- 230000001965 increasing effect Effects 0.000 claims description 44
- 210000003734 kidney Anatomy 0.000 claims description 44
- 210000002966 serum Anatomy 0.000 claims description 43
- 210000001185 bone marrow Anatomy 0.000 claims description 42
- 208000024891 symptom Diseases 0.000 claims description 38
- 108010091086 Recombinases Proteins 0.000 claims description 37
- 230000000694 effects Effects 0.000 claims description 36
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 34
- 238000011161 development Methods 0.000 claims description 29
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 28
- 210000002540 macrophage Anatomy 0.000 claims description 28
- 238000003556 assay Methods 0.000 claims description 27
- 210000001671 embryonic stem cell Anatomy 0.000 claims description 27
- 101150066555 lacZ gene Proteins 0.000 claims description 27
- 230000001363 autoimmune Effects 0.000 claims description 24
- 102000018120 Recombinases Human genes 0.000 claims description 23
- 108091033319 polynucleotide Proteins 0.000 claims description 22
- 102000040430 polynucleotide Human genes 0.000 claims description 22
- 239000002157 polynucleotide Substances 0.000 claims description 22
- 102000004127 Cytokines Human genes 0.000 claims description 21
- 108090000695 Cytokines Proteins 0.000 claims description 21
- 210000004180 plasmocyte Anatomy 0.000 claims description 20
- 230000001105 regulatory effect Effects 0.000 claims description 20
- 230000008595 infiltration Effects 0.000 claims description 19
- 238000001764 infiltration Methods 0.000 claims description 19
- 210000001161 mammalian embryo Anatomy 0.000 claims description 19
- 230000000626 neurodegenerative effect Effects 0.000 claims description 19
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 claims description 18
- 102100022338 Integrin alpha-M Human genes 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 108700024394 Exon Proteins 0.000 claims description 17
- 230000004968 inflammatory condition Effects 0.000 claims description 17
- 239000003550 marker Substances 0.000 claims description 17
- 108020004414 DNA Proteins 0.000 claims description 16
- 230000005856 abnormality Effects 0.000 claims description 16
- 230000007423 decrease Effects 0.000 claims description 16
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 16
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 claims description 14
- 102100032912 CD44 antigen Human genes 0.000 claims description 13
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 claims description 13
- 210000004443 dendritic cell Anatomy 0.000 claims description 13
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 13
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 12
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 12
- 102000013462 Interleukin-12 Human genes 0.000 claims description 12
- 108010065805 Interleukin-12 Proteins 0.000 claims description 12
- 102000003814 Interleukin-10 Human genes 0.000 claims description 11
- 108090000174 Interleukin-10 Proteins 0.000 claims description 11
- 208000008771 Lymphadenopathy Diseases 0.000 claims description 11
- 206010041660 Splenomegaly Diseases 0.000 claims description 11
- 208000018555 lymphatic system disease Diseases 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 210000001616 monocyte Anatomy 0.000 claims description 11
- 102100025137 Early activation antigen CD69 Human genes 0.000 claims description 10
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 claims description 10
- 210000004379 membrane Anatomy 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 10
- 108091005957 yellow fluorescent proteins Proteins 0.000 claims description 10
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 208000017169 kidney disease Diseases 0.000 claims description 9
- 230000003902 lesion Effects 0.000 claims description 9
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 8
- 102000013691 Interleukin-17 Human genes 0.000 claims description 8
- 108050003558 Interleukin-17 Proteins 0.000 claims description 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 8
- 230000006735 deficit Effects 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 230000000750 progressive effect Effects 0.000 claims description 8
- 108010043121 Green Fluorescent Proteins Proteins 0.000 claims description 7
- 102000004144 Green Fluorescent Proteins Human genes 0.000 claims description 7
- 102100022297 Integrin alpha-X Human genes 0.000 claims description 7
- 108020005196 Mitochondrial DNA Proteins 0.000 claims description 7
- 108091093105 Nuclear DNA Proteins 0.000 claims description 7
- 108010048367 enhanced green fluorescent protein Proteins 0.000 claims description 7
- 210000003714 granulocyte Anatomy 0.000 claims description 7
- 239000005090 green fluorescent protein Substances 0.000 claims description 7
- 230000004065 mitochondrial dysfunction Effects 0.000 claims description 7
- 201000008171 proliferative glomerulonephritis Diseases 0.000 claims description 7
- 230000004580 weight loss Effects 0.000 claims description 7
- 102000053602 DNA Human genes 0.000 claims description 6
- 108091005941 EBFP Proteins 0.000 claims description 6
- 102100037850 Interferon gamma Human genes 0.000 claims description 6
- 108010074328 Interferon-gamma Proteins 0.000 claims description 6
- 230000003429 anti-cardiolipin effect Effects 0.000 claims description 6
- 230000003460 anti-nuclear Effects 0.000 claims description 6
- 108010082025 cyan fluorescent protein Proteins 0.000 claims description 6
- 230000008021 deposition Effects 0.000 claims description 6
- -1 eYFP Proteins 0.000 claims description 6
- 230000006540 mitochondrial respiration Effects 0.000 claims description 6
- 230000006798 recombination Effects 0.000 claims description 6
- 238000005215 recombination Methods 0.000 claims description 6
- 229940124598 therapeutic candidate Drugs 0.000 claims description 6
- 102100021943 C-C motif chemokine 2 Human genes 0.000 claims description 5
- 101710155857 C-C motif chemokine 2 Proteins 0.000 claims description 5
- 108060001084 Luciferase Proteins 0.000 claims description 5
- 239000005089 Luciferase Substances 0.000 claims description 5
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 claims description 5
- 108091005948 blue fluorescent proteins Proteins 0.000 claims description 5
- 108010021843 fluorescent protein 583 Proteins 0.000 claims description 5
- 230000003325 follicular Effects 0.000 claims description 5
- 210000003289 regulatory T cell Anatomy 0.000 claims description 5
- 210000005239 tubule Anatomy 0.000 claims description 5
- 230000002407 ATP formation Effects 0.000 claims description 4
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 claims description 4
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 claims description 4
- 101100381525 Mus musculus Bcl6 gene Proteins 0.000 claims description 4
- 230000003356 anti-rheumatic effect Effects 0.000 claims description 4
- 239000003435 antirheumatic agent Substances 0.000 claims description 4
- 230000013011 mating Effects 0.000 claims description 4
- 230000035755 proliferation Effects 0.000 claims description 4
- 230000000241 respiratory effect Effects 0.000 claims description 4
- 210000002469 basement membrane Anatomy 0.000 claims description 3
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 claims 4
- 101000935845 Aliivibrio fischeri Blue fluorescence protein Proteins 0.000 claims 1
- 101000935842 Escherichia coli O127:H6 (strain E2348/69 / EPEC) Major structural subunit of bundle-forming pilus Proteins 0.000 claims 1
- 101001079872 Homo sapiens RING finger protein 112 Proteins 0.000 claims 1
- 208000034189 Sclerosis Diseases 0.000 claims 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 1
- 238000010171 animal model Methods 0.000 abstract description 31
- 208000019802 Sexually transmitted disease Diseases 0.000 abstract 1
- 229940124606 potential therapeutic agent Drugs 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 332
- 108090000623 proteins and genes Proteins 0.000 description 97
- 239000003814 drug Substances 0.000 description 79
- 108090000765 processed proteins & peptides Proteins 0.000 description 75
- 229920001184 polypeptide Polymers 0.000 description 74
- 102000004196 processed proteins & peptides Human genes 0.000 description 74
- 102000039446 nucleic acids Human genes 0.000 description 59
- 108020004707 nucleic acids Proteins 0.000 description 59
- 241000699666 Mus <mouse, genus> Species 0.000 description 52
- 241000700159 Rattus Species 0.000 description 49
- 229940079593 drug Drugs 0.000 description 46
- 230000008685 targeting Effects 0.000 description 45
- 238000012360 testing method Methods 0.000 description 34
- 238000010186 staining Methods 0.000 description 33
- 239000013598 vector Substances 0.000 description 31
- 102000004169 proteins and genes Human genes 0.000 description 28
- 238000004458 analytical method Methods 0.000 description 27
- 230000018109 developmental process Effects 0.000 description 27
- 235000018102 proteins Nutrition 0.000 description 26
- 208000035475 disorder Diseases 0.000 description 25
- 238000005259 measurement Methods 0.000 description 25
- 239000000203 mixture Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 229940124597 therapeutic agent Drugs 0.000 description 23
- 238000011282 treatment Methods 0.000 description 23
- UJVHVMNGOZXSOZ-VKHMYHEASA-N L-BMAA Chemical compound CNC[C@H](N)C(O)=O UJVHVMNGOZXSOZ-VKHMYHEASA-N 0.000 description 22
- 125000003275 alpha amino acid group Chemical group 0.000 description 22
- 230000004048 modification Effects 0.000 description 21
- 238000012986 modification Methods 0.000 description 21
- 230000006870 function Effects 0.000 description 20
- 238000001727 in vivo Methods 0.000 description 20
- 239000000427 antigen Substances 0.000 description 18
- 108091007433 antigens Proteins 0.000 description 18
- 102000036639 antigens Human genes 0.000 description 18
- 101100383813 Mus musculus C9orf72 gene Proteins 0.000 description 17
- 210000003719 b-lymphocyte Anatomy 0.000 description 17
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 16
- 230000001976 improved effect Effects 0.000 description 16
- 239000002609 medium Substances 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 235000001014 amino acid Nutrition 0.000 description 15
- 230000005021 gait Effects 0.000 description 15
- 210000002569 neuron Anatomy 0.000 description 15
- 206010061296 Motor dysfunction Diseases 0.000 description 14
- 230000006399 behavior Effects 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 14
- 230000002757 inflammatory effect Effects 0.000 description 14
- 238000003780 insertion Methods 0.000 description 14
- 230000037431 insertion Effects 0.000 description 14
- 210000004185 liver Anatomy 0.000 description 14
- 210000000287 oocyte Anatomy 0.000 description 14
- 238000010586 diagram Methods 0.000 description 13
- 230000004064 dysfunction Effects 0.000 description 13
- 230000001404 mediated effect Effects 0.000 description 13
- 230000004044 response Effects 0.000 description 13
- 230000009261 transgenic effect Effects 0.000 description 13
- 229960005486 vaccine Drugs 0.000 description 13
- 101000989501 Homo sapiens Guanine nucleotide exchange factor C9orf72 Proteins 0.000 description 12
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 12
- 206010044565 Tremor Diseases 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 12
- 102000045815 human C9orf72 Human genes 0.000 description 12
- 210000003141 lower extremity Anatomy 0.000 description 12
- 230000002068 genetic effect Effects 0.000 description 11
- 230000036542 oxidative stress Effects 0.000 description 11
- 210000000278 spinal cord Anatomy 0.000 description 11
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 10
- 108091081024 Start codon Proteins 0.000 description 10
- 230000037396 body weight Effects 0.000 description 10
- 230000008859 change Effects 0.000 description 10
- 210000004698 lymphocyte Anatomy 0.000 description 10
- 108020004999 messenger RNA Proteins 0.000 description 10
- 238000006467 substitution reaction Methods 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 10
- 241001529936 Murinae Species 0.000 description 9
- 108010029485 Protein Isoforms Proteins 0.000 description 9
- 102000001708 Protein Isoforms Human genes 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 210000000265 leukocyte Anatomy 0.000 description 9
- 210000003205 muscle Anatomy 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 108020004705 Codon Proteins 0.000 description 8
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 8
- 102100040247 Tumor necrosis factor Human genes 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 210000002865 immune cell Anatomy 0.000 description 8
- 210000000987 immune system Anatomy 0.000 description 8
- 230000000926 neurological effect Effects 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 238000012762 unpaired Student’s t-test Methods 0.000 description 8
- 238000008157 ELISA kit Methods 0.000 description 7
- 238000000540 analysis of variance Methods 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 210000002257 embryonic structure Anatomy 0.000 description 7
- 230000028993 immune response Effects 0.000 description 7
- 230000003137 locomotive effect Effects 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 210000000066 myeloid cell Anatomy 0.000 description 7
- 210000000440 neutrophil Anatomy 0.000 description 7
- 238000001543 one-way ANOVA Methods 0.000 description 7
- 239000013074 reference sample Substances 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 6
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 6
- 210000005056 cell body Anatomy 0.000 description 6
- 230000000875 corresponding effect Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 230000013632 homeostatic process Effects 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 230000009545 invasion Effects 0.000 description 6
- 230000033001 locomotion Effects 0.000 description 6
- 239000002773 nucleotide Substances 0.000 description 6
- 125000003729 nucleotide group Chemical group 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 208000016261 weight loss Diseases 0.000 description 6
- 108060003951 Immunoglobulin Proteins 0.000 description 5
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 230000003542 behavioural effect Effects 0.000 description 5
- 102000005936 beta-Galactosidase Human genes 0.000 description 5
- 108010005774 beta-Galactosidase Proteins 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 210000000805 cytoplasm Anatomy 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 5
- 238000010195 expression analysis Methods 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 206010020718 hyperplasia Diseases 0.000 description 5
- 102000018358 immunoglobulin Human genes 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 210000000472 morula Anatomy 0.000 description 5
- 210000000653 nervous system Anatomy 0.000 description 5
- 210000004940 nucleus Anatomy 0.000 description 5
- 230000004962 physiological condition Effects 0.000 description 5
- 239000003642 reactive oxygen metabolite Substances 0.000 description 5
- 210000000130 stem cell Anatomy 0.000 description 5
- 230000009885 systemic effect Effects 0.000 description 5
- 210000001541 thymus gland Anatomy 0.000 description 5
- 238000011144 upstream manufacturing Methods 0.000 description 5
- 230000002485 urinary effect Effects 0.000 description 5
- 230000003442 weekly effect Effects 0.000 description 5
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 4
- 108010051219 Cre recombinase Proteins 0.000 description 4
- 102000006395 Globulins Human genes 0.000 description 4
- 108010044091 Globulins Proteins 0.000 description 4
- 206010051920 Glomerulonephropathy Diseases 0.000 description 4
- 101001043809 Homo sapiens Interleukin-7 receptor subunit alpha Proteins 0.000 description 4
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 4
- 102100021593 Interleukin-7 receptor subunit alpha Human genes 0.000 description 4
- 102100033467 L-selectin Human genes 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 208000005392 Spasm Diseases 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 208000037979 autoimmune inflammatory disease Diseases 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 210000000349 chromosome Anatomy 0.000 description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- 238000002224 dissection Methods 0.000 description 4
- 210000002242 embryoid body Anatomy 0.000 description 4
- 230000002327 eosinophilic effect Effects 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 210000003527 eukaryotic cell Anatomy 0.000 description 4
- 238000013401 experimental design Methods 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 208000013967 frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Diseases 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 230000001434 glomerular Effects 0.000 description 4
- 206010061989 glomerulosclerosis Diseases 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 238000007489 histopathology method Methods 0.000 description 4
- 238000002744 homologous recombination Methods 0.000 description 4
- 230000006801 homologous recombination Effects 0.000 description 4
- 230000001771 impaired effect Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000007659 motor function Effects 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 238000012453 sprague-dawley rat model Methods 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 3
- ZDTFMPXQUSBYRL-UUOKFMHZSA-N 2-Aminoadenosine Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ZDTFMPXQUSBYRL-UUOKFMHZSA-N 0.000 description 3
- 108020005345 3' Untranslated Regions Proteins 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 108700028369 Alleles Proteins 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 241000699800 Cricetinae Species 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 3
- 241000699694 Gerbillinae Species 0.000 description 3
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 3
- 102100025305 Integrin alpha-2 Human genes 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 208000016285 Movement disease Diseases 0.000 description 3
- 241000699729 Muridae Species 0.000 description 3
- 101000687343 Mus musculus PR domain zinc finger protein 1 Proteins 0.000 description 3
- 108010004217 Natural Cytotoxicity Triggering Receptor 1 Proteins 0.000 description 3
- 102100032870 Natural cytotoxicity triggering receptor 1 Human genes 0.000 description 3
- 229930193140 Neomycin Natural products 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 238000003559 RNA-seq method Methods 0.000 description 3
- 102000005686 Serum Globulins Human genes 0.000 description 3
- 108010045362 Serum Globulins Proteins 0.000 description 3
- 108700019146 Transgenes Proteins 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 230000035508 accumulation Effects 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 229960003767 alanine Drugs 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 210000004436 artificial bacterial chromosome Anatomy 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 210000001652 frontal lobe Anatomy 0.000 description 3
- 238000010353 genetic engineering Methods 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 210000005260 human cell Anatomy 0.000 description 3
- 210000004276 hyalin Anatomy 0.000 description 3
- 230000036737 immune function Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000006742 locomotor activity Effects 0.000 description 3
- 210000003563 lymphoid tissue Anatomy 0.000 description 3
- 230000001589 lymphoproliferative effect Effects 0.000 description 3
- 201000001268 lymphoproliferative syndrome Diseases 0.000 description 3
- 230000002438 mitochondrial effect Effects 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 229960004927 neomycin Drugs 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 230000036284 oxygen consumption Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 150000004713 phosphodiesters Chemical class 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 210000001236 prokaryotic cell Anatomy 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000011514 reflex Effects 0.000 description 3
- 238000010825 rotarod performance test Methods 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 210000001550 testis Anatomy 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 230000005030 transcription termination Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- 229960004295 valine Drugs 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 3
- 108020003589 5' Untranslated Regions Proteins 0.000 description 2
- OPIFSICVWOWJMJ-AEOCFKNESA-N 5-bromo-4-chloro-3-indolyl beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CNC2=CC=C(Br)C(Cl)=C12 OPIFSICVWOWJMJ-AEOCFKNESA-N 0.000 description 2
- ZAYHVCMSTBRABG-JXOAFFINSA-N 5-methylcytidine Chemical compound O=C1N=C(N)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ZAYHVCMSTBRABG-JXOAFFINSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 206010004173 Basophilia Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- 210000004366 CD4-positive T-lymphocyte Anatomy 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000016918 Complement C3 Human genes 0.000 description 2
- 108010028780 Complement C3 Proteins 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 108010053770 Deoxyribonucleases Proteins 0.000 description 2
- 102000016911 Deoxyribonucleases Human genes 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- 206010015548 Euthanasia Diseases 0.000 description 2
- 206010017577 Gait disturbance Diseases 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 108010025815 Kanamycin Kinase Proteins 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 208000008238 Muscle Spasticity Diseases 0.000 description 2
- 208000010428 Muscle Weakness Diseases 0.000 description 2
- 206010028372 Muscular weakness Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 108091092724 Noncoding DNA Proteins 0.000 description 2
- 108091005461 Nucleic proteins Proteins 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 108010052160 Site-specific recombinase Proteins 0.000 description 2
- 102000004598 Small Nuclear Ribonucleoproteins Human genes 0.000 description 2
- 108010003165 Small Nuclear Ribonucleoproteins Proteins 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 230000006044 T cell activation Effects 0.000 description 2
- 238000010459 TALEN Methods 0.000 description 2
- 108091023045 Untranslated Region Proteins 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 108700005077 Viral Genes Proteins 0.000 description 2
- 108010017070 Zinc Finger Nucleases Proteins 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 238000003766 bioinformatics method Methods 0.000 description 2
- 210000002459 blastocyst Anatomy 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- 210000001736 capillary Anatomy 0.000 description 2
- 238000012754 cardiac puncture Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000005779 cell damage Effects 0.000 description 2
- 208000037887 cell injury Diseases 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 235000013330 chicken meat Nutrition 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000010339 dilation Effects 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- LBOJYSIDWZQNJS-CVEARBPZSA-N dizocilpine Chemical compound C12=CC=CC=C2[C@]2(C)C3=CC=CC=C3C[C@H]1N2 LBOJYSIDWZQNJS-CVEARBPZSA-N 0.000 description 2
- 230000008482 dysregulation Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000007159 enucleation Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000003979 eosinophil Anatomy 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 210000003414 extremity Anatomy 0.000 description 2
- 210000003194 forelimb Anatomy 0.000 description 2
- 238000012239 gene modification Methods 0.000 description 2
- 230000004547 gene signature Effects 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 238000010363 gene targeting Methods 0.000 description 2
- 102000054766 genetic haplotypes Human genes 0.000 description 2
- 230000005017 genetic modification Effects 0.000 description 2
- 235000013617 genetically modified food Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 230000002710 gonadal effect Effects 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 206010020745 hyperreflexia Diseases 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000013394 immunophenotyping Methods 0.000 description 2
- 238000012744 immunostaining Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000012678 infectious agent Substances 0.000 description 2
- 210000002074 inflammatory monocyte Anatomy 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- 229960003136 leucine Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 230000004777 loss-of-function mutation Effects 0.000 description 2
- 210000003071 memory t lymphocyte Anatomy 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000004898 mitochondrial function Effects 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 230000006764 neuronal dysfunction Effects 0.000 description 2
- 230000008906 neuronal response Effects 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000009103 reabsorption Effects 0.000 description 2
- 210000005084 renal tissue Anatomy 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 238000011808 rodent model Methods 0.000 description 2
- 238000013077 scoring method Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 210000001044 sensory neuron Anatomy 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 238000010374 somatic cell nuclear transfer Methods 0.000 description 2
- 208000018198 spasticity Diseases 0.000 description 2
- 230000003393 splenic effect Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- 108700026220 vif Genes Proteins 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MNULEGDCPYONBU-WMBHJXFZSA-N (1r,4s,5e,5'r,6'r,7e,10s,11r,12s,14r,15s,16s,18r,19s,20r,21e,25s,26r,27s,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trio Polymers O([C@@H]1CC[C@@H](/C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)O[C@H]([C@H]2C)[C@H]1C)CC)[C@]12CC[C@@H](C)[C@@H](C[C@H](C)O)O1 MNULEGDCPYONBU-WMBHJXFZSA-N 0.000 description 1
- MNULEGDCPYONBU-DJRUDOHVSA-N (1s,4r,5z,5'r,6'r,7e,10s,11r,12s,14r,15s,18r,19r,20s,21e,26r,27s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers O([C@H]1CC[C@H](\C=C/C=C/C[C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@H](C)[C@@H](O)C(C)C(=O)[C@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)OC([C@H]2C)C1C)CC)[C@]12CC[C@@H](C)[C@@H](CC(C)O)O1 MNULEGDCPYONBU-DJRUDOHVSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- RIFDKYBNWNPCQK-IOSLPCCCSA-N (2r,3s,4r,5r)-2-(hydroxymethyl)-5-(6-imino-3-methylpurin-9-yl)oxolane-3,4-diol Chemical compound C1=2N(C)C=NC(=N)C=2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O RIFDKYBNWNPCQK-IOSLPCCCSA-N 0.000 description 1
- MNULEGDCPYONBU-YNZHUHFTSA-N (4Z,18Z,20Z)-22-ethyl-7,11,14,15-tetrahydroxy-6'-(2-hydroxypropyl)-5',6,8,10,12,14,16,28,29-nonamethylspiro[2,26-dioxabicyclo[23.3.1]nonacosa-4,18,20-triene-27,2'-oxane]-3,9,13-trione Polymers CC1C(C2C)OC(=O)\C=C/C(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)C\C=C/C=C\C(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-YNZHUHFTSA-N 0.000 description 1
- MNULEGDCPYONBU-VVXVDZGXSA-N (5e,5'r,7e,10s,11r,12s,14s,15r,16r,18r,19s,20r,21e,26r,29s)-4-ethyl-11,12,15,19-tetrahydroxy-6'-[(2s)-2-hydroxypropyl]-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers C([C@H](C)[C@@H](O)[C@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@H](C)/C=C/C(=O)OC([C@H]1C)[C@H]2C)\C=C\C=C\C(CC)CCC2OC21CC[C@@H](C)C(C[C@H](C)O)O2 MNULEGDCPYONBU-VVXVDZGXSA-N 0.000 description 1
- RKSLVDIXBGWPIS-UAKXSSHOSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 RKSLVDIXBGWPIS-UAKXSSHOSA-N 0.000 description 1
- QLOCVMVCRJOTTM-TURQNECASA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-prop-1-ynylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C#CC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 QLOCVMVCRJOTTM-TURQNECASA-N 0.000 description 1
- PISWNSOQFZRVJK-XLPZGREQSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-2-sulfanylidenepyrimidin-4-one Chemical compound S=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 PISWNSOQFZRVJK-XLPZGREQSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- UQNAFPHGVPVTAL-UHFFFAOYSA-N 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C1=C2C=CC=C1S(=O)(=O)N UQNAFPHGVPVTAL-UHFFFAOYSA-N 0.000 description 1
- YMHOBZXQZVXHBM-UHFFFAOYSA-N 2,5-dimethoxy-4-bromophenethylamine Chemical compound COC1=CC(CCN)=C(OC)C=C1Br YMHOBZXQZVXHBM-UHFFFAOYSA-N 0.000 description 1
- UJVHVMNGOZXSOZ-UHFFFAOYSA-N 2-amino-3-(methylamino)propanoic acid Chemical compound CNCC(N)C(O)=O UJVHVMNGOZXSOZ-UHFFFAOYSA-N 0.000 description 1
- JRYMOPZHXMVHTA-DAGMQNCNSA-N 2-amino-7-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1h-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound C1=CC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O JRYMOPZHXMVHTA-DAGMQNCNSA-N 0.000 description 1
- RHFUOMFWUGWKKO-XVFCMESISA-N 2-thiocytidine Chemical compound S=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RHFUOMFWUGWKKO-XVFCMESISA-N 0.000 description 1
- LMMLLWZHCKCFQA-UGKPPGOTSA-N 4-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-prop-1-ynyloxolan-2-yl]pyrimidin-2-one Chemical compound C1=CC(N)=NC(=O)N1[C@]1(C#CC)O[C@H](CO)[C@@H](O)[C@H]1O LMMLLWZHCKCFQA-UGKPPGOTSA-N 0.000 description 1
- XXSIICQLPUAUDF-TURQNECASA-N 4-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-prop-1-ynylpyrimidin-2-one Chemical compound O=C1N=C(N)C(C#CC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XXSIICQLPUAUDF-TURQNECASA-N 0.000 description 1
- MNULEGDCPYONBU-UHFFFAOYSA-N 4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione Polymers CC1C(C2C)OC(=O)C=CC(C)C(O)C(C)C(=O)C(C)C(O)C(C)C(=O)C(C)(O)C(O)C(C)CC=CC=CC(CC)CCC2OC21CCC(C)C(CC(C)O)O2 MNULEGDCPYONBU-UHFFFAOYSA-N 0.000 description 1
- ZAYHVCMSTBRABG-UHFFFAOYSA-N 5-Methylcytidine Natural products O=C1N=C(N)C(C)=CN1C1C(O)C(O)C(CO)O1 ZAYHVCMSTBRABG-UHFFFAOYSA-N 0.000 description 1
- AGFIRQJZCNVMCW-UAKXSSHOSA-N 5-bromouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 AGFIRQJZCNVMCW-UAKXSSHOSA-N 0.000 description 1
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 1
- XXKILKPSIMIHOA-UHFFFAOYSA-N 5-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide Chemical compound C1=C([N+]([O-])=O)C2=NC(=O)C(=O)N=C2C2=C1C(S(=O)(=O)N)=CC=C2 XXKILKPSIMIHOA-UHFFFAOYSA-N 0.000 description 1
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 1
- BXJHWYVXLGLDMZ-UHFFFAOYSA-N 6-O-methylguanine Chemical compound COC1=NC(N)=NC2=C1NC=N2 BXJHWYVXLGLDMZ-UHFFFAOYSA-N 0.000 description 1
- UEHOMUNTZPIBIL-UUOKFMHZSA-N 6-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-7h-purin-8-one Chemical compound O=C1NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O UEHOMUNTZPIBIL-UUOKFMHZSA-N 0.000 description 1
- HCAJQHYUCKICQH-VPENINKCSA-N 8-Oxo-7,8-dihydro-2'-deoxyguanosine Chemical compound C1=2NC(N)=NC(=O)C=2NC(=O)N1[C@H]1C[C@H](O)[C@@H](CO)O1 HCAJQHYUCKICQH-VPENINKCSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 239000000774 AMPA receptor agonist Substances 0.000 description 1
- 239000000775 AMPA receptor antagonist Substances 0.000 description 1
- 229940098747 AMPA receptor antagonist Drugs 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 206010073485 Abdominal lymphadenopathy Diseases 0.000 description 1
- 208000000187 Abnormal Reflex Diseases 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 241000699725 Acomys Species 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 102000006822 Agouti Signaling Protein Human genes 0.000 description 1
- 108010072151 Agouti Signaling Protein Proteins 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 102100026882 Alpha-synuclein Human genes 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- UIFFUZWRFRDZJC-UHFFFAOYSA-N Antimycin A1 Natural products CC1OC(=O)C(CCCCCC)C(OC(=O)CC(C)C)C(C)OC(=O)C1NC(=O)C1=CC=CC(NC=O)=C1O UIFFUZWRFRDZJC-UHFFFAOYSA-N 0.000 description 1
- NQWZLRAORXLWDN-UHFFFAOYSA-N Antimycin-A Natural products CCCCCCC(=O)OC1C(C)OC(=O)C(NC(=O)c2ccc(NC=O)cc2O)C(C)OC(=O)C1CCCC NQWZLRAORXLWDN-UHFFFAOYSA-N 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 108010045123 Blasticidin-S deaminase Proteins 0.000 description 1
- 101710148099 Blue fluorescence protein Proteins 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 101100518995 Caenorhabditis elegans pax-3 gene Proteins 0.000 description 1
- 241000700192 Calomyscus sp. Species 0.000 description 1
- BMZRVOVNUMQTIN-UHFFFAOYSA-N Carbonyl Cyanide para-Trifluoromethoxyphenylhydrazone Chemical compound FC(F)(F)OC1=CC=C(NN=C(C#N)C#N)C=C1 BMZRVOVNUMQTIN-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108091005944 Cerulean Proteins 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 1
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 1
- 108700010070 Codon Usage Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 241000484025 Cuniculus Species 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 238000007399 DNA isolation Methods 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101001091269 Escherichia coli Hygromycin-B 4-O-kinase Proteins 0.000 description 1
- 241000702191 Escherichia virus P1 Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 101150007884 Gata6 gene Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 1
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 208000022461 Glomerular disease Diseases 0.000 description 1
- 206010018370 Glomerulonephritis membranoproliferative Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241001559542 Hippocampus hippocampus Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 1
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 1
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 1
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 1
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 101150002416 Igf2 gene Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 229940123572 Kainate receptor antagonist Drugs 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- LCGISIDBXHGCDW-VKHMYHEASA-N L-glutamine amide Chemical compound NC(=O)[C@@H](N)CCC(N)=O LCGISIDBXHGCDW-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 101150040658 LHX2 gene Proteins 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- 241000270322 Lepidosauria Species 0.000 description 1
- 108010013709 Leukocyte Common Antigens Proteins 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 102100025931 MOB kinase activator 3B Human genes 0.000 description 1
- 101710112695 MOB kinase activator 3B Proteins 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 208000004451 Membranoproliferative Glomerulonephritis Diseases 0.000 description 1
- 206010027906 Monocytosis Diseases 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000711408 Murine respirovirus Species 0.000 description 1
- 241000398750 Muroidea Species 0.000 description 1
- 101100508438 Mus musculus Ifnk gene Proteins 0.000 description 1
- 101100518997 Mus musculus Pax3 gene Proteins 0.000 description 1
- 101100451662 Mus musculus Prm1 gene Proteins 0.000 description 1
- 241000699669 Mus saxicola Species 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 229910003251 Na K Inorganic materials 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 101100070530 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) het-6 gene Proteins 0.000 description 1
- 241000380800 Nordus Species 0.000 description 1
- 241001452677 Ogataea methanolica Species 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 101150049281 PRM1 gene Proteins 0.000 description 1
- 108091093037 Peptide nucleic acid Proteins 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 101710168705 Protamine-1 Proteins 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 102000044126 RNA-Binding Proteins Human genes 0.000 description 1
- 108700020471 RNA-Binding Proteins Proteins 0.000 description 1
- 101100383814 Rattus norvegicus C9orf72 gene Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
- 101710141795 Ribonuclease inhibitor Proteins 0.000 description 1
- 229940122208 Ribonuclease inhibitor Drugs 0.000 description 1
- 102100037968 Ribonuclease inhibitor Human genes 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 241000235347 Schizosaccharomyces pombe Species 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 206010041415 Spastic paralysis Diseases 0.000 description 1
- 102100040435 Sperm protamine P1 Human genes 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 101001091268 Streptomyces hygroscopicus Hygromycin-B 7''-O-kinase Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 108091036066 Three prime untranslated region Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 101710159648 Uncharacterized protein Proteins 0.000 description 1
- 208000027740 Upper motor neuron dysfunction Diseases 0.000 description 1
- 241000545067 Venus Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 230000010530 Virus Neutralization Effects 0.000 description 1
- 108010027570 Xanthine phosphoribosyltransferase Proteins 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 208000028752 abnormal posture Diseases 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- DPKHZNPWBDQZCN-UHFFFAOYSA-N acridine orange free base Chemical compound C1=CC(N(C)C)=CC2=NC3=CC(N(C)C)=CC=C3C=C21 DPKHZNPWBDQZCN-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000012574 advanced DMEM Substances 0.000 description 1
- 238000012867 alanine scanning Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- UIFFUZWRFRDZJC-SBOOETFBSA-N antimycin A Chemical compound C[C@H]1OC(=O)[C@H](CCCCCC)[C@@H](OC(=O)CC(C)C)[C@H](C)OC(=O)[C@H]1NC(=O)C1=CC=CC(NC=O)=C1O UIFFUZWRFRDZJC-SBOOETFBSA-N 0.000 description 1
- PVEVXUMVNWSNIG-UHFFFAOYSA-N antimycin A3 Natural products CC1OC(=O)C(CCCC)C(OC(=O)CC(C)C)C(C)OC(=O)C1NC(=O)C1=CC=CC(NC=O)=C1O PVEVXUMVNWSNIG-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 230000008721 basement membrane thickening Effects 0.000 description 1
- 230000006736 behavioral deficit Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 208000015322 bone marrow disease Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000012669 compression test Methods 0.000 description 1
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 1
- 210000003618 cortical neuron Anatomy 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229950004794 dizocilpine Drugs 0.000 description 1
- VZFRNCSOCOPNDB-AJKFJWDBSA-N domoic acid Chemical compound OC(=O)[C@@H](C)\C=C\C=C(/C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VZFRNCSOCOPNDB-AJKFJWDBSA-N 0.000 description 1
- VZFRNCSOCOPNDB-UHFFFAOYSA-N domoic acid Natural products OC(=O)C(C)C=CC=C(C)C1CNC(C(O)=O)C1CC(O)=O VZFRNCSOCOPNDB-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 239000002359 drug metabolite Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000001819 effect on gene Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000001378 electrochemiluminescence detection Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 230000022770 endosome transport Effects 0.000 description 1
- 230000005183 environmental health Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 231100000318 excitotoxic Toxicity 0.000 description 1
- 230000003492 excitotoxic effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 238000005558 fluorometry Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000037433 frameshift Effects 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 101150003286 gata4 gene Proteins 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 230000037442 genomic alteration Effects 0.000 description 1
- 210000001280 germinal center Anatomy 0.000 description 1
- 210000005086 glomerual capillary Anatomy 0.000 description 1
- 210000000585 glomerular basement membrane Anatomy 0.000 description 1
- 231100000852 glomerular disease Toxicity 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 208000010726 hind limb paralysis Diseases 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002390 hyperplastic effect Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000013388 immunohistochemistry analysis Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000019016 inability to swallow Diseases 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000007154 intracellular accumulation Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- VZFRNCSOCOPNDB-OXYNIABMSA-N isodomoic acid D Natural products CC(C=C/C=C(/C)C1CNC(C1CC(=O)O)C(=O)O)C(=O)O VZFRNCSOCOPNDB-OXYNIABMSA-N 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 1
- 229950006874 kainic acid Drugs 0.000 description 1
- 239000002909 kainic acid receptor agonist Substances 0.000 description 1
- 239000002873 kainic acid receptor antagonist Substances 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 101150115794 lhx5 gene Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 150000002678 macrocyclic compounds Chemical group 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 210000000713 mesentery Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 230000037230 mobility Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000004973 motor coordination Effects 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 238000010984 neurological examination Methods 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 229930191479 oligomycin Natural products 0.000 description 1
- MNULEGDCPYONBU-AWJDAWNUSA-N oligomycin A Polymers O([C@H]1CC[C@H](/C=C/C=C/C[C@@H](C)[C@H](O)[C@@](C)(O)C(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@H](O)[C@@H](C)/C=C/C(=O)O[C@@H]([C@@H]2C)[C@@H]1C)CC)[C@@]12CC[C@H](C)[C@H](C[C@@H](C)O)O1 MNULEGDCPYONBU-AWJDAWNUSA-N 0.000 description 1
- 238000012346 open field test Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001769 paralizing effect Effects 0.000 description 1
- 230000001936 parietal effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 210000001716 patrolling monocyte Anatomy 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 210000001986 peyer's patch Anatomy 0.000 description 1
- 101150079312 pgk1 gene Proteins 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 210000000557 podocyte Anatomy 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000036544 posture Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 108010045647 puromycin N-acetyltransferase Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 108010054624 red fluorescent protein Proteins 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 231100001028 renal lesion Toxicity 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000003161 ribonuclease inhibitor Substances 0.000 description 1
- 229940080817 rotenone Drugs 0.000 description 1
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 1
- RHFUOMFWUGWKKO-UHFFFAOYSA-N s2C Natural products S=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 RHFUOMFWUGWKKO-UHFFFAOYSA-N 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000037152 sensory function Effects 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 231100001055 skeletal defect Toxicity 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 210000003478 temporal lobe Anatomy 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- TUGDLVFMIQZYPA-UHFFFAOYSA-N tetracopper;tetrazinc Chemical compound [Cu+2].[Cu+2].[Cu+2].[Cu+2].[Zn+2].[Zn+2].[Zn+2].[Zn+2] TUGDLVFMIQZYPA-UHFFFAOYSA-N 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- HDZZVAMISRMYHH-KCGFPETGSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O HDZZVAMISRMYHH-KCGFPETGSA-N 0.000 description 1
- 210000004926 tubular epithelial cell Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000005089 vacuolized cytoplasm Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 210000004340 zona pellucida Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/027—New breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0276—Knockout animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/02—Breeding vertebrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/90—Stable introduction of foreign DNA into chromosome
- C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
- C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0306—Animal model for genetic diseases
- A01K2267/0318—Animal model for neurodegenerative disease, e.g. non- Alzheimer's
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
- A01K2267/0381—Animal model for diseases of the hematopoietic system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0393—Animal model comprising a reporter system for screening tests
Abstract
Description
本願は、2015年5月29日に出願された米国仮出願第62/168,171号、2015年9月25日に出願された米国仮出願第62/232,658号、および2015年10月23日に出願された米国仮出願第62/245,382号からの優先権の利益を主張し、これらの内容全体が本明細書中に参照によって組み込まれる。
32698_10152US01_SequenceListingと名付けられた、56kbの、ASCIIテキストファイルによる配列表であって、2016年5月19日に作成され、EFS−Webを介して米国特許商標庁へと提出された配列表は、参照により本明細書に組み込まれる。
本発明は、本明細書で記載される特定の方法および実験条件に限定されるものではない。なぜなら、そのような方法および条件は変化しうるからである。本発明の範囲は、特許請求の範囲により規定されるので、本明細書で使用される用語法は、特定の実施形態について記載することだけを目的とするものであり、限定的であることを意図するものではないこともまた理解されたい。
ある特定の実施形態の詳細な説明
C9ORF72
C9ORF72配列
C9ORF72遺伝子座における破壊を有する非ヒト動物を利用する方法
(実施例1)
非ヒトC9ORF72遺伝子座における破壊の作出
C9orf72遺伝子座における破壊を有する非ヒト動物についての行動解析
C9orf72遺伝子座における破壊を有する非ヒト動物についての免疫表現型解析
(実施例4)
C9orf72遺伝子座における破壊を有する非ヒト動物への、神経毒素の投与
均等物
Claims (42)
- 齧歯動物であって、そのゲノム内に、C9orf72遺伝子座における全コード配列の欠失を含む齧歯動物。
- 前記欠失が、少なくともエクソン2〜11の全体または部分的な欠失を含む、請求項1に記載の齧歯動物。
- 前記C9orf72遺伝子座が、レポーター遺伝子を含む、前記請求項のいずれか一項に記載の齧歯動物。
- 前記レポーター遺伝子が、C9orf72プロモーターに作動可能に連結している、請求項3に記載の齧歯動物。
- 前記C9orf72プロモーターが、内因性プロモーターである、請求項4に記載の齧歯動物。
- 前記C9orf72遺伝子座が、エクソン2のコード部分〜エクソン11のコード部分を含むC9orf72ゲノム配列を欠き、レポーター遺伝子を含む、請求項3から5のいずれか一項に記載の齧歯動物。
- 前記レポーター遺伝子が、前記C9orf72遺伝子座のエクソン1に作動可能に連結している、請求項6に記載の齧歯動物。
- 前記レポーター遺伝子が、lacZ、ルシフェラーゼ、緑色蛍光タンパク質(GFP)、増強型GFP(eGFP)、シアン蛍光タンパク質(CFP)、黄色蛍光タンパク質(YFP)、増強型黄色蛍光タンパク質(eYFP)、青色蛍光タンパク質(BFP)、増強型青色蛍光タンパク質(eBFP)、DsRed、およびMmGFPからなる群から選択される、請求項3から7のいずれか一項に記載の齧歯動物。
- ラットまたはマウスである、前記請求項のいずれか一項に記載の齧歯動物。
- 前記欠失についてホモ接合性である、請求項1に記載の齧歯動物。
- 前記欠失についてヘテロ接合性である、請求項1に記載の齧歯動物。
- 発生の間、任意選択で、約36週齢となった後、または約40週齢となった後において、ALSおよび/またはFTDの1または複数の症状を発症する、請求項1から11のいずれか一項に記載の齧歯動物。
- 約36週齢となった後において、進行性の運動欠損を発症し、約40週齢となった後において、下位運動ニューロン病変を発症し、かつ/または約36週齢となった後において、体重の減少をきたす、請求項1から12のいずれか一項に記載の齧歯動物。
- 発生の間に、以下:
(i)運動ニューロンにおけるミトコンドリア機能不全であって、ミトコンドリア呼吸、基底呼吸、最大呼吸、予備呼吸能、ATP産生、およびプロトン漏出のうちの1もしくは複数の減少によって特徴付けられるか;または対照齧歯動物もしくは基準齧歯動物の運動ニューロンのミトコンドリアDNA対核DNA比と比較した、ミトコンドリアDNA対核DNA比の増加によって特徴付けられるミトコンドリア機能不全;
(ii)任意選択で、約35週齢となった後、または端点を含めて約35〜41週齢となった後の、糸球体腎炎の1または複数の症状;
(iii)約8週齢となった後の脾腫;
(iv)約8週齢となった後のリンパ節症であって、任意選択で、端点を含めて約12〜18週齢となった後の、触知可能であるリンパ節症;
(v)形質細胞、単球、顆粒球、およびF4/80+マクロファージのうちの1または複数の浸潤であって、任意選択で、約8週齢となった後の、かつ、60週齢までに検出可能である浸潤;
(vi)約35週齢となった後の、腎臓内のF4/80+マクロファージの浸潤;
(vii)約8週齢となった後の、IL−10、IL−12、IL−17、IFN−γ、TNF−α、およびMCP−1のうちの1または複数の血清サイトカインレベルの増加;
(viii)約8週齢となった後の、IL−12の血清レベルの増加であって、基準非ヒト動物または対照非ヒト動物と比較して、約6倍またはこれを超える増加;
(ix)端点を含めて約28〜35週齢となった後の、基底膜の肥厚、円柱形成、免疫複合体の沈着、膜増殖性糸球体腎炎、間質性単核球性炎症、糸球体硬化症、好塩基性尿細管、またはこれらの組合せによって特徴付けられる腎疾患;
(x)端点を含めて約28〜35週齢となった後の、脾臓、リンパ節、骨髄、腎臓、および血液のうちの1または複数における、骨髄系樹状細胞集団の増加であって、任意選択で、該骨髄系樹状細胞集団が、CD45+CD11b+CD11c+MHCII+として特徴付けられる増加;
(xi)約8週齢となった後の、1または複数の自己抗体の血清レベルの増加であって、任意選択で、1または複数の自己抗体が、抗リウマチ因子(抗RF)抗体、抗dsDNA抗体、抗核抗体(ANA)、抗スミス(抗Sm)抗体、抗カルジオリピン抗体、およびこれらの組合せから選択される増加;
(xii)端点を含めて約28〜35週齢となった後の、脾臓、リンパ節、骨髄、腎臓、および血液のうちの1または複数における、F4/80+マクロファージレベルの増加であって、任意選択で、該F4/80+マクロファージが、CD45+CD11b+F4/80+Ly6G−として特徴付けられる増加;
(xiii)端点を含めて約28〜35週齢となった後の、脾臓、リンパ節、骨髄、腎臓、および血液のうちの1または複数における、T細胞集団の増加であって、任意選択で、該T細胞集団が、CD8+CD44+、CD8+CD69+、CD8+PD1+、CD4+CD44+、CD4+CD69+またはCD4+PD1+として特徴付けられる増加;
(xiv)端点を含めて約28〜35週齢となった後の、脾臓および/もしくはリンパ節における、調節性T細胞集団の増加であって、該調節性T細胞集団が、CD4+FoxP3+として特徴付けられる増加;または約26週齢となった後の、脾臓、リンパ節、および/もしくは血液における、濾胞性ヘルパーT(Tfh)細胞の増加であって、該Tfh細胞集団が、CD4+CXCR5+CD44+ICOS+PD−1+Bcl−6+として特徴付けられる増加;
(xv)端点を含めて約8〜60週齢となった後の、脾臓、リンパ節、および骨髄のうちの1または複数における、形質細胞集団の増加であって、任意選択で、該形質細胞集団が、CD45+CD19−B220−CD138+またはCD45+CD19intB220intCD138+として特徴付けられる増加;
(xvi)自己免疫性リンパ増殖症候群(ALPS);あるいは
(xvii)発生の間におけるループス腎炎
のうちの1または複数を発症する、請求項1から12のいずれか一項に記載の齧歯動物。 - そのゲノムが、C9orf72遺伝子座における全コード配列の欠失を含む単離齧歯動物細胞または単離齧歯動物組織。
- 請求項15に記載の単離齧歯動物細胞から作製された不死化細胞株。
- 齧歯動物胚性幹細胞であって、そのゲノムが、C9orf72遺伝子座における全コード配列の欠失を含む齧歯動物胚性幹細胞。
- 請求項17に記載の胚性幹細胞から生み出された齧歯動物胚。
- 齧歯動物のゲノムが、C9orf72遺伝子座における全コード配列の欠失を含む齧歯動物を作製する方法であって、
齧歯動物の該ゲノムを、それが、C9orf72遺伝子座における全コード配列の欠失を含むように改変し、これにより、該齧歯動物を作製するステップ
を含む方法。 - 前記改変するステップを、
(a)C9orf72遺伝子座における全コード配列を欠失させるように、核酸配列を、齧歯動物胚性幹細胞へと導入するステップであって、核酸配列が、該C9orf72遺伝子座と相同なポリヌクレオチドを含むステップと;
(b)(a)から、遺伝子改変された齧歯動物胚性幹細胞を得るステップと;
(c)(b)の、該遺伝子改変された齧歯動物胚性幹細胞を使用して、齧歯動物を作り出すステップと
を含むプロセスにより達成する、請求項19に記載の方法。 - 前記核酸配列が、1または複数の選択マーカーを含む、請求項20に記載の方法。
- 前記核酸配列が、1または複数の部位特異的組換え部位を含む、請求項20または21に記載の方法。
- 前記核酸配列が、切出しを導くように配向させたリコンビナーゼ認識部位に挟まれた、リコンビナーゼ遺伝子と選択マーカーとを含む、請求項22に記載の方法。
- 前記核酸配列が、任意選択で前記選択マーカーの下流にあるレポーター遺伝子をさらに含む、請求項23に記載の方法。
- 前記リコンビナーゼ遺伝子が、分化細胞内の該リコンビナーゼ遺伝子の発現は駆動するが、未分化細胞内の該リコンビナーゼ遺伝子の発現は駆動しないプロモーターに作動可能に連結している、請求項24に記載の方法。
- 前記リコンビナーゼ遺伝子が、転写的にコンピテントであり、発生的に調節されたプロモーターに作動可能に連結している、請求項24に記載の方法。
- 前記プロモーターが、配列番号5、配列番号6、または配列番号7であるかまたはこれを含む、請求項26に記載の方法。
- 前記欠失についてホモ接合性の齧歯動物を作り出すように、(c)において生み出された前記齧歯動物を交配させるステップをさらに含む、請求項20から27のいずれか一項に記載の方法。
- 前記欠失が、少なくともエクソン2〜11の全体または部分的な欠失を含む、請求項19または20に記載の方法。
- 前記欠失が、エクソン2のコード部分〜エクソン11のコード部分を含む、請求項29に記載の方法。
- 前記C9orf72遺伝子座が、レポーター遺伝子を含む、請求項29または30に記載の方法。
- 前記レポーター遺伝子が、C9orf72プロモーターに作動可能に連結している、請求項31に記載の方法。
- 前記C9orf72プロモーターが、内因性プロモーターである、請求項32に記載の方法。
- 前記C9orf72遺伝子座が、エクソン2〜10を欠き、レポーター遺伝子を含む、請求項31から33のいずれか一項に記載の方法。
- 前記レポーター遺伝子が、前記C9orf72遺伝子座のエクソン1に作動可能に連結している、請求項34に記載の方法。
- 前記レポーター遺伝子が、lacZ、ルシフェラーゼ、GFP、eGFP、CFP、YFP、eYFP、BFP、eBFP、DsRed、およびMmGFPからなる群から選択される、請求項32から35のいずれか一項に記載の方法。
- 前記齧歯動物が、ラットまたはマウスである、請求項19から36のいずれか一項に記載の方法。
- 請求項19から37のいずれか一項に記載の方法により得ることができる齧歯動物。
- 齧歯動物における疾患または状態を処置するための、治療剤候補を同定する方法であって、
(a)候補薬剤を、請求項1から14のいずれか一項に記載の齧歯動物へと投与するステップと;
(b)1または複数のアッセイを実施して、該候補薬剤が、該疾患または状態と関連する1または複数の徴候、症状、および/または状態に対して効果を有するのかどうかを決定するステップと;
(c)該疾患または状態と関連する、該1または複数の徴候、症状、および/または状態に対して効果を有する該候補薬剤を、該治療剤候補として同定するステップと
を含む方法。 - 前記疾患または状態が、神経変性疾患または神経変性状態、炎症性疾患または炎症性状態、自己免疫疾患または自己免疫状態、全身性エリテマトーデス(SLE)、自己免疫性リンパ増殖症候群(ALPS)、およびループス腎炎からなる群から選択される、請求項39に記載の方法。
- ALPSが、IL−10、抗リウマチ因子(抗RF)抗体、抗核抗体(ANA)、またはこれらの組合せの血清レベルの増加によって特徴付けられ;ループス腎炎が、メサンギウムの増殖および/もしくは拡大、または1もしくは複数の尿細管異常によって特徴付けられる、請求項40に記載の方法。
- 前記神経変性疾患もしくは神経変性状態が、筋萎縮性側索硬化症(ALS)もしくは前頭側頭型認知症(FTD)であるか、前記炎症性疾患もしくは炎症性状態が、糸球体腎炎であるか、または前記自己免疫疾患もしくは自己免疫状態が、糸球体腎炎である、請求項40に記載の方法。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562168171P | 2015-05-29 | 2015-05-29 | |
US62/168,171 | 2015-05-29 | ||
US201562232658P | 2015-09-25 | 2015-09-25 | |
US62/232,658 | 2015-09-25 | ||
US201562245382P | 2015-10-23 | 2015-10-23 | |
US62/245,382 | 2015-10-23 | ||
PCT/US2016/034304 WO2016196185A1 (en) | 2015-05-29 | 2016-05-26 | Non-human animals having a disruption in a c9orf72 locus |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019163680A Division JP6884831B2 (ja) | 2015-05-29 | 2019-09-09 | C9orf72遺伝子座における破壊を有する非ヒト動物 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018518165A true JP2018518165A (ja) | 2018-07-12 |
JP2018518165A5 JP2018518165A5 (ja) | 2019-06-27 |
JP6619822B2 JP6619822B2 (ja) | 2019-12-11 |
Family
ID=56194557
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017561678A Active JP6619822B2 (ja) | 2015-05-29 | 2016-05-26 | C9orf72遺伝子座における破壊を有する非ヒト動物 |
JP2019163680A Active JP6884831B2 (ja) | 2015-05-29 | 2019-09-09 | C9orf72遺伝子座における破壊を有する非ヒト動物 |
JP2021080959A Withdrawn JP2021118745A (ja) | 2015-05-29 | 2021-05-12 | C9orf72遺伝子座における破壊を有する非ヒト動物 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019163680A Active JP6884831B2 (ja) | 2015-05-29 | 2019-09-09 | C9orf72遺伝子座における破壊を有する非ヒト動物 |
JP2021080959A Withdrawn JP2021118745A (ja) | 2015-05-29 | 2021-05-12 | C9orf72遺伝子座における破壊を有する非ヒト動物 |
Country Status (15)
Country | Link |
---|---|
US (2) | US10285388B2 (ja) |
EP (2) | EP3302048B1 (ja) |
JP (3) | JP6619822B2 (ja) |
KR (2) | KR102190661B1 (ja) |
CN (1) | CN107920498A (ja) |
AU (2) | AU2016270587B2 (ja) |
BR (1) | BR112017025507A2 (ja) |
CA (1) | CA2986048C (ja) |
ES (1) | ES2784360T3 (ja) |
HK (1) | HK1248465A1 (ja) |
IL (2) | IL255385A0 (ja) |
MX (1) | MX2017015369A (ja) |
RU (2) | RU2725737C2 (ja) |
SG (1) | SG10201911257YA (ja) |
WO (1) | WO2016196185A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2018007840A (es) * | 2015-12-23 | 2019-05-02 | Crispr Therapeutics Ag | Materiales y metodos para el tratamiento de la esclerosis lateral amiotrofica y/o la degeneracion lobar frontotemporal. |
JP7026678B2 (ja) | 2016-09-30 | 2022-02-28 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | C9orf72座位中にヘキサヌクレオチドリピート伸長を有する非ヒト動物 |
AU2017394032B8 (en) | 2017-01-21 | 2020-10-22 | Guangzhou Hanfang Pharmaceutical Co., Ltd. | Use of paeoniflorin-6'-o-benzenesulfonate in treatment of sjögren's syndrome |
CN107693542B (zh) * | 2017-09-05 | 2020-03-10 | 中山大学附属第三医院 | 一种系统性红斑狼疮动物模型的构建方法及其应用 |
CN109452229B (zh) * | 2018-11-19 | 2021-10-22 | 百奥赛图(北京)医药科技股份有限公司 | 狗源化pd-1基因改造动物模型的制备方法及应用 |
WO2020131632A1 (en) | 2018-12-20 | 2020-06-25 | Regeneron Pharmaceuticals, Inc. | Nuclease-mediated repeat expansion |
CN113046390B (zh) * | 2020-03-09 | 2024-01-09 | 百奥赛图江苏基因生物技术有限公司 | Csf1r基因人源化的非人动物及其构建方法和应用 |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5523226A (en) | 1993-05-14 | 1996-06-04 | Biotechnology Research And Development Corp. | Transgenic swine compositions and methods |
US5670356A (en) | 1994-12-12 | 1997-09-23 | Promega Corporation | Modified luciferase |
US5874304A (en) | 1996-01-18 | 1999-02-23 | University Of Florida Research Foundation, Inc. | Humanized green fluorescent protein genes and methods |
WO1999005266A2 (en) | 1997-07-26 | 1999-02-04 | Wisconsin Alumni Research Foundation | Trans-species nuclear transfer |
US6586251B2 (en) | 2000-10-31 | 2003-07-01 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US20050144655A1 (en) | 2000-10-31 | 2005-06-30 | Economides Aris N. | Methods of modifying eukaryotic cells |
US6596541B2 (en) | 2000-10-31 | 2003-07-22 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US7105348B2 (en) | 2000-10-31 | 2006-09-12 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
AUPR451401A0 (en) | 2001-04-20 | 2001-05-24 | Monash University | A method of nuclear transfer |
US7612250B2 (en) | 2002-07-29 | 2009-11-03 | Trustees Of Tufts College | Nuclear transfer embryo formation method |
SI1802193T1 (sl) | 2004-10-19 | 2014-08-29 | Regeneron Pharmaceuticals, Inc. | Postopek za generiranje miši, homozigotne za genetsko modifikacijo |
CN101117633B (zh) | 2006-08-03 | 2011-07-20 | 上海交通大学附属儿童医院 | 一种细胞核移植方法 |
JP2008307007A (ja) * | 2007-06-15 | 2008-12-25 | Bayer Schering Pharma Ag | 出生後のヒト組織由来未分化幹細胞から誘導したヒト多能性幹細胞 |
DK3064599T3 (en) | 2008-02-15 | 2019-04-08 | Synthetic Genomics Inc | METHODS IN VITRO FOR COMBINING AND COMBINATORY CONSTRUCTION OF NUCLEIC ACID MOLECULES |
US8470594B2 (en) * | 2008-04-15 | 2013-06-25 | President And Fellows Of Harvard College | Methods for identifying agents that affect the survival of motor neurons |
RU2425880C2 (ru) * | 2009-07-30 | 2011-08-10 | Учреждение Российской академии наук Институт общей генетики им. Н.И. Вавилова РАН | Способ получения трансгенных мышей |
WO2011020005A1 (en) | 2009-08-14 | 2011-02-17 | Regeneron Pharmaceuticals, Inc. | miRNA-REGULATED DIFFERENTIATION-DEPENDENT SELF-DELETING CASSETTE |
KR20120050485A (ko) | 2009-08-14 | 2012-05-18 | 레비비코르 인코포레이션 | 당뇨병 치료를 위한 복수 형질전환 돼지 |
EP3202914B2 (en) * | 2011-08-31 | 2023-06-28 | The University of Manchester | Method for treating a neurodegenerative disease |
WO2013041577A1 (en) * | 2011-09-20 | 2013-03-28 | Vib Vzw | Methods for the diagnosis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration |
DK2847335T3 (en) | 2012-04-25 | 2018-08-13 | Regeneron Pharma | NUCLEASED MEDIUM TARGETING WITH LARGE TARGET VECTORS |
EP2906697A4 (en) | 2012-10-15 | 2016-06-22 | Ionis Pharmaceuticals Inc | METHODS OF MONITORING C9ORF72 EXPRESSION |
FI2906696T4 (fi) | 2012-10-15 | 2023-03-18 | Menetelmiä c9orf72:n ilmentymisen moduloimiseksi | |
US8697359B1 (en) | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
EP3561050B1 (en) | 2013-02-20 | 2021-12-08 | Regeneron Pharmaceuticals, Inc. | Genetic modification of rats |
ES2888250T3 (es) | 2013-04-16 | 2022-01-03 | Regeneron Pharma | Modificación direccionada del genoma de rata |
KR102251168B1 (ko) | 2013-10-25 | 2021-05-13 | 셀렉티스 | 고 반복 모티프를 포함하는 dna 서열에 대한 효율적이고 특이적인 표적화를 위한 희소-절단 엔도뉴클레아제의 설계 |
AU2014362248A1 (en) | 2013-12-12 | 2016-06-16 | Massachusetts Institute Of Technology | Compositions and methods of use of CRISPR-Cas systems in nucleotide repeat disorders |
EP3750907A3 (en) | 2014-03-18 | 2021-04-28 | University of Massachusetts | Raav-based compositions and methods for treating amyotrophic lateral sclerosis |
WO2015153760A2 (en) | 2014-04-01 | 2015-10-08 | Sangamo Biosciences, Inc. | Methods and compositions for prevention or treatment of a nervous system disorder |
CA2953499C (en) | 2014-06-23 | 2023-10-24 | Regeneron Pharmaceuticals, Inc. | Nuclease-mediated dna assembly |
HUE041584T2 (hu) | 2014-06-26 | 2019-05-28 | Regeneron Pharma | Célzott genetikai módosítások és alkalmazási módszerek és készítmények |
AU2015349692B2 (en) | 2014-11-21 | 2021-10-28 | Regeneron Pharmaceuticals, Inc. | Methods and compositions for targeted genetic modification using paired guide RNAs |
KR102313073B1 (ko) | 2014-12-05 | 2021-10-18 | 리제너론 파마슈티칼스 인코포레이티드 | 인간화 분화 클러스터 47 유전자를 가진 비인간 동물 |
BR112017013104A2 (pt) | 2014-12-19 | 2018-05-15 | Regeneron Pharma | métodos para modificar um locus genômico alvo em uma célula, para intensificar a recombinação homóloga em um locus genômico alvo em uma célula e para produzir uma geração f0 de um animal não humano. |
US10793855B2 (en) | 2015-01-06 | 2020-10-06 | Ionis Pharmaceuticals, Inc. | Compositions for modulating expression of C9ORF72 antisense transcript |
WO2016174056A1 (en) | 2015-04-27 | 2016-11-03 | Genethon | Compositions and methods for the treatment of nucleotide repeat expansion disorders |
DK3289076T3 (da) | 2015-05-01 | 2022-01-17 | Prec Biosciences Inc | Præcis sletning af kromosomale sekvenser in vivo |
CA3035810A1 (en) | 2015-09-02 | 2017-03-09 | University Of Massachusetts | Detection of gene loci with crispr arrayed repeats and/or polychromatic single guide ribonucleic acids |
MX2018007840A (es) | 2015-12-23 | 2019-05-02 | Crispr Therapeutics Ag | Materiales y metodos para el tratamiento de la esclerosis lateral amiotrofica y/o la degeneracion lobar frontotemporal. |
WO2017178590A1 (en) | 2016-04-14 | 2017-10-19 | Université de Lausanne | Treatment and/or prevention of dna-triplet repeat diseases or disorders |
WO2018022480A1 (en) | 2016-07-25 | 2018-02-01 | Mayo Foundation For Medical Education And Research | Treating cancer |
JP7026678B2 (ja) | 2016-09-30 | 2022-02-28 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | C9orf72座位中にヘキサヌクレオチドリピート伸長を有する非ヒト動物 |
WO2018078134A1 (en) | 2016-10-28 | 2018-05-03 | Genethon | Compositions and methods for the treatment of myotonic dystrophy |
WO2018078131A1 (en) | 2016-10-28 | 2018-05-03 | Genethon | Compositions and methods for the treatment of myotonic dystrophy |
EP3592365A4 (en) | 2017-03-10 | 2021-01-13 | The Board Of Regents Of The University Of Texas System | TREATMENT OF ENDOTHELIAL CORNEAL DYSTROPHY OF FUCHS |
JP7327803B2 (ja) | 2017-05-09 | 2023-08-16 | ユニバーシティ オブ マサチューセッツ | 筋萎縮性側索硬化症(als)を処置する方法 |
AU2018355343A1 (en) | 2017-10-24 | 2020-05-07 | Sangamo Therapeutics, Inc. | Methods and compositions for the treatment of rare diseases |
BR112020025306A2 (pt) * | 2018-06-18 | 2021-03-09 | Denali Therapeutics Inc. | Proteínas de fusão compreendendo progranulina |
-
2016
- 2016-05-26 WO PCT/US2016/034304 patent/WO2016196185A1/en active Application Filing
- 2016-05-26 CA CA2986048A patent/CA2986048C/en active Active
- 2016-05-26 BR BR112017025507-3A patent/BR112017025507A2/pt active Search and Examination
- 2016-05-26 KR KR1020177037383A patent/KR102190661B1/ko active IP Right Grant
- 2016-05-26 EP EP16731693.4A patent/EP3302048B1/en active Active
- 2016-05-26 RU RU2017145143A patent/RU2725737C2/ru active
- 2016-05-26 JP JP2017561678A patent/JP6619822B2/ja active Active
- 2016-05-26 RU RU2020115485A patent/RU2020115485A/ru unknown
- 2016-05-26 CN CN201680031520.6A patent/CN107920498A/zh active Pending
- 2016-05-26 EP EP20158032.1A patent/EP3689139A1/en active Pending
- 2016-05-26 AU AU2016270587A patent/AU2016270587B2/en active Active
- 2016-05-26 SG SG10201911257YA patent/SG10201911257YA/en unknown
- 2016-05-26 KR KR1020207035238A patent/KR102377189B1/ko active IP Right Grant
- 2016-05-26 MX MX2017015369A patent/MX2017015369A/es unknown
- 2016-05-26 ES ES16731693T patent/ES2784360T3/es active Active
- 2016-05-26 US US15/165,307 patent/US10285388B2/en active Active
-
2017
- 2017-11-01 IL IL255385A patent/IL255385A0/en active IP Right Grant
-
2018
- 2018-06-08 HK HK18107516.0A patent/HK1248465A1/zh unknown
-
2019
- 2019-03-27 US US16/366,826 patent/US11547101B2/en active Active
- 2019-09-09 JP JP2019163680A patent/JP6884831B2/ja active Active
-
2021
- 2021-03-24 AU AU2021201827A patent/AU2021201827B2/en active Active
- 2021-05-12 JP JP2021080959A patent/JP2021118745A/ja not_active Withdrawn
- 2021-09-05 IL IL286176A patent/IL286176A/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6884831B2 (ja) | C9orf72遺伝子座における破壊を有する非ヒト動物 | |
JP7193509B2 (ja) | 上位及び下位運動ニューロン機能並びに知覚の減衰を示す非ヒト動物 | |
KR20210005661A (ko) | 변형된 아미노펩티다제 n(anpep) 유전자를 갖는 병원체-내성 동물 | |
NZ737000B2 (en) | Non-human animals having a disruption in a c9orf72 locus | |
JP2012200249A (ja) | コンディショナルノックアウト動物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190523 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190523 |
|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20190523 |
|
A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20190605 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190614 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190909 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20191112 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20191115 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6619822 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |