JP6745826B2 - 改善されたウイルスによる形質導入のための化合物 - Google Patents
改善されたウイルスによる形質導入のための化合物 Download PDFInfo
- Publication number
- JP6745826B2 JP6745826B2 JP2018017184A JP2018017184A JP6745826B2 JP 6745826 B2 JP6745826 B2 JP 6745826B2 JP 2018017184 A JP2018017184 A JP 2018017184A JP 2018017184 A JP2018017184 A JP 2018017184A JP 6745826 B2 JP6745826 B2 JP 6745826B2
- Authority
- JP
- Japan
- Prior art keywords
- cells
- cell
- virus
- stem cells
- transduced
- 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.)
- Expired - Fee Related
Links
- 238000010361 transduction Methods 0.000 title claims description 84
- 230000026683 transduction Effects 0.000 title claims description 84
- 150000001875 compounds Chemical class 0.000 title description 102
- 230000003612 virological effect Effects 0.000 title description 58
- 230000001976 improved effect Effects 0.000 title description 8
- 210000004027 cell Anatomy 0.000 claims description 582
- 239000013598 vector Substances 0.000 claims description 172
- 210000003958 hematopoietic stem cell Anatomy 0.000 claims description 149
- 238000000034 method Methods 0.000 claims description 141
- 230000014509 gene expression Effects 0.000 claims description 96
- 108090000623 proteins and genes Proteins 0.000 claims description 96
- 108091033319 polynucleotide Proteins 0.000 claims description 93
- 239000002157 polynucleotide Substances 0.000 claims description 93
- 102000040430 polynucleotide Human genes 0.000 claims description 93
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 91
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 88
- 229920001184 polypeptide Polymers 0.000 claims description 84
- 241000700605 Viruses Species 0.000 claims description 65
- 238000004806 packaging method and process Methods 0.000 claims description 47
- 241000713666 Lentivirus Species 0.000 claims description 40
- 108091005904 Hemoglobin subunit beta Proteins 0.000 claims description 35
- 108020004414 DNA Proteins 0.000 claims description 33
- 102100021519 Hemoglobin subunit beta Human genes 0.000 claims description 33
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 33
- QAOBBBBDJSWHMU-WMBBNPMCSA-N 16,16-dimethylprostaglandin E2 Chemical compound CCCCC(C)(C)[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O QAOBBBBDJSWHMU-WMBBNPMCSA-N 0.000 claims description 30
- -1 /or Species 0.000 claims description 25
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 24
- 230000001965 increasing effect Effects 0.000 claims description 20
- 238000012258 culturing Methods 0.000 claims description 16
- 239000012212 insulator Substances 0.000 claims description 15
- 230000008488 polyadenylation Effects 0.000 claims description 15
- 238000000338 in vitro Methods 0.000 claims description 14
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims description 13
- 108700001624 vesicular stomatitis virus G Proteins 0.000 claims description 13
- 230000010076 replication Effects 0.000 claims description 12
- 239000001963 growth medium Substances 0.000 claims description 11
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 10
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 claims description 9
- 229960000237 vorinostat Drugs 0.000 claims description 9
- 101710091045 Envelope protein Proteins 0.000 claims description 8
- 102000003964 Histone deacetylase Human genes 0.000 claims description 8
- 108090000353 Histone deacetylase Proteins 0.000 claims description 8
- 101710188315 Protein X Proteins 0.000 claims description 8
- 229930189037 Trapoxin Natural products 0.000 claims description 8
- 230000002950 deficient Effects 0.000 claims description 8
- 108010060597 trapoxin A Proteins 0.000 claims description 8
- 229960000604 valproic acid Drugs 0.000 claims description 8
- 108010027178 cyclic hydroxamic acid-containing peptide 1 Proteins 0.000 claims description 7
- 239000003102 growth factor Substances 0.000 claims description 6
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 6
- 101000760602 Homo sapiens ATP-binding cassette sub-family D member 1 Proteins 0.000 claims description 5
- 108091027981 Response element Proteins 0.000 claims description 5
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 claims description 5
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical group ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 claims description 5
- 108010002156 Depsipeptides Proteins 0.000 claims description 4
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 claims description 4
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 claims description 4
- 102000047168 human ABCD1 Human genes 0.000 claims description 4
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 claims description 4
- 229960005184 panobinostat Drugs 0.000 claims description 4
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 4
- 229960002232 sodium phenylbutyrate Drugs 0.000 claims description 4
- VPZRWNZGLKXFOE-UHFFFAOYSA-M sodium phenylbutyrate Chemical compound [Na+].[O-]C(=O)CCCC1=CC=CC=C1 VPZRWNZGLKXFOE-UHFFFAOYSA-M 0.000 claims description 4
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims 4
- 102100027723 Endogenous retrovirus group K member 6 Rec protein Human genes 0.000 claims 1
- 210000000130 stem cell Anatomy 0.000 description 123
- 239000000203 mixture Substances 0.000 description 106
- 150000003180 prostaglandins Chemical class 0.000 description 82
- 102000008866 Prostaglandin E receptors Human genes 0.000 description 70
- 108010088540 Prostaglandin E receptors Proteins 0.000 description 70
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 56
- 241001430294 unidentified retrovirus Species 0.000 description 54
- 238000001415 gene therapy Methods 0.000 description 53
- 230000011664 signaling Effects 0.000 description 53
- 230000001177 retroviral effect Effects 0.000 description 46
- 230000001225 therapeutic effect Effects 0.000 description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 35
- 150000007523 nucleic acids Chemical class 0.000 description 30
- 239000002245 particle Substances 0.000 description 30
- 239000003623 enhancer Substances 0.000 description 29
- 102000039446 nucleic acids Human genes 0.000 description 29
- 108020004707 nucleic acids Proteins 0.000 description 29
- 238000011282 treatment Methods 0.000 description 29
- 239000013603 viral vector Substances 0.000 description 29
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 28
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 28
- 210000001519 tissue Anatomy 0.000 description 28
- 208000015181 infectious disease Diseases 0.000 description 25
- 238000012546 transfer Methods 0.000 description 25
- 201000010099 disease Diseases 0.000 description 24
- 239000013612 plasmid Substances 0.000 description 24
- 102000004169 proteins and genes Human genes 0.000 description 24
- 235000018102 proteins Nutrition 0.000 description 23
- 101000899111 Homo sapiens Hemoglobin subunit beta Proteins 0.000 description 22
- 239000000556 agonist Substances 0.000 description 22
- 210000003743 erythrocyte Anatomy 0.000 description 22
- 230000019491 signal transduction Effects 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 108060003196 globin Proteins 0.000 description 20
- 238000001727 in vivo Methods 0.000 description 20
- 208000007056 sickle cell anemia Diseases 0.000 description 20
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- 230000002159 abnormal effect Effects 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 17
- 208000018706 hematopoietic system disease Diseases 0.000 description 17
- 208000034737 hemoglobinopathy Diseases 0.000 description 17
- 125000003275 alpha amino acid group Chemical group 0.000 description 16
- 238000009472 formulation Methods 0.000 description 16
- 230000001105 regulatory effect Effects 0.000 description 16
- 239000003814 drug Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 102100024643 ATP-binding cassette sub-family D member 1 Human genes 0.000 description 14
- 210000001185 bone marrow Anatomy 0.000 description 14
- 102000018146 globin Human genes 0.000 description 14
- 230000037361 pathway Effects 0.000 description 14
- 201000011452 Adrenoleukodystrophy Diseases 0.000 description 13
- 102100039064 Interleukin-3 Human genes 0.000 description 13
- 108010049137 Member 1 Subfamily D ATP Binding Cassette Transporter Proteins 0.000 description 13
- 208000005980 beta thalassemia Diseases 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 238000012217 deletion Methods 0.000 description 13
- 230000037430 deletion Effects 0.000 description 13
- 239000002609 medium Substances 0.000 description 13
- 230000004048 modification Effects 0.000 description 13
- 238000012986 modification Methods 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 238000012384 transportation and delivery Methods 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 12
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 11
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 11
- 102000036693 Thrombopoietin Human genes 0.000 description 11
- 108010041111 Thrombopoietin Proteins 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 230000001919 adrenal effect Effects 0.000 description 11
- 230000008901 benefit Effects 0.000 description 11
- 239000006143 cell culture medium Substances 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 239000005090 green fluorescent protein Substances 0.000 description 11
- 239000002243 precursor Substances 0.000 description 11
- 230000006798 recombination Effects 0.000 description 11
- 238000005215 recombination Methods 0.000 description 11
- 238000006467 substitution reaction Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 238000013518 transcription Methods 0.000 description 11
- 230000035897 transcription Effects 0.000 description 11
- 102100027685 Hemoglobin subunit alpha Human genes 0.000 description 10
- 108010054147 Hemoglobins Proteins 0.000 description 10
- 102000001554 Hemoglobins Human genes 0.000 description 10
- 102100034349 Integrase Human genes 0.000 description 10
- 208000002903 Thalassemia Diseases 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- 210000000267 erythroid cell Anatomy 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 230000002458 infectious effect Effects 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 230000010354 integration Effects 0.000 description 10
- 210000000440 neutrophil Anatomy 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 108091005902 Hemoglobin subunit alpha Proteins 0.000 description 9
- 201000006288 alpha thalassemia Diseases 0.000 description 9
- 210000000601 blood cell Anatomy 0.000 description 9
- 238000004113 cell culture Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003937 drug carrier Substances 0.000 description 9
- 210000003593 megakaryocyte Anatomy 0.000 description 9
- 230000002463 transducing effect Effects 0.000 description 9
- 108020004635 Complementary DNA Proteins 0.000 description 8
- 241000701022 Cytomegalovirus Species 0.000 description 8
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 8
- 108091005886 Hemoglobin subunit gamma Proteins 0.000 description 8
- 102100038617 Hemoglobin subunit gamma-2 Human genes 0.000 description 8
- 101001009007 Homo sapiens Hemoglobin subunit alpha Proteins 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 241000714474 Rous sarcoma virus Species 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000010804 cDNA synthesis Methods 0.000 description 8
- 239000002299 complementary DNA Substances 0.000 description 8
- 229960002986 dinoprostone Drugs 0.000 description 8
- 230000003394 haemopoietic effect Effects 0.000 description 8
- 238000003780 insertion Methods 0.000 description 8
- 230000037431 insertion Effects 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 8
- 210000002540 macrophage Anatomy 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 201000001119 neuropathy Diseases 0.000 description 8
- 230000007823 neuropathy Effects 0.000 description 8
- 208000033808 peripheral neuropathy Diseases 0.000 description 8
- 230000001124 posttranscriptional effect Effects 0.000 description 8
- 230000000069 prophylactic effect Effects 0.000 description 8
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 8
- 150000003384 small molecules Chemical class 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 238000001890 transfection Methods 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- 108090000397 Caspase 3 Proteins 0.000 description 7
- 102100029855 Caspase-3 Human genes 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 101001033279 Homo sapiens Interleukin-3 Proteins 0.000 description 7
- 108010091086 Recombinases Proteins 0.000 description 7
- 102000018120 Recombinases Human genes 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 125000000539 amino acid group Chemical group 0.000 description 7
- 208000007502 anemia Diseases 0.000 description 7
- 210000003719 b-lymphocyte Anatomy 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 210000001671 embryonic stem cell Anatomy 0.000 description 7
- 208000014951 hematologic disease Diseases 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 239000002773 nucleotide Substances 0.000 description 7
- 125000003729 nucleotide group Chemical group 0.000 description 7
- 230000032258 transport Effects 0.000 description 7
- VJGGHXVGBSZVMZ-QIZQQNKQSA-N Cloprostenol Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)OC1=CC=CC(Cl)=C1 VJGGHXVGBSZVMZ-QIZQQNKQSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 6
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 6
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 6
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 6
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 6
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 6
- 108010002386 Interleukin-3 Proteins 0.000 description 6
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 6
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 6
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 6
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 6
- 241000713869 Moloney murine leukemia virus Species 0.000 description 6
- 102100029215 Signaling lymphocytic activation molecule Human genes 0.000 description 6
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 6
- 230000002411 adverse Effects 0.000 description 6
- 210000003651 basophil Anatomy 0.000 description 6
- 230000004071 biological effect Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229950008654 butaprost Drugs 0.000 description 6
- 210000004443 dendritic cell Anatomy 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 229940126864 fibroblast growth factor Drugs 0.000 description 6
- 229940029303 fibroblast growth factor-1 Drugs 0.000 description 6
- 229940076264 interleukin-3 Drugs 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 6
- 235000020778 linoleic acid Nutrition 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 210000004698 lymphocyte Anatomy 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 6
- XRISENIKJUKIHD-LHQZMKCDSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(e,4r)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentyl]heptanoate Chemical compound CCCC1([C@H](O)C\C=C\[C@@H]2[C@H](C(=O)C[C@H]2O)CCCCCCC(=O)OC)CCC1 XRISENIKJUKIHD-LHQZMKCDSA-N 0.000 description 6
- 210000000274 microglia Anatomy 0.000 description 6
- 210000001616 monocyte Anatomy 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 6
- 230000029812 viral genome replication Effects 0.000 description 6
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 5
- LLVVDFDWPQHXBA-QEJIITRLSA-N 11-Deoxy-16,16-dimethyl-PGE2 Chemical compound CCCCC(C)(C)[C@H](O)\C=C\[C@H]1CCC(=O)[C@@H]1C\C=C/CCCC(O)=O LLVVDFDWPQHXBA-QEJIITRLSA-N 0.000 description 5
- XSGQFHNPNWBVPT-DSFPJDRCSA-N 15-Methyl-15S-PGE2 Chemical compound CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XSGQFHNPNWBVPT-DSFPJDRCSA-N 0.000 description 5
- XSGQFHNPNWBVPT-VFXMVCAWSA-N 15-methyl-15R-PGE2 Chemical compound CCCCC[C@@](C)(O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XSGQFHNPNWBVPT-VFXMVCAWSA-N 0.000 description 5
- DXWJXQSQVUJRNS-YYWARMNLSA-N 16-Phenyl-tetranor-PGE2 Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H](C(=O)C[C@H]1O)C\C=C/CCCC(O)=O)C1=CC=CC=C1 DXWJXQSQVUJRNS-YYWARMNLSA-N 0.000 description 5
- DDLZLOKCJHBUHD-WAVHTBQISA-N 6-bromoindirubin-3'-oxime Chemical compound O=C/1NC2=CC(Br)=CC=C2C\1=C\1/C(=N/O)/C2=CC=CC=C2N/1 DDLZLOKCJHBUHD-WAVHTBQISA-N 0.000 description 5
- WMLGLMGSFIXSGO-KTXJXPLISA-N 9-Deoxy-9-methylene-16,16-dimethyl -PGE2 Chemical compound CCCCC(C)(C)[C@H](O)\C=C\[C@H]1[C@H](O)CC(=C)[C@@H]1C\C=C/CCCC(O)=O WMLGLMGSFIXSGO-KTXJXPLISA-N 0.000 description 5
- VKEJXDXJUFQESA-DLMPNJEASA-N 9-Deoxy-9-methylene-PGE2 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=C)[C@@H]1C\C=C/CCCC(O)=O VKEJXDXJUFQESA-DLMPNJEASA-N 0.000 description 5
- 241000713704 Bovine immunodeficiency virus Species 0.000 description 5
- 108020004705 Codon Proteins 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 241000713730 Equine infectious anemia virus Species 0.000 description 5
- 241000713800 Feline immunodeficiency virus Species 0.000 description 5
- 241000700586 Herpesviridae Species 0.000 description 5
- 208000026350 Inborn Genetic disease Diseases 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 5
- 241000713311 Simian immunodeficiency virus Species 0.000 description 5
- 241000700584 Simplexvirus Species 0.000 description 5
- 239000004473 Threonine Substances 0.000 description 5
- 108020004440 Thymidine kinase Proteins 0.000 description 5
- 108700019146 Transgenes Proteins 0.000 description 5
- 102000013814 Wnt Human genes 0.000 description 5
- 108050003627 Wnt Proteins 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000001994 activation Methods 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 210000001772 blood platelet Anatomy 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 210000004700 fetal blood Anatomy 0.000 description 5
- 208000016361 genetic disease Diseases 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 210000003897 hepatic stem cell Anatomy 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 210000001178 neural stem cell Anatomy 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 230000002207 retinal effect Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 210000002027 skeletal muscle Anatomy 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- UQZVCDCIMBLVNR-TWYODKAFSA-N sulprostone Chemical compound O[C@@H]1CC(=O)[C@H](C\C=C/CCCC(=O)NS(=O)(=O)C)[C@H]1\C=C\[C@@H](O)COC1=CC=CC=C1 UQZVCDCIMBLVNR-TWYODKAFSA-N 0.000 description 5
- 229960003400 sulprostone Drugs 0.000 description 5
- 229960002898 threonine Drugs 0.000 description 5
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 4
- JEJQBJWFMRKQJY-UHFFFAOYSA-N 12-methoxydodec-2-enoic acid Chemical compound COCCCCCCCCCC=CC(O)=O JEJQBJWFMRKQJY-UHFFFAOYSA-N 0.000 description 4
- WTJYDBMHYPQFNJ-ZUVVJKHESA-N 19R-Hydroxy-PGE2 Chemical compound C[C@@H](O)CCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O WTJYDBMHYPQFNJ-ZUVVJKHESA-N 0.000 description 4
- UMMADZJLZAPZAW-XOWPVRJPSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;(z)-7-[(1r,2r,3r,5s)-3,5-dihydroxy-2-[(e,3s)-3-hydroxy-3-methyloct-1-enyl]cyclopentyl]hept-5-enoic acid Chemical compound OCC(N)(CO)CO.CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O UMMADZJLZAPZAW-XOWPVRJPSA-N 0.000 description 4
- 102100027211 Albumin Human genes 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- 108700028369 Alleles Proteins 0.000 description 4
- 101800004538 Bradykinin Proteins 0.000 description 4
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 4
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 4
- 102100036008 CD48 antigen Human genes 0.000 description 4
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 4
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- ZXRVKCBLGJOCEE-UHFFFAOYSA-N Gaboxadol Chemical compound C1NCCC2=C1ONC2=O ZXRVKCBLGJOCEE-UHFFFAOYSA-N 0.000 description 4
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 4
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 4
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 4
- 239000012981 Hank's balanced salt solution Substances 0.000 description 4
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 4
- 101000716130 Homo sapiens CD48 antigen Proteins 0.000 description 4
- 101001035503 Homo sapiens Hemoglobin subunit delta Proteins 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 108090000467 Interferon-beta Proteins 0.000 description 4
- 102100035792 Kininogen-1 Human genes 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- 102100038082 Natural killer cell receptor 2B4 Human genes 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 4
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 4
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 4
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 108010052160 Site-specific recombinase Proteins 0.000 description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 4
- 102000006601 Thymidine Kinase Human genes 0.000 description 4
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 4
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 4
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000735 allogeneic effect Effects 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000001130 astrocyte Anatomy 0.000 description 4
- 229960002274 atenolol Drugs 0.000 description 4
- BTNNPSLJPBRMLZ-LGMDPLHJSA-N benfotiamine Chemical compound C=1C=CC=CC=1C(=O)SC(/CCOP(O)(O)=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N BTNNPSLJPBRMLZ-LGMDPLHJSA-N 0.000 description 4
- 229960002873 benfotiamine Drugs 0.000 description 4
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- PRQROPMIIGLWRP-BZSNNMDCSA-N chemotactic peptide Chemical compound CSCC[C@H](NC=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PRQROPMIIGLWRP-BZSNNMDCSA-N 0.000 description 4
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 4
- 229960002559 chlorotrianisene Drugs 0.000 description 4
- 229960001761 chlorpropamide Drugs 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 4
- 229960004042 diazoxide Drugs 0.000 description 4
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 4
- 239000002612 dispersion medium Substances 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 210000003979 eosinophil Anatomy 0.000 description 4
- 230000000925 erythroid effect Effects 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 229950004346 gaboxadol Drugs 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 210000003714 granulocyte Anatomy 0.000 description 4
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 210000005260 human cell Anatomy 0.000 description 4
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 description 4
- 229960002240 iloprost Drugs 0.000 description 4
- 210000004263 induced pluripotent stem cell Anatomy 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 229940124280 l-arginine Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 210000000822 natural killer cell Anatomy 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 229960001783 nicardipine Drugs 0.000 description 4
- 210000003924 normoblast Anatomy 0.000 description 4
- 210000000963 osteoblast Anatomy 0.000 description 4
- 210000005259 peripheral blood Anatomy 0.000 description 4
- 239000011886 peripheral blood Substances 0.000 description 4
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 4
- 229960002508 pindolol Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 238000010839 reverse transcription Methods 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 229930182884 serinolamide Natural products 0.000 description 4
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 4
- 229940083618 sodium nitroprusside Drugs 0.000 description 4
- DMRMZQATXPQOTP-GWTDSMLYSA-M sodium;(4ar,6r,7r,7as)-6-(6-amino-8-bromopurin-9-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4h-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol Chemical compound [Na+].C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1Br DMRMZQATXPQOTP-GWTDSMLYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000013589 supplement Substances 0.000 description 4
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 4
- 238000013519 translation Methods 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- 238000011311 validation assay Methods 0.000 description 4
- 210000002845 virion Anatomy 0.000 description 4
- 229910000166 zirconium phosphate Inorganic materials 0.000 description 4
- UNSRRHDPHVZAHH-YOILPLPUSA-N (5Z,8Z,11Z)-icosatrienoic acid Chemical compound CCCCCCCC\C=C/C\C=C/C\C=C/CCCC(O)=O UNSRRHDPHVZAHH-YOILPLPUSA-N 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- TUXFWOHFPFBNEJ-GJGHEGAFSA-N 13,14-dihydro-Delta(12)-prostaglandin J2 Chemical compound CCCCC[C@H](O)C\C=C1/[C@@H](C\C=C/CCCC(O)=O)C=CC1=O TUXFWOHFPFBNEJ-GJGHEGAFSA-N 0.000 description 3
- XTNOEYFQXCQKLC-UHFFFAOYSA-N 18-(oxiren-2-yl)octadeca-15,17-dienoic acid Chemical compound C1=C(C=CC=CCCCCCCCCCCCCCC(=O)O)O1 XTNOEYFQXCQKLC-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 3
- UNSRRHDPHVZAHH-UHFFFAOYSA-N 6beta,11alpha-Dihydroxy-3alpha,5alpha-cyclopregnan-20-on Natural products CCCCCCCCC=CCC=CCC=CCCCC(O)=O UNSRRHDPHVZAHH-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- 108010044267 Abnormal Hemoglobins Proteins 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 102100035785 Acyl-CoA-binding protein Human genes 0.000 description 3
- 108091093088 Amplicon Proteins 0.000 description 3
- 108010064733 Angiotensins Proteins 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 3
- 102100031366 Ankyrin-1 Human genes 0.000 description 3
- 101710191059 Ankyrin-1 Proteins 0.000 description 3
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 101100289995 Caenorhabditis elegans mac-1 gene Proteins 0.000 description 3
- 241000713756 Caprine arthritis encephalitis virus Species 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 102100037241 Endoglin Human genes 0.000 description 3
- 102000003969 Fibroblast growth factor 4 Human genes 0.000 description 3
- 108090000381 Fibroblast growth factor 4 Proteins 0.000 description 3
- 102000003968 Fibroblast growth factor 6 Human genes 0.000 description 3
- 108090000382 Fibroblast growth factor 6 Proteins 0.000 description 3
- 208000034502 Haemoglobin C disease Diseases 0.000 description 3
- 108010068308 Hemoglobin H Proteins 0.000 description 3
- 208000012925 Hemoglobin H disease Diseases 0.000 description 3
- 101710132405 Hemoglobin subunit beta-A Proteins 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- 101000929799 Homo sapiens Acyl-CoA-binding protein Proteins 0.000 description 3
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 3
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 3
- 101000610551 Homo sapiens Prominin-1 Proteins 0.000 description 3
- 102100022338 Integrin alpha-M Human genes 0.000 description 3
- 102000003996 Interferon-beta Human genes 0.000 description 3
- 102000003815 Interleukin-11 Human genes 0.000 description 3
- 108090000177 Interleukin-11 Proteins 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- 229930188389 Lanatoside Natural products 0.000 description 3
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 208000024556 Mendelian disease Diseases 0.000 description 3
- 102100030856 Myoglobin Human genes 0.000 description 3
- 108010062374 Myoglobin Proteins 0.000 description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102100040120 Prominin-1 Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000007327 Protamines Human genes 0.000 description 3
- 108010007568 Protamines Proteins 0.000 description 3
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 3
- 108091034057 RNA (poly(A)) Proteins 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000700647 Variola virus Species 0.000 description 3
- 241000711975 Vesicular stomatitis virus Species 0.000 description 3
- 108091093126 WHP Posttrascriptional Response Element Proteins 0.000 description 3
- YFGQJKBUXPKSAW-ZUDKKNPISA-N [(2r,3r,4s)-6-[(2r,3s,4s)-4-hydroxy-6-[(2r,3s,4s)-4-hydroxy-6-[[(3s,9s,10s,13r,17r)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2h-furan-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-2-methyloxan-3-yl]oxy-2-methyloxan-3-y Chemical compound O([C@H]1[C@@H](OC(C)=O)CC(O[C@@H]1C)O[C@H]1[C@@H](O)CC(O[C@@H]1C)O[C@H]1[C@@H](O)CC(O[C@@H]1C)O[C@@H]1CC2[C@]([C@@H]3C(C4(CC[C@@H]([C@@]4(C)CC3)C=3COC(=O)C=3)O)CC2)(C)CC1)C1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O YFGQJKBUXPKSAW-ZUDKKNPISA-N 0.000 description 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 3
- 101150045969 abcD1 gene Proteins 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 210000001789 adipocyte Anatomy 0.000 description 3
- 210000004504 adult stem cell Anatomy 0.000 description 3
- AHANXAKGNAKFSK-PDBXOOCHSA-N all-cis-icosa-11,14,17-trienoic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCCCC(O)=O AHANXAKGNAKFSK-PDBXOOCHSA-N 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229960002470 bimatoprost Drugs 0.000 description 3
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 description 3
- 210000003443 bladder cell Anatomy 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 229960005296 carboprost tromethamine Drugs 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 210000001612 chondrocyte Anatomy 0.000 description 3
- 229960004409 cloprostenol Drugs 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 210000004748 cultured cell Anatomy 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 241001493065 dsRNA viruses Species 0.000 description 3
- PRHHYVQTPBEDFE-UHFFFAOYSA-N eicosatrienoic acid Natural products CCCCCC=CCC=CCCCCC=CCCCC(O)=O PRHHYVQTPBEDFE-UHFFFAOYSA-N 0.000 description 3
- 238000004520 electroporation Methods 0.000 description 3
- 206010014599 encephalitis Diseases 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 108700004025 env Genes Proteins 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 229960004979 fampridine Drugs 0.000 description 3
- 210000001357 hemopoietic progenitor cell Anatomy 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 3
- 229960004801 imipramine Drugs 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229960001388 interferon-beta Drugs 0.000 description 3
- 229940074383 interleukin-11 Drugs 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- XXUPXHKCPIKWLR-JHUOEJJVSA-N isopropyl unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OC(C)C XXUPXHKCPIKWLR-JHUOEJJVSA-N 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 229960001160 latanoprost Drugs 0.000 description 3
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 210000005265 lung cell Anatomy 0.000 description 3
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 238000001167 microscope projection photolithography Methods 0.000 description 3
- 229960005249 misoprostol Drugs 0.000 description 3
- 238000010369 molecular cloning Methods 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 230000001400 myeloablative effect Effects 0.000 description 3
- 210000000066 myeloid cell Anatomy 0.000 description 3
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 3
- 210000004165 myocardium Anatomy 0.000 description 3
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 3
- 229960001597 nifedipine Drugs 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 210000004248 oligodendroglia Anatomy 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- 210000002571 pancreatic alpha cell Anatomy 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 229960005152 pentetrazol Drugs 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 description 3
- 229960003634 pimozide Drugs 0.000 description 3
- 108700004029 pol Genes Proteins 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 3
- 229950008679 protamine sulfate Drugs 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 210000004116 schwann cell Anatomy 0.000 description 3
- 210000004927 skin cell Anatomy 0.000 description 3
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 3
- 210000002325 somatostatin-secreting cell Anatomy 0.000 description 3
- 241000894007 species Species 0.000 description 3
- ODJLBQGVINUMMR-HZXDTFASSA-N strophanthidin Chemical compound C1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C[C@@]5(O)CC4)C=O)CC[C@@]32C)=CC(=O)OC1 ODJLBQGVINUMMR-HZXDTFASSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229960004458 tafluprost Drugs 0.000 description 3
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 description 3
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 3
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 3
- XNRNNGPBEPRNAR-JQBLCGNGSA-N thromboxane B2 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1OC(O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O XNRNNGPBEPRNAR-JQBLCGNGSA-N 0.000 description 3
- 230000005030 transcription termination Effects 0.000 description 3
- 229960002368 travoprost Drugs 0.000 description 3
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 3
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 3
- 229960005032 treprostinil Drugs 0.000 description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- 150000005671 trienes Chemical class 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- 229950008081 unoprostone isopropyl Drugs 0.000 description 3
- 210000005167 vascular cell Anatomy 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 2
- WWMXHYUXIKWXSR-AAHOZRAYSA-N (z)-7-[(1r,2r,3r)-3-hydroxy-2-[(e,3r)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-1-enyl]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H](C(=O)C[C@H]1O)C\C=C/CCCC(O)=O)OC1=CC=CC(C(F)(F)F)=C1 WWMXHYUXIKWXSR-AAHOZRAYSA-N 0.000 description 2
- FOBVMYJQWZOGGJ-XYRJXBATSA-N 17-phenyl-18,19,20-trinor-prostaglandin E2 Chemical group C([C@H](O)\C=C\[C@@H]1[C@H](C(=O)C[C@H]1O)C\C=C/CCCC(O)=O)CC1=CC=CC=C1 FOBVMYJQWZOGGJ-XYRJXBATSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 2
- AZIGEYVZEVXWAD-NZGURKHLSA-N 20-hydroxyprostaglandin E2 Chemical compound OCCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O AZIGEYVZEVXWAD-NZGURKHLSA-N 0.000 description 2
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 2
- NMKSAYKQLCHXDK-UHFFFAOYSA-N 3,3-diphenyl-N-(1-phenylethyl)-1-propanamine Chemical compound C=1C=CC=CC=1C(C)NCCC(C=1C=CC=CC=1)C1=CC=CC=C1 NMKSAYKQLCHXDK-UHFFFAOYSA-N 0.000 description 2
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 2
- 102100036664 Adenosine deaminase Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 238000012935 Averaging Methods 0.000 description 2
- 108010081589 Becaplermin Proteins 0.000 description 2
- IYGYMKDQCDOMRE-QRWMCTBCSA-N Bicculine Chemical compound O([C@H]1C2C3=CC=4OCOC=4C=C3CCN2C)C(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-QRWMCTBCSA-N 0.000 description 2
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 description 2
- 108010049974 Bone Morphogenetic Protein 6 Proteins 0.000 description 2
- 108010049870 Bone Morphogenetic Protein 7 Proteins 0.000 description 2
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 description 2
- 102100022525 Bone morphogenetic protein 6 Human genes 0.000 description 2
- 102100022544 Bone morphogenetic protein 7 Human genes 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 102100028892 Cardiotrophin-1 Human genes 0.000 description 2
- 108010008951 Chemokine CXCL12 Proteins 0.000 description 2
- 102000009016 Cholera Toxin Human genes 0.000 description 2
- 108010049048 Cholera Toxin Proteins 0.000 description 2
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 2
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 2
- 102100022641 Coagulation factor IX Human genes 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- 101100210337 Drosophila melanogaster wntD gene Proteins 0.000 description 2
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 2
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 2
- 102100039950 Eukaryotic initiation factor 4A-I Human genes 0.000 description 2
- 241000714165 Feline leukemia virus Species 0.000 description 2
- 101710099785 Ferritin, heavy subunit Proteins 0.000 description 2
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 108090000380 Fibroblast growth factor 5 Proteins 0.000 description 2
- 102100028073 Fibroblast growth factor 5 Human genes 0.000 description 2
- 229920001917 Ficoll Polymers 0.000 description 2
- 241000711950 Filoviridae Species 0.000 description 2
- 241000710781 Flaviviridae Species 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 2
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 2
- 241000713813 Gibbon ape leukemia virus Species 0.000 description 2
- 102000053171 Glial Fibrillary Acidic Human genes 0.000 description 2
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 2
- 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 2
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 description 2
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 101150113453 Gsk3a gene Proteins 0.000 description 2
- 241000713858 Harvey murine sarcoma virus Species 0.000 description 2
- 102000003693 Hedgehog Proteins Human genes 0.000 description 2
- 108090000031 Hedgehog Proteins Proteins 0.000 description 2
- 102100039894 Hemoglobin subunit delta Human genes 0.000 description 2
- 108091005903 Hemoglobin subunit delta Proteins 0.000 description 2
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 2
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 2
- 101000881679 Homo sapiens Endoglin Proteins 0.000 description 2
- 101000959666 Homo sapiens Eukaryotic initiation factor 4A-I Proteins 0.000 description 2
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 2
- 101001076292 Homo sapiens Insulin-like growth factor II Proteins 0.000 description 2
- 101000716729 Homo sapiens Kit ligand Proteins 0.000 description 2
- 101001086862 Homo sapiens Pulmonary surfactant-associated protein B Proteins 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 2
- 102100025947 Insulin-like growth factor II Human genes 0.000 description 2
- 102100034353 Integrase Human genes 0.000 description 2
- 108010061833 Integrases Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 102000003816 Interleukin-13 Human genes 0.000 description 2
- 108090000176 Interleukin-13 Proteins 0.000 description 2
- 102000003812 Interleukin-15 Human genes 0.000 description 2
- 108090000172 Interleukin-15 Proteins 0.000 description 2
- 102000013691 Interleukin-17 Human genes 0.000 description 2
- 108050003558 Interleukin-17 Proteins 0.000 description 2
- 102100039879 Interleukin-19 Human genes 0.000 description 2
- 108050009288 Interleukin-19 Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 102100039897 Interleukin-5 Human genes 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102100021592 Interleukin-7 Human genes 0.000 description 2
- 108010002586 Interleukin-7 Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 102100026871 Interleukin-9 Human genes 0.000 description 2
- 108010002335 Interleukin-9 Proteins 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-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
- 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
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 101001022947 Lithobates catesbeianus Ferritin, lower subunit Proteins 0.000 description 2
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 241000713862 Moloney murine sarcoma virus Species 0.000 description 2
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 2
- 101000873683 Mus musculus Succinyl-CoA:3-ketoacid coenzyme A transferase 2B, mitochondrial Proteins 0.000 description 2
- 229930193140 Neomycin Natural products 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 description 2
- 102000004230 Neurotrophin 3 Human genes 0.000 description 2
- 108090000742 Neurotrophin 3 Proteins 0.000 description 2
- 102000003683 Neurotrophin-4 Human genes 0.000 description 2
- 108090000099 Neurotrophin-4 Proteins 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 241000711504 Paramyxoviridae Species 0.000 description 2
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 description 2
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102100028251 Phosphoglycerate kinase 1 Human genes 0.000 description 2
- 101710139464 Phosphoglycerate kinase 1 Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000002808 Pituitary adenylate cyclase-activating polypeptide Human genes 0.000 description 2
- 108010004684 Pituitary adenylate cyclase-activating polypeptide Proteins 0.000 description 2
- 102100037935 Polyubiquitin-C Human genes 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 102100023087 Protein S100-A4 Human genes 0.000 description 2
- 101710149951 Protein Tat Proteins 0.000 description 2
- 102000052575 Proto-Oncogene Human genes 0.000 description 2
- 108700020978 Proto-Oncogene Proteins 0.000 description 2
- 102100032617 Pulmonary surfactant-associated protein B Human genes 0.000 description 2
- 102000009572 RNA Polymerase II Human genes 0.000 description 2
- 108010009460 RNA Polymerase II Proteins 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 206010043390 Thalassaemia alpha Diseases 0.000 description 2
- 206010043391 Thalassaemia beta Diseases 0.000 description 2
- XNRNNGPBEPRNAR-UHFFFAOYSA-N Thromboxane B2 Natural products CCCCCC(O)C=CC1OC(O)CC(O)C1CC=CCCCC(O)=O XNRNNGPBEPRNAR-UHFFFAOYSA-N 0.000 description 2
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 2
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 2
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 2
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 2
- 241000710959 Venezuelan equine encephalitis virus Species 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 108020000999 Viral RNA Proteins 0.000 description 2
- 101150010310 WNT-4 gene Proteins 0.000 description 2
- 101150109862 WNT-5A gene Proteins 0.000 description 2
- 101150019524 WNT2 gene Proteins 0.000 description 2
- 102000052547 Wnt-1 Human genes 0.000 description 2
- 108700020987 Wnt-1 Proteins 0.000 description 2
- 102000052556 Wnt-2 Human genes 0.000 description 2
- 108700020986 Wnt-2 Proteins 0.000 description 2
- 102000052549 Wnt-3 Human genes 0.000 description 2
- 108700020985 Wnt-3 Proteins 0.000 description 2
- 102000052548 Wnt-4 Human genes 0.000 description 2
- 108700020984 Wnt-4 Proteins 0.000 description 2
- 102000043366 Wnt-5a Human genes 0.000 description 2
- 108700020483 Wnt-5a Proteins 0.000 description 2
- 208000023940 X-Linked Combined Immunodeficiency disease Diseases 0.000 description 2
- 101100485097 Xenopus laevis wnt11b gene Proteins 0.000 description 2
- 108010084455 Zeocin Proteins 0.000 description 2
- 239000003070 absorption delaying agent Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000002617 apheresis Methods 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 230000017047 asymmetric cell division Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- AACMFFIUYXGCOC-UHFFFAOYSA-N bicuculline Natural products CN1CCc2cc3OCOc3cc2C1C4OCc5c6OCOc6ccc45 AACMFFIUYXGCOC-UHFFFAOYSA-N 0.000 description 2
- 229930189065 blasticidin Natural products 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- CJGYSWNGNKCJSB-YVLZZHOMSA-N bucladesine Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1 CJGYSWNGNKCJSB-YVLZZHOMSA-N 0.000 description 2
- 229960005263 bucladesine Drugs 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 108010041776 cardiotrophin 1 Proteins 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000002648 chondrogenic effect Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000001143 conditioned effect Effects 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 238000011461 current therapy Methods 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- IYGYMKDQCDOMRE-UHFFFAOYSA-N d-Bicucullin Natural products CN1CCC2=CC=3OCOC=3C=C2C1C1OC(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 210000003981 ectoderm Anatomy 0.000 description 2
- 230000005014 ectopic expression Effects 0.000 description 2
- 210000001900 endoderm Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 108010078428 env Gene Products Proteins 0.000 description 2
- 101150030339 env gene Proteins 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960002602 fendiline Drugs 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 108700004026 gag Genes Proteins 0.000 description 2
- 101150098622 gag gene Proteins 0.000 description 2
- 230000037442 genomic alteration Effects 0.000 description 2
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 229960002885 histidine Drugs 0.000 description 2
- 102000055151 human KITLG Human genes 0.000 description 2
- 229960002474 hydralazine Drugs 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000002743 insertional mutagenesis Methods 0.000 description 2
- 229940068935 insulin-like growth factor 2 Drugs 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 229940076144 interleukin-10 Drugs 0.000 description 2
- 229940117681 interleukin-12 Drugs 0.000 description 2
- 229940028885 interleukin-4 Drugs 0.000 description 2
- 229940100602 interleukin-5 Drugs 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 229940100994 interleukin-7 Drugs 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940118526 interleukin-9 Drugs 0.000 description 2
- 210000004005 intermediate erythroblast Anatomy 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 238000001638 lipofection Methods 0.000 description 2
- 238000009630 liquid culture Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000000135 megakaryocyte-erythroid progenitor cell Anatomy 0.000 description 2
- 210000003716 mesoderm Anatomy 0.000 description 2
- 229960004452 methionine Drugs 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 230000003039 myelosuppressive effect Effects 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- GUMBZKISKUIHJB-UHFFFAOYSA-N n'-[4-(2,4-dichlorophenyl)-5-(1h-imidazol-2-yl)pyrimidin-2-yl]-n-(5-nitropyridin-2-yl)ethane-1,2-diamine Chemical compound N1=CC([N+](=O)[O-])=CC=C1NCCNC(N=C1C=2C(=CC(Cl)=CC=2)Cl)=NC=C1C1=NC=CN1 GUMBZKISKUIHJB-UHFFFAOYSA-N 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 229940032018 neurotrophin 3 Drugs 0.000 description 2
- 229940097998 neurotrophin 4 Drugs 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000003836 peripheral circulation Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 2
- UFTCZKMBJOPXDM-XXFCQBPRSA-N pituitary adenylate cyclase-activating polypeptide Chemical compound C([C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CN=CN1 UFTCZKMBJOPXDM-XXFCQBPRSA-N 0.000 description 2
- 108010000685 platelet-derived growth factor AB Proteins 0.000 description 2
- 210000001778 pluripotent stem cell Anatomy 0.000 description 2
- 101150088264 pol gene Proteins 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- WGCXTGBZBFBQPP-UHFFFAOYSA-N prostaglandin E2 methyl ester Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(=O)OC WGCXTGBZBFBQPP-UHFFFAOYSA-N 0.000 description 2
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 2
- 238000012429 release testing Methods 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 108700004030 rev Genes Proteins 0.000 description 2
- 101150098213 rev gene Proteins 0.000 description 2
- 229960003452 romidepsin Drugs 0.000 description 2
- 108010091666 romidepsin Proteins 0.000 description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- IFEJLMHZNQJGQU-KXXGZHCCSA-M sodium;(z)-7-[(1r,2r,3r,5s)-2-[(e,3r)-4-(3-chlorophenoxy)-3-hydroxybut-1-enyl]-3,5-dihydroxycyclopentyl]hept-5-enoate Chemical compound [Na+].C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC([O-])=O)OC1=CC=CC(Cl)=C1 IFEJLMHZNQJGQU-KXXGZHCCSA-M 0.000 description 2
- 230000003393 splenic effect Effects 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000009168 stem cell therapy Methods 0.000 description 2
- 238000009580 stem-cell therapy Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000011285 therapeutic regimen Methods 0.000 description 2
- 239000004308 thiabendazole Substances 0.000 description 2
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 2
- 235000010296 thiabendazole Nutrition 0.000 description 2
- 229960004546 thiabendazole Drugs 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 230000001361 thrombopoietic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- YSSBJODGIYRAMI-UHFFFAOYSA-N vesamicol Chemical compound OC1CCCCC1N1CCC(C=2C=CC=CC=2)CC1 YSSBJODGIYRAMI-UHFFFAOYSA-N 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
- VYTZWRCSPHQSFX-GBNDHIKLSA-N (-)-corey lactone Chemical compound O1C(=O)C[C@@H]2[C@@H](CO)[C@H](O)C[C@@H]21 VYTZWRCSPHQSFX-GBNDHIKLSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- QQTQLHVRUZWVQZ-WYFSZTNASA-N (4-benzamidophenyl) (z)-7-[(1r,2r,3r)-3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]hept-4-enoate Chemical compound C([C@H]1C(=O)C[C@@H](O)[C@@H]1OCC(O)COC=1C=CC=CC=1)C\C=C/CCC(=O)OC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 QQTQLHVRUZWVQZ-WYFSZTNASA-N 0.000 description 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- LOQMSUDLLHPPHQ-FMIVXFBMSA-N (e)-3-[4-[[2-[furan-2-ylsulfonyl(2-methylpropyl)amino]-5-(trifluoromethyl)phenoxy]methyl]phenyl]prop-2-enoic acid Chemical compound C=1C=COC=1S(=O)(=O)N(CC(C)C)C1=CC=C(C(F)(F)F)C=C1OCC1=CC=C(\C=C\C(O)=O)C=C1 LOQMSUDLLHPPHQ-FMIVXFBMSA-N 0.000 description 1
- MXDQOCKVVLKVJS-QKIVIXBWSA-N (z)-7-[(1r,2r,3r)-3-methoxy-2-[(e,3s)-3-methoxyoct-1-enyl]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound CCCCC[C@H](OC)\C=C\[C@H]1[C@H](OC)CC(=O)[C@@H]1C\C=C/CCCC(O)=O MXDQOCKVVLKVJS-QKIVIXBWSA-N 0.000 description 1
- AIOFTOLPMOTZKD-OPVFONCOSA-N (z)-7-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-[(e,3r)-3-hydroxy-4,4-dimethyloct-1-enyl]cyclopentyl]hept-5-enoic acid Chemical compound CCCCC(C)(C)[C@H](O)\C=C\[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1C\C=C/CCCC(O)=O AIOFTOLPMOTZKD-OPVFONCOSA-N 0.000 description 1
- XXTBGKDWFYXGDZ-KJCKJCAZSA-N (z)-7-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-[(e,4s)-4-hydroxy-4-(1-prop-2-enylcyclobutyl)but-1-enyl]cyclopentyl]hept-5-enoic acid Chemical compound C([C@H](O)C1(CC=C)CCC1)\C=C\[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1C\C=C/CCCC(O)=O XXTBGKDWFYXGDZ-KJCKJCAZSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- YRTJDWROBKPZNV-UHFFFAOYSA-N 15-Oxoprostaglandin E2 Natural products CCCCCC(=O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O YRTJDWROBKPZNV-UHFFFAOYSA-N 0.000 description 1
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- BVGVPUMSPSNRRQ-CNOJNPITSA-N 2-[3-[(1r,2s,3r)-3-hydroxy-2-[(e,3s)-3-hydroxy-5-[2-(methoxymethyl)phenyl]pent-1-enyl]-5-oxocyclopentyl]sulfanylpropylsulfanyl]acetic acid Chemical compound COCC1=CC=CC=C1CC[C@H](O)\C=C\[C@@H]1[C@@H](SCCCSCC(O)=O)C(=O)C[C@H]1O BVGVPUMSPSNRRQ-CNOJNPITSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- 108020005345 3' Untranslated Regions Proteins 0.000 description 1
- KWRRIFVHVJWXPU-HVCOQRSISA-N 4-[2-[(1r,2r,3r)-3-hydroxy-2-[(e,3s,5s)-3-hydroxy-5-methylnon-1-enyl]-5-oxocyclopentyl]acetyl]cyclohexane-1-carboxylic acid Chemical compound CCCC[C@H](C)C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)C1CCC(C(O)=O)CC1 KWRRIFVHVJWXPU-HVCOQRSISA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- YRTJDWROBKPZNV-RSNVZYGJSA-N 8-iso-15-keto-PGE2 Chemical compound CCCCCC(=O)\C=C\[C@H]1[C@H](O)CC(=O)[C@H]1C\C=C/CCCC(O)=O YRTJDWROBKPZNV-RSNVZYGJSA-N 0.000 description 1
- 101150094949 APRT gene Proteins 0.000 description 1
- 101150084229 ATXN1 gene Proteins 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 102100029457 Adenine phosphoribosyltransferase Human genes 0.000 description 1
- 108010024223 Adenine phosphoribosyltransferase Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- 208000003829 American Hemorrhagic Fever Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102100029470 Apolipoprotein E Human genes 0.000 description 1
- 101710095339 Apolipoprotein E Proteins 0.000 description 1
- 241000712892 Arenaviridae Species 0.000 description 1
- 241000712891 Arenavirus Species 0.000 description 1
- 201000009695 Argentine hemorrhagic fever Diseases 0.000 description 1
- 241001533362 Astroviridae Species 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000702628 Birnaviridae Species 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 206010005176 Blindness congenital Diseases 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 208000034200 Bolivian hemorrhagic fever Diseases 0.000 description 1
- 108010049955 Bone Morphogenetic Protein 4 Proteins 0.000 description 1
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 1
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 1
- VYLJAYXZTOTZRR-BTPDVQIOSA-N CC(C)(O)[C@H]1CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2CC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3[C@@H](O)[C@H](O)[C@@]12C Chemical compound CC(C)(O)[C@H]1CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2CC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3[C@@H](O)[C@H](O)[C@@]12C VYLJAYXZTOTZRR-BTPDVQIOSA-N 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100022002 CD59 glycoprotein Human genes 0.000 description 1
- AQGNHMOJWBZFQQ-UHFFFAOYSA-N CT 99021 Chemical compound CC1=CNC(C=2C(=NC(NCCNC=3N=CC(=CC=3)C#N)=NC=2)C=2C(=CC(Cl)=CC=2)Cl)=N1 AQGNHMOJWBZFQQ-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- 102100035371 Chymotrypsin-like elastase family member 1 Human genes 0.000 description 1
- 101710138848 Chymotrypsin-like elastase family member 1 Proteins 0.000 description 1
- 241001533399 Circoviridae Species 0.000 description 1
- 108091062157 Cis-regulatory element Proteins 0.000 description 1
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010010099 Combined immunodeficiency Diseases 0.000 description 1
- 108010051219 Cre recombinase Proteins 0.000 description 1
- 201000003075 Crimean-Congo hemorrhagic fever Diseases 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- OJLOPKGSLYJEMD-LNQMSSPSSA-N Cyotec Chemical compound CCCCC(C)(O)CC=C[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-LNQMSSPSSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 101001027406 Danio rerio Fibroblast growth factor 8b Proteins 0.000 description 1
- 208000005156 Dehydration Diseases 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 102100036912 Desmin Human genes 0.000 description 1
- 108010044052 Desmin Proteins 0.000 description 1
- 206010012559 Developmental delay Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102100023226 Early growth response protein 1 Human genes 0.000 description 1
- 241000710945 Eastern equine encephalitis virus Species 0.000 description 1
- 208000030820 Ebola disease Diseases 0.000 description 1
- 101710099240 Elastase-1 Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 108010036395 Endoglin Proteins 0.000 description 1
- 108700041152 Endoplasmic Reticulum Chaperone BiP Proteins 0.000 description 1
- 102100021451 Endoplasmic reticulum chaperone BiP Human genes 0.000 description 1
- 101710121417 Envelope glycoprotein Proteins 0.000 description 1
- 241001455610 Ephemerovirus Species 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 241000579695 European bat 1 lyssavirus Species 0.000 description 1
- 101150092822 FGF5 gene Proteins 0.000 description 1
- 108010046276 FLP recombinase Proteins 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108050002074 Fibroblast growth factor 17 Proteins 0.000 description 1
- 102100035308 Fibroblast growth factor 17 Human genes 0.000 description 1
- 102100037665 Fibroblast growth factor 9 Human genes 0.000 description 1
- 108090000367 Fibroblast growth factor 9 Proteins 0.000 description 1
- 102100037362 Fibronectin Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102100020997 Fractalkine Human genes 0.000 description 1
- 241000714188 Friend murine leukemia virus Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108700042658 GAP-43 Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 101000834253 Gallus gallus Actin, cytoplasmic 1 Proteins 0.000 description 1
- 101001035782 Gallus gallus Hemoglobin subunit beta Proteins 0.000 description 1
- 101000650147 Gallus gallus Protein Wnt-9a Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101710166362 Globin-3 Proteins 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 1
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 208000012766 Growth delay Diseases 0.000 description 1
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 1
- 101150116759 HBA2 gene Proteins 0.000 description 1
- 108010027992 HSP70 Heat-Shock Proteins Proteins 0.000 description 1
- 102000018932 HSP70 Heat-Shock Proteins Human genes 0.000 description 1
- 101150112743 HSPA5 gene Proteins 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- 101150052743 Hba1 gene Proteins 0.000 description 1
- 101710089250 Heat shock 70 kDa protein 5 Proteins 0.000 description 1
- 101710113864 Heat shock protein 90 Proteins 0.000 description 1
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 description 1
- 208000018565 Hemochromatosis Diseases 0.000 description 1
- 108010081925 Hemoglobin Subunits Proteins 0.000 description 1
- 208000032982 Hemorrhagic Fever with Renal Syndrome Diseases 0.000 description 1
- 241000893570 Hendra henipavirus Species 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 241000700739 Hepadnaviridae Species 0.000 description 1
- 241000724675 Hepatitis E virus Species 0.000 description 1
- 208000037262 Hepatitis delta Diseases 0.000 description 1
- 241000724709 Hepatitis delta virus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 101100054326 Homo sapiens ABCD1 gene Proteins 0.000 description 1
- 101000756632 Homo sapiens Actin, cytoplasmic 1 Proteins 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 description 1
- 101000897400 Homo sapiens CD59 glycoprotein Proteins 0.000 description 1
- 101001033280 Homo sapiens Cytokine receptor common subunit beta Proteins 0.000 description 1
- 101001049697 Homo sapiens Early growth response protein 1 Proteins 0.000 description 1
- 101000854520 Homo sapiens Fractalkine Proteins 0.000 description 1
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 1
- 101000988802 Homo sapiens Hematopoietic prostaglandin D synthase Proteins 0.000 description 1
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 description 1
- 101000934372 Homo sapiens Macrosialin Proteins 0.000 description 1
- 101001030069 Homo sapiens Major vault protein Proteins 0.000 description 1
- 101001057156 Homo sapiens Melanoma-associated antigen C2 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101001023043 Homo sapiens Myoblast determination protein 1 Proteins 0.000 description 1
- 101001086210 Homo sapiens Osteocalcin Proteins 0.000 description 1
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 241000713297 Influenza C virus Species 0.000 description 1
- 208000002979 Influenza in Birds Diseases 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 102100025756 Keratin, type II cytoskeletal 5 Human genes 0.000 description 1
- 108010070553 Keratin-5 Proteins 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- MIJPAVRNWPDMOR-ZAFYKAAXSA-N L-ascorbic acid 2-phosphate Chemical compound OC[C@H](O)[C@H]1OC(=O)C(OP(O)(O)=O)=C1O MIJPAVRNWPDMOR-ZAFYKAAXSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- 239000004158 L-cystine Substances 0.000 description 1
- 235000019393 L-cystine Nutrition 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 235000019454 L-leucine Nutrition 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
- 229930195722 L-methionine Natural products 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- KKCIOUWDFWQUBT-AWEZNQCLSA-N L-thyronine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1OC1=CC=C(O)C=C1 KKCIOUWDFWQUBT-AWEZNQCLSA-N 0.000 description 1
- 241001520693 Lagos bat lyssavirus Species 0.000 description 1
- 206010023927 Lassa fever Diseases 0.000 description 1
- 201000003533 Leber congenital amaurosis Diseases 0.000 description 1
- 102100039564 Leukosialin Human genes 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 208000015439 Lysosomal storage disease Diseases 0.000 description 1
- 241000711828 Lyssavirus Species 0.000 description 1
- 241000712898 Machupo mammarenavirus Species 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 102100025136 Macrosialin Human genes 0.000 description 1
- 208000000932 Marburg Virus Disease Diseases 0.000 description 1
- 201000011013 Marburg hemorrhagic fever Diseases 0.000 description 1
- 241000713821 Mason-Pfizer monkey virus Species 0.000 description 1
- 210000002361 Megakaryocyte Progenitor Cell Anatomy 0.000 description 1
- 102100027252 Melanoma-associated antigen C2 Human genes 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- 108010051679 Methylmalonyl-CoA carboxytransferase Proteins 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 101000989934 Mus musculus Hemoglobin subunit alpha Proteins 0.000 description 1
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 1
- 241000713883 Myeloproliferative sarcoma virus Species 0.000 description 1
- 102100035077 Myoblast determination protein 1 Human genes 0.000 description 1
- FABQUVYDAXWUQP-UHFFFAOYSA-N N4-(1,3-benzodioxol-5-ylmethyl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine Chemical compound COC1=CC=CC(C=2N=C(N)N=C(NCC=3C=C4OCOC4=CC=3)C=2)=C1 FABQUVYDAXWUQP-UHFFFAOYSA-N 0.000 description 1
- 102000048850 Neoplasm Genes Human genes 0.000 description 1
- 108700019961 Neoplasm Genes Proteins 0.000 description 1
- 102100023195 Nephrin Human genes 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 241000714209 Norwalk virus Species 0.000 description 1
- STJFYCWYHROASW-UHFFFAOYSA-N O-methyl-glaucamine Natural products CN1CCC2=CC(OC)=C(OC)C=C2C2OC(OC)C3=C4OCOC4=CC=C3C12 STJFYCWYHROASW-UHFFFAOYSA-N 0.000 description 1
- 241000725177 Omsk hemorrhagic fever virus Species 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 241000150452 Orthohantavirus Species 0.000 description 1
- 241000712464 Orthomyxoviridae Species 0.000 description 1
- 102100031475 Osteocalcin Human genes 0.000 description 1
- 108091081548 Palindromic sequence Proteins 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 241000051107 Paraechinus aethiopicus Species 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 241000701945 Parvoviridae Species 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- 108010043958 Peptoids Proteins 0.000 description 1
- 241000150350 Peribunyaviridae Species 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100024819 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 102100021923 Prolow-density lipoprotein receptor-related protein 1 Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010037742 Rabies Diseases 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 102000004879 Racemases and epimerases Human genes 0.000 description 1
- 108090001066 Racemases and epimerases Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 241000702247 Reoviridae Species 0.000 description 1
- 241001068263 Replication competent viruses Species 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- 241000711931 Rhabdoviridae Species 0.000 description 1
- 241000713124 Rift Valley fever virus Species 0.000 description 1
- FBQUXLIJKPWCAO-AZIFJQEOSA-N Rivenprost Chemical compound COCC1=CC=CC(C[C@H](O)\C=C\[C@@H]2[C@H](C(=O)C[C@H]2O)CCSCCCC(=O)OC)=C1 FBQUXLIJKPWCAO-AZIFJQEOSA-N 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 108010085149 S100 Calcium-Binding Protein A4 Proteins 0.000 description 1
- 241000785917 Savia Species 0.000 description 1
- 101710163413 Signaling lymphocytic activation molecule Proteins 0.000 description 1
- 241001529934 Simian T-lymphotropic virus 3 Species 0.000 description 1
- 241000713877 Simian sarcoma-associated virus Species 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 241000713675 Spumavirus Species 0.000 description 1
- 241000713820 Squirrel monkey retrovirus Species 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 102000001435 Synapsin Human genes 0.000 description 1
- 108050009621 Synapsin Proteins 0.000 description 1
- 208000012827 T-B+ severe combined immunodeficiency due to gamma chain deficiency Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043395 Thalassaemia sickle cell Diseases 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 208000004006 Tick-borne encephalitis Diseases 0.000 description 1
- 108010010574 Tn3 resolvase Proteins 0.000 description 1
- 241000710924 Togaviridae Species 0.000 description 1
- 241000711517 Torovirus Species 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 1
- 108091061763 Triple-stranded DNA Proteins 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 108010056354 Ubiquitin C Proteins 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 201000009693 Venezuelan hemorrhagic fever Diseases 0.000 description 1
- 241000711970 Vesiculovirus Species 0.000 description 1
- 108010087302 Viral Structural Proteins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000010094 Visna Diseases 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 241000710951 Western equine encephalitis virus Species 0.000 description 1
- 208000006110 Wiskott-Aldrich syndrome Diseases 0.000 description 1
- 241001492404 Woodchuck hepatitis virus Species 0.000 description 1
- 208000010796 X-linked adrenoleukodystrophy Diseases 0.000 description 1
- 201000007146 X-linked severe combined immunodeficiency Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 206010051895 acute chest syndrome Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 150000001298 alcohols Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 210000004436 artificial bacterial chromosome Anatomy 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 206010064097 avian influenza Diseases 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 210000000018 basophilic myelocyte Anatomy 0.000 description 1
- 210000003791 basophilic promyelocyte Anatomy 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 210000001109 blastomere Anatomy 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001716 carbazoles Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000008004 cell lysis buffer Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 231100000778 chemical safety assessment Toxicity 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- HWLZQESIRAGTAT-UHFFFAOYSA-N cyclopenta[b]furan-2-one Chemical compound C1=CC2=CC(=O)OC2=C1 HWLZQESIRAGTAT-UHFFFAOYSA-N 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 229940099378 cytotec Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 210000004544 dc2 Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000000991 decompressive effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 210000005045 desmin Anatomy 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000003762 eosinophilic myelocyte Anatomy 0.000 description 1
- 210000004772 eosinophilic promyelocyte Anatomy 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 230000008508 epithelial proliferation Effects 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 210000003013 erythroid precursor cell Anatomy 0.000 description 1
- 230000000913 erythropoietic effect Effects 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 229940032383 estrumate Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 150000002220 fluorenes Chemical class 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 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
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000001654 germ layer Anatomy 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000003278 haem Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229940045347 hemabate Drugs 0.000 description 1
- 208000009429 hemophilia B Diseases 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- VYLJAYXZTOTZRR-UHFFFAOYSA-N hopane-6alpha,7beta,22-triol Natural products C12CCC3C4(C)CCCC(C)(C)C4C(O)C(O)C3(C)C1(C)CCC1C2(C)CCC1C(C)(O)C VYLJAYXZTOTZRR-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 102000055647 human CSF2RB Human genes 0.000 description 1
- 229960000027 human factor ix Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 208000037798 influenza B Diseases 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 210000004966 intestinal stem cell Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 229940090993 isolyte s Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 210000003738 lymphoid progenitor cell Anatomy 0.000 description 1
- GRPSNTXTTSBKGW-BVGHQBMWSA-J magnesium;potassium;sodium;(3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol;triacetate;chloride Chemical compound [Na+].[Mg+2].[Cl-].[K+].CC([O-])=O.CC([O-])=O.CC([O-])=O.OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O GRPSNTXTTSBKGW-BVGHQBMWSA-J 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 238000009126 molecular therapy Methods 0.000 description 1
- 208000005871 monkeypox Diseases 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000002894 multi-fate stem cell Anatomy 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 210000001665 muscle stem cell Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 210000003887 myelocyte Anatomy 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 108700004028 nef Genes Proteins 0.000 description 1
- 101150023385 nef gene Proteins 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 108010027531 nephrin Proteins 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000005155 neural progenitor cell Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229950003144 nocloprost Drugs 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000005937 nuclear translocation Effects 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 210000004976 peripheral blood cell Anatomy 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 230000003169 placental effect Effects 0.000 description 1
- 210000004991 placental stem cell Anatomy 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 108010017843 platelet-derived growth factor A Proteins 0.000 description 1
- 229930001119 polyketide Natural products 0.000 description 1
- 125000000830 polyketide group Chemical group 0.000 description 1
- 229930001118 polyketide hybrid Natural products 0.000 description 1
- 125000003308 polyketide hybrid group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 201000011264 priapism Diseases 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000004765 promyelocyte Anatomy 0.000 description 1
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 210000002763 pyramidal cell Anatomy 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000012175 pyrosequencing Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- MYFATKRONKHHQL-UHFFFAOYSA-N rhodamine 123 Chemical compound [Cl-].COC(=O)C1=CC=CC=C1C1=C2C=CC(=[NH2+])C=C2OC2=CC(N)=CC=C21 MYFATKRONKHHQL-UHFFFAOYSA-N 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 210000000468 rubriblast Anatomy 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- HVAKSLUOHARFLM-UHFFFAOYSA-N selenium;sodium Chemical compound [Se][Na] HVAKSLUOHARFLM-UHFFFAOYSA-N 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 201000003624 spinocerebellar ataxia type 1 Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BVTYOCKAKQQPEE-UHFFFAOYSA-N superphane Chemical compound C1=2CCC3=C4CCC=2C(=C2CC5)CCC4=C5C4=C3CCC1=C2CC4 BVTYOCKAKQQPEE-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 108700004027 tat Genes Proteins 0.000 description 1
- 101150098170 tat gene Proteins 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 101150059019 vif gene Proteins 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000000605 viral structure Anatomy 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 108700026215 vpr Genes Proteins 0.000 description 1
- 101150024249 vpr gene Proteins 0.000 description 1
- 108700026222 vpu Genes Proteins 0.000 description 1
- 101150090490 vpu gene Proteins 0.000 description 1
- 101150040614 vpx gene Proteins 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—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
- C12N15/86—Viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- 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
- C12N15/86—Viral vectors
- C12N15/867—Retroviral vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0647—Haematopoietic stem cells; Uncommitted or multipotent progenitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/02—Compounds of the arachidonic acid pathway, e.g. prostaglandins, leukotrienes
-
- 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
- C12N2510/00—Genetically modified cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16041—Use of virus, viral particle or viral elements as a vector
- C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- 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
- C12N2810/00—Vectors comprising a targeting moiety
- C12N2810/50—Vectors comprising as targeting moiety peptide derived from defined protein
- C12N2810/60—Vectors comprising as targeting moiety peptide derived from defined protein from viruses
- C12N2810/6072—Vectors comprising as targeting moiety peptide derived from defined protein from viruses negative strand RNA viruses
- C12N2810/6081—Vectors comprising as targeting moiety peptide derived from defined protein from viruses negative strand RNA viruses rhabdoviridae, e.g. VSV
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Hematology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plant Pathology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Virology (AREA)
- Cell Biology (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Developmental Biology & Embryology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本出願は、2011年9月30日に出願された米国仮特許出願第61/541,736号の利益を、米国特許法§119(e)の下、主張する。この出願はその全体が本明細書において参照として援用される。
本出願に付随する配列表は、紙コピーの代わりにテキスト形式で提供され、これによって参照により本明細書に組み込まれる。配列表を含むテキストファイルの名称はBLBD_006_01WO_ST25.txtである。テキストファイルは30KBであり、2012年9月27日に作成され、EFS−Webを介して電子的に提出されている。
技術分野
本発明は、一般には、細胞へのウイルスによる形質導入の方法の有効性を改善することに関する。より詳細には、本発明は、治療適応症に対して有用であり得る、ヒト造血幹細胞(HSC)などの細胞へのウイルスおよび/またはウイルスベクターを用いた形質導入の効率を改善するために有用な方法および材料を提供する。
食品医薬品局(Food and Drug Administration)(FDA)は、販売のためのいかなるヒト遺伝子治療製品もまだ承認していない。現行の遺伝子治療は実験的なものであり、臨床試験において大きな成功は証明されていない。1990年に開始された最初の遺伝子治療の臨床試験からほとんど進歩していない。1999年に、18歳のJesse Gelsingerが死亡して、遺伝子治療は重大な妨げに直面した。Jesseは、オルニチントランスカルバミラーゼ欠損症(ornithine transcarboxylase deficiency)(OTCD)に対する遺伝子治療試験に参加していた。彼は、処置を開始した4日後に多臓器不全により死亡した。彼の死亡はアデノウイルスキャリアに対する重度の免疫応答によって誘発されたものと考えられている。
本発明は、一般に、ウイルスによる形質導入効率を改善するための、プロスタグランジンEP受容体シグナル伝達を増加させる化合物を含む方法および組成物を提供する。本発明の組成物および方法は、さらに、ウイルスおよび/またはウイルスベクターを用いてヒト造血幹細胞(HSC)などの細胞に形質導入するための、より安全であり、より信頼できる方法を提供する。組成物および方法は、造血幹細胞遺伝子治療を用いた処置に適した治療適応症に対して有用である。
本発明は、例えば、以下の項目も提供する。
(項目1)
レトロウイルスと一緒に培養した細胞の形質導入効率を上昇させるための方法であって、該細胞および該レトロウイルスを、プロスタグランジンEP受容体シグナル伝達を増加させる化合物を含む培養培地中で培養する工程を含む方法。
(項目2)
前記細胞が幹細胞または前駆細胞である、項目1に記載の方法。
(項目3)
前記幹細胞または前駆細胞が、胚性幹細胞および人工多能性幹細胞からなる群から選択される、項目2に記載の方法。
(項目4)
前記幹細胞または前駆細胞が、間葉幹細胞、造血幹細胞、神経幹細胞、網膜幹細胞、心筋幹細胞、骨格筋幹細胞、脂肪組織由来幹細胞、軟骨形成幹細胞、肝幹細胞、腎幹細胞、および膵幹細胞からなる群から選択される、項目2に記載の方法。
(項目5)
前記幹細胞または前駆細胞が造血幹細胞または造血前駆細胞である、項目2に記載の方法。
(項目6)
前記細胞が、骨芽細胞、軟骨細胞、脂肪細胞、骨格筋、心筋、ニューロン、星状膠細胞、オリゴデンドロサイト、シュワン細胞、網膜細胞、角膜細胞、皮膚細胞、単球、マクロファージ、好中球、好塩基球、好酸球、赤血球、巨核球、樹状細胞、Tリンパ球、Bリンパ球、NK細胞、胃細胞、腸細胞、平滑筋細胞、血管細胞、膀胱細胞、膵アルファ細胞、膵ベータ細胞、膵デルタ細胞、肝細胞、腎細胞、副腎細胞、および肺細胞からなる群から選択される、項目1に記載の方法。
(項目7)
前記細胞が造血幹細胞または造血前駆細胞である、項目1に記載の方法。
(項目8)
前記造血幹細胞または造血前駆細胞の少なくとも約50%が形質導入されている、項目7に記載の方法。
(項目9)
前記造血幹細胞または造血前駆細胞の少なくとも約75%が形質導入されている、項目7に記載の方法。
(項目10)
前記造血幹細胞または造血前駆細胞の少なくとも約90%が形質導入されている、項目7に記載の方法。
(項目11)
プロスタグランジンEP受容体シグナル伝達を増加させる前記化合物が、PGA2;PGB2;PGD2;PGE1;PGE2;PGF2;PGI2;PGH2;PGJ2;ならびにその前駆体、代謝産物、誘導体および類似体からなる群から選択される、項目1から10までのいずれか一項に記載の方法。
(項目12)
プロスタグランジンEP受容体シグナル伝達を増加させる前記化合物が、15d−PGJ2;デルタ12−PGJ2;2−ヒドロキシヘプタデカトリエン酸(HHT);トロンボキサンA2;トロンボキサンB2;イロプロスト;トレプロスチニル;トラボプロスト;カルボプロスト・トロメタミン;タフルプロスト;ラタノプロスト;ビマトプロスト;イソプロピルウノプロストン;クロプロステノール;エストロファン;スーパーファン;ミソプロストール;ブタプロスト;リノール酸;13(s)−HODE;LY171883;ミード酸;エイコサトリエン酸;エポキシエイコサトリエン酸;ONO−259;Cay1039;PGE2受容体アゴニスト;16,16−ジメチルPGE2;19(R)−ヒドロキシPGE2;16,16−ジメチルPGE2p−(p−アセトアミドベンズアミド)フェニルエステル;11−デオキシ−16,16−ジメチルPGE2;9−デオキシ−9−メチレン−16,16−ジメチルPGE2;9−デオキシ−9−メチレンPGE2;スルプロストン;PGE2セリノールアミド;PGE2メチルエステル;16−フェニルテトラノルPGE2;15(S)−15−メチルPGE2;15(R)−15−メチルPGE2;BIO;8−ブロモ−cAMP;フォルスコリン;Bapta−AM;フェンジリン;ニカルジピン;ニフェジピン;ピモジド;ストロファンチジン;ラナトシド;L−Arg;ニトロプルシドナトリウム;バナジン酸ナトリウム;ブラジキニン;メベベリン;フルランドレノリド;アテノロール;ピンドロール;ガボキサドール;キヌレン酸;ヒドララジン;チアベンダゾール;ビククリン;ベサミコール;ペルボシド;イミプラミン;クロルプロパミド;1,5−ペンタメチレンテトラゾール;4−アミノピリジン;ジアゾキシド;ベンフォチアミン;12−メトキシドデセン酸;N−ホルミル−Met−Leu−Phe;ガラミン;IAA94;およびクロロトリアニセンからなる群から選択される、項目1から10までのいずれか一項に記載の方法。
(項目13)
プロスタグランジンEP受容体シグナル伝達を増加させる前記化合物が、プロスタグランジンE2(PGE2)、または16,16−ジメチルPGE2からなる群から選択される、項目1から10までのいずれか一項に記載の方法。
(項目14)
前記細胞およびレトロウイルスをヒストン脱アセチル化酵素(HDAC)阻害剤の存在下で培養する工程をさらに含む、項目1から13までのいずれか一項に記載の方法。
(項目15)
前記HDAC阻害剤が、トリコスタチンA(TSA)、バルプロ酸(VPA)、酪酸ナトリウム、スベロイルアニリドヒドロキサム酸(SAHA)、フェニル酪酸ナトリウム、デプシペプチド、トラポキシン(TPX)、環状ヒドロキサム酸含有ペプチド1(CHAPl)、MS−275、LBH589、およびPXD−101からなる群から選択される、項目14に記載の方法。
(項目16)
前記レトロウイルスがレンチウイルスである、項目1から15までのいずれか一項に記載の方法。
(項目17)
前記レトロウイルスがヒト免疫不全ウイルス(HIV)ウイルスである、項目1から16までのいずれか一項に記載の方法。
(項目18)
前記レトロウイルスが水疱性口内炎ウイルスGタンパク質(VSV−G)エンベロープタンパク質でシュードタイピングされている、項目1から17までのいずれか一項に記載の方法。
(項目19)
前記細胞を、形質導入の前にプロスタグランジンEP受容体シグナル伝達を増加させる前記化合物の存在下で培養する、項目1から18までのいずれか一項に記載の方法。
(項目20)
前記細胞を、プロスタグランジンEP受容体シグナル伝達を増加させる前記化合物と一緒に少なくとも約2時間にわたって培養する、項目19に記載の方法。
(項目21)
前記細胞を、プロスタグランジンEP受容体シグナル伝達を増加させる前記化合物と一緒に少なくとも約4時間にわたって培養する、項目19に記載の方法。
(項目22)
前記細胞を、形質導入の間にプロスタグランジンEP受容体シグナル伝達を増加させる前記化合物の存在下で培養する、項目1から19までのいずれか一項に記載の方法。
(項目23)
前記細胞を、プロスタグランジンEP受容体シグナル伝達を増加させる前記化合物の存在下で少なくとも約24時間にわたって培養する、項目22に記載の方法。
(項目24)
前記細胞を、形質導入の最初の24時間の間に、プロスタグランジンEP受容体シグナル伝達を増加させる前記化合物の存在下で培養する、項目21から23までのいずれか一項に記載の方法。
(項目25)
前記細胞を、形質導入の最初の48時間の間に、プロスタグランジンEP受容体シグナル伝達を増加させる前記化合物の存在下で培養する、項目21から24までのいずれか一項に記載の方法。
(項目26)
前記レトロウイルスが、
a)左側の(5’)レトロウイルスLTRと、
b)目的の遺伝子に作動可能に連結した発現制御配列と、
c)右側の(3’)レトロウイルスLTRと
を含むベクターを含む、項目1から25までのいずれか一項に記載の方法。
(項目27)
前記レトロウイルスが、
a)左側の(5’)HIV−1 LTRと、
b)プサイパッケージング配列(Ψ+)と、
c)HIV−1セントラルポリプリントラクト/DNAフラップ(cPPT/FLAP)と、
d)rev応答エレメント(RRE)と、
e)目的の遺伝子に作動可能に連結したβ−グロビンプロモーターおよびβ−グロビン遺伝子座制御領域(LCR)と、
f)
i)1つまたは複数のインスレーターエレメント、または
ii)ウサギβ−グロビンポリA配列(rβgpA)
を含む右側の(3’)レトロウイルスLTRと
を含むベクターを含む、項目8から26までのいずれか一項に記載の方法。
(項目28)
前記造血幹細胞または造血前駆細胞を異常ヘモグロビン症に罹患している患者に投与する、項目8から26までのいずれか一項に記載の方法。
(項目29)
前記異常ヘモグロビン症がβ−サラセミアまたは鎌状赤血球症である、項目28に記載の方法。
(項目30)
前記レトロウイルスが、
(a)左側の(5’)HIV−1 LTRと、
(b)プサイ(Ψ)パッケージングシグナルと、
(c)cPPT/FLAPと、
(d)RREと、
(e)ヒトABCD1ポリペプチドをコードするポリヌクレオチドに作動可能に連結したMNDプロモーターと、
(f)右側の(3’)HIV−1 LTRと、
(g)ウサギβ−グロビンポリアデニル化配列と
を含むベクターを含む、項目8から26までのいずれか一項に記載の方法。
(項目31)
前記レトロウイルスが複製欠損性である、項目1から30までのいずれか一項に記載の方法。
(項目32)
前記造血幹細胞または造血前駆細胞を副腎白質ジストロフィーまたは副腎脊髄神経障害に罹患している患者に投与する、項目30に記載の方法。
配列番号1は、ヒトアルファグロビンcDNAのポリヌクレオチド配列を示す。
A.概要
本発明は、一般には、改善された遺伝子治療組成物、およびそれを使用して、遺伝的障害を処置する、予防する、または軽減する方法に関する。遺伝子治療に関する1つの著しい難題は、被験体に送達される治療用遺伝子を含む細胞の形質導入効率を上昇させることであり、ここで、調整された細胞は非形質導入細胞に対する内因性の選択的利点を有さない。
別段の定義のない限り、本明細書において使用される全ての技術用語および科学用語は、本発明が属する技術分野の当業者に一般に理解されるものと同じ意味を有する。本発明の目的に関して、以下の用語が下で定義されている。
sequence)の調節解除された発現をもたらす可能性がある組み込み部位の影響(すなわち、位置の影響;例えば、Burgess−Beusseら、2002年、Proc. Natl. Acad. Sci.、USA、99巻:16433頁;Zhanら、2001年、Hum. Genet.、109巻:471頁を参照されたい)から保護することに寄与し得る。いくつかの実施形態では、移行ベクターは、3’LTRに1つまたは複数のインスレーターエレメントを含み、プロウイルスを宿主ゲノムに組み込む際に、プロウイルスは、3’LTRの重複によって5’LTRまたは3’LTRの両方に1つまたは複数のインスレーターを含む。本発明において使用するための適切なインスレーターとしては、これだけに限定されないが、ニワトリβ−グロビンインスレーター(参照により本明細書に組み込まれるChungら、1993年、Cell 74巻:505頁;Chungら、1997年、PNAS 94巻:575頁;およびBellら、1999年、Cell 98巻:387頁を参照されたい)が挙げられる。インスレーターエレメントの例としては、これだけに限定されないが、ニワトリHS4などのβ−グロビン遺伝子座由来のインスレーターが挙げられる。
好ましい実施形態では、本発明のベクターおよび/またはプラスミドは、1つまたは複数の目的のポリヌクレオチド、例えば、グロビン遺伝子またはABCD1遺伝子を含む。ある実施形態では、目的のポリヌクレオチド、例えばグロビン遺伝子は、造血性の疾患または障害の処置、予防、または軽減において治療効果をもたらすポリペプチドをコードし、該ポリペプチドは、「治療用ポリペプチド」と称することができる。例えば、その完全な開示および特許請求の範囲が参照により本明細書に詳細に組み込まれる米国特許第6,051,402号および同第7,901,671号を参照されたい。例えば、配列番号1、配列番号5、配列番号10、および配列番号14を参照されたい。
レトロウイルスベクターおよびレンチウイルスベクターは試験され、目的の遺伝子を広範囲の標的細胞のゲノムに安定に導入するための、例えば治療的ポリペプチドをエンコードするための、適切な送達ビヒクルであることが見いだされている。本発明は、一部において、遺伝子治療を提供するために被験体に投与される細胞の集団に対する遺伝子治療ベクターの改善された送達を意図している。
本発明は、一部において、標的細胞への形質導入効率を有意に増加させる方法および組成物を意図している。いかなる特定の理論にも縛られることを望むことなく、本発明の組成物および方法を用いて、有意に少ないウイルスを用いて有意に多くの細胞に形質導入し、それにより、治療用細胞のゲノムにおけるゲノムの変質(alteration)および/または癌原遺伝子の挿入活性化のリスクを最小化することができることが意図されている。治療用細胞における癌原遺伝子の挿入活性化および他のゲノムの変質のリスクを最小化することは、それにより、がん様特性を含む形質導入された細胞がin vivoにおいてクローン的に増大し、がん、腫瘍または異常な細胞増殖を伴う他の疾患を生じさせる機会が最小限になるので、適切な遺伝子治療プロトコールを案出することおける重要な考慮事項である。さらに、当技術分野では、大量のウイルスを用いて形質導入することは、一般に、形質導入された細胞に対して細胞傷害性である可能性があることが留意されている。したがって、本発明の組成物および方法により、形質導入された細胞の生存性がさらに増強される。したがって、本発明は、より安全かつより効率的な遺伝子治療を提供する。
25巻:18S:1065頁を参照されたい)、酪酸ナトリウム(NaBu)(例えば、Hanら、(2007年)Immunology Letters 108巻:143〜150頁を参照されたい)、SAHA(スベロイルアニリドヒドロキサム酸またはボリノスタット)(例えば、Kellyら、(2005年)Nature Clinical Practice Oncology 2巻:150〜157頁を参照されたい)、フェニル酪酸ナトリウム(例えば、Goreら、(2006年)Cancer Research 66巻:6361〜6369頁を参照されたい)、デプシペプチド(FR901228、FK228)(例えば、Zhuら、(2003年)Current Medicinal Chemistry 3巻(3号):187〜199頁を参照されたい)、トラポキシン(TPX)(例えば、Furumaiら、(2001年)PNAS 98巻(1号):87〜92頁を参照されたい)、環状ヒドロキサム酸含有ペプチド1(CHAP1)(Furumai 上記を参照されたい)、MS−275(例えば、参照により本明細書に組み込まれるCarninciら、WO2008/126932を参照されたい))、LBH589(例えば、参照により本明細書に組み込まれるGohら、WO2008/108741を参照されたい)およびPXD−101(Goh、上記を参照されたい)を限定せずに含むHDAC阻害剤が挙げられる。
Essential Medium(登録商標)、F−12K medium(登録商標)、Iscove’s Modified Dulbecco’s Medium(登録商標)、RPMI−1640 medium(登録商標)、およびserum−free medium for culture and expansion of hematopoietic cells SFEM(登録商標)が挙げられる。多くの培地は、ピルビン酸ナトリウムを含む、または含まない低グルコース調合物としても利用可能である。
本発明は、さらに、レトロウイルスおよびプロスタグランジンシグナル伝達を増加させる化合物1つまたは複数を含む培養培地における細胞の培養物を含む、細胞に基づく組成物を意図している。本明細書全体を通して考察されている通り、特定の実施形態では、本組成物および方法は、ex vivoおよびin vivoにおける細胞に基づく遺伝子治療に有用である。いくつかの実施形態では、細胞培養培地は、薬学的に許容される細胞培養培地である。
本発明の製剤および組成物は、単独で、または1つまたは複数の他の治療のモダリティと組み合わせて、細胞、組織、器官、または動物に投与するための、薬学的に許容されるまたは生理的に許容される溶液(例えば、培養培地)中に製剤化された、本明細書に記載の、任意の数の形質導入された細胞または形質導入されていない細胞またはそれらの組み合わせ、ウイルスベクター、ポリペプチド、ポリヌクレオチド、および1つまたは複数の化合物、例えば、プロスタグランジンシグナル伝達を増加させる化合物および/またはHDAC阻害剤の組み合わせを含んでよい。
形質導入された細胞および対応するレトロウイルスベクターにより、遺伝子治療の改善された方法がもたらされる。本明細書で使用される場合、「遺伝子治療」という用語は、細胞のゲノムへの遺伝子の導入を指す。種々の実施形態では、本発明のウイルスベクターは、造血幹細胞治療に適した単一遺伝子の疾患、障害、もしくは状態または造血系の疾患、障害、もしくは状態を有すると診断された被験体またはそれを有する疑いがある被験体に治癒的、予防的、または軽減的利益をもたらすポリペプチドをコードする治療用導入遺伝子を発現する造血発現制御配列を含む。
形質導入のための細胞の予備刺激
CD34+細胞(AllCells)のバイアルを1つ、37℃で1〜2分間インキュベートすることによって解凍し、内容物を15mLのコニカルチューブ中10mLの幹細胞成長培地(Stem Cell Growth Media)(以降SCGMと称される)に移した。細胞を標準の卓上遠心分離機において1500RPMで5分間回転させ、10mLのSCGMに再懸濁させ、血球計で計数した。適切な数の細胞と相関する体積を新しい15mLのコニカルチューブに移し、再度1500RPMで5分間回転させた。細胞をSCGM+1×サイトカイン(100ng/mLのSCF、100ng/mLのTPO、100ng/mLのFltL、および30ng/mLのIL−3)中に所望の細胞濃度まで再懸濁させ、標準の加湿組織培養インキュベーター(5%CO2)内、37℃で滅菌非接着性表面上にプレーティングした。
形質導入
予備刺激した細胞(実施例1)を18〜24時間培養した後に計数した。細胞を収集し、1500RPMで5分間回転させた。予備刺激したCD34+細胞1.2×106個を60μLの10×サイトカイン(1000ng/mLのSCF、1000ng/mLのTPO、1000ng/mLのFltL、および300ng/mLのIL−3)、7.8μLの硫酸プロタミン、111μLのウイルス上清、および361.2μLのSCGMに再懸濁させた。90μLの細胞/ウイルス懸濁液(細胞約200,000個)を標準の非接着性96ウェルプレートの各ウェルに加えた。このウイルスによる形質導入ステップの間に、dmPGE2を100μM、50μM、25μM、12.5μM、1μM、または0μMの最終濃度で加えた。ウイルスストックの力価は2.7×108TU/mLであり、感染多重度(MOI)は約25であった。
細胞のdmPGE2刺激
予め処理したdmPGE2(Cayman Chemicals)1mgから、DMSO中10mMのdmPGE2の一定分量を調製した。簡単に述べると、dmPGE2のバイアルに、酢酸メチルが蒸発するまで空気をピペットで入れた。263μLのDMSOをバイアルに存在するPGE2に加え、25μLの一定分量を1.5mLのEppendorfチューブに加え、−80℃で保管した。dmPGE2をSCGMで段階希釈することによって10×作業ストック溶液を調製し、次いで、表2に従って適切な作業濃度で細胞に加えた。次いで、細胞を標準の加湿組織培養インキュベーター(5%CO2)内、37℃でインキュベートした。
バリデーションアッセイ
バリデーションアッセイのための細胞の調製
細胞を、ウイルスおよびdmPGE2と一緒に24時間培養した後に、洗浄し、その後、機能バリデーションアッセイを行った。細胞を96ウェルU底プレートに移し、標準の卓上遠心分離機において1500RPMで5分間回転させることによって、洗浄を実施した。培地を吸引し、細胞を200μLのSCGMに再懸濁させた。細胞を、再度1500RPMで5分間回転させ、培地を吸引した。細胞を、再度200μLのSCGMに再懸濁させ、次いで、1500RPMで5分間回転させ、再度培地を吸引した。特定の機能バリデーションアッセイは下に記載されている。
洗浄した細胞を、200μLのSCGM+1×サイトカイン(実施例1に記載の通り)に再懸濁させ、追加の800μLのSCGM+1×サイトカインを含有する標準の12ウェル非接着性組織培養プレートに移した。細胞をさらに6日間、標準の加湿組織培養インキュベーター(5%CO2)内で維持し、次いで、ベクターのコピー数の解析(実施例5)およびFACS分析に供した。FACS分析については、細胞を、ウイルスにコードされる導入遺伝子、緑色蛍光タンパク質(GFP)の存在についてアッセイした。培養細胞のプール内のウイルスにより標識された細胞の発生頻度を集団内のGFP+細胞の発生頻度として数量化した。標識された細胞の平均蛍光強度を数量化した。種々の濃度のdmPGE2を用いた7日間の液体培養アッセイの結果が表3に示されている。
洗浄した細胞を、200μLのSCGMに再懸濁させ、次いで、サイトカインを補充したメチルセルロース(例えば、Methocult M4434 Classic)の一定分量3mLに移した。次いで、1.5mLをとがっていない16−ゲージの針を使用して平行35mm組織培養ディッシュに移した。ディッシュを、標準の加湿組織培養インキュベーター内で14〜16日間維持し、コロニーを、サイズ、形態、および細胞の組成についてスコア化した。次いで、個々のコロニーをその後ベクターのコピー数の解析(実施例5)のために選定したか、または35mmディッシュ全体の内容物をプールし、次いで、ベクターのコピー数の解析(実施例5)に供した。
細胞を、200μLのSCGMに再懸濁させ、計数し、次いで、予めプレーティングしたMS−5間質層に、種々の希釈(100U/mL−100μg/mLのpen−strepを補充したStemSpan SFEM(StemCell Technologies、Cat番号09650)200μL中、1ウェル当たり細胞2000個;1000個;500個;250個;125個;62個;31個;16個)で、かつ1希釈当たり24反復で移した。週に1回の間隔で100μLを新鮮な培地100μLで交換した。5週目に、培養物を収穫した。100μLを破棄し、細胞を残りの100μLで洗い流し、ウェルを新鮮な培地50μLですすぎ、全内容物を、Methocult(商標)H4434中に播種し、細胞懸濁液150μLを600μLのMethocult H4434を用いてホモジナイズし、12ウェルプレートの1つのウェルに14日間プレーティングした。次いで、コロニーを計数した。各希釈について分析した少なくとも1つのコロニー(細胞40個超)を含有するウェルの数およびウェルの総数を用い、L−calcソフトウェア(Stem cell technologies)を使用してLTC−ICの発生頻度および95%信頼区間を算出した。各処理群からの100コロニーを選び取って100個の異なるウェルに入れ、ベクターの存在について個別にスコア化した。各処理群から100コロニーをプールし、ゲノムDNAを抽出し、平均ベクターコピー数をqPCRによって評価した(実施例5)。
dmPGE2が最小限の残留毒性でヒト長期造血幹細胞へのウイルスによる形質導入を促進するかどうかを決定するために、形質導入された細胞を洗浄し、リン酸緩衝食塩水(PBS)に再懸濁させ、放射線照射した成体NSGマウスの尾静脈へと移植した。マウスを、標準のIACUC動物管理ガイドラインに従って病原体を含まない環境に収容した。計画した時点で、末梢血に対するヒトドナーに由来する寄与を、標準のプロトコールによってマウスから収集することによって数量化した。簡単に述べると、2%デキストランを用いて赤血球をペレット化し、次いで、上清を赤血球溶解緩衝液で処理することによってさらに清澄にした。次いで、単核細胞をMajetiらによる、Cell Stem Cell 2007年に記載されている通りフルオロフォアとコンジュゲートした抗体を用いて染色し、LSR−II(Becton Dickinson)でフローサイトメトリーによって分析した。
dmPGE2により、レンチウイルスベクターの組み込み部位の優先度が変化するかどうかを決定するために、dmPGE2処理した、ウイルスにより形質導入されたヒト造血幹細胞および造血前駆細胞を移植したマウス由来の骨髄試料、ならびにモック処理した、ウイルスにより形質導入されたヒト造血幹細胞および造血前駆細胞を移植したマウス由来の骨髄試料を、線形増幅媒介PCRに供した(Cartier、(2009年)Science 326巻(5954号):818〜23頁)。簡単に述べると、1〜1000ngのDNAが、レトロウイルスLTR特異的ビオチン化プライマーを使用した線形PCRのための鋳型としての機能を果たした。線形PCR産物を常磁性ビーズで分離した。さらに第2鎖DNA合成、制限消化(Tsp509I、NlaIIIまたはHpyCH4IV)およびリンカーカセットのライゲーションを半固体相で実現し、その後に2つの追加の指数関数的PCRステップを続けた。生じたLAM−PCRアンプリコンを、454パイロシークエンシング(GS Flx;Roche Diagnostics)のために、追加の指数関数的PCRを実施してGS Flx特異的増幅および配列決定プライマーAおよびBをLAM−PCRアンプリコンの両末端に付加することによってさらに調製した。プライマーの設計は製造者によって示された通り行った。異なる試料を単一の配列決定の実行で同時に分析するために6塩基の認識配列をプライマーAに組み入れた。精製されたLAM−PCR産物40ngを使用した。PCR条件は以下の通りであった:95℃で120秒間の最初の変性;95℃で45秒間、60℃で45秒間および72℃で60秒間を12サイクル;72℃で300秒間の最後の伸長。LAM−PCRアンプリコン配列をトリミングし、BLASTを使用してアラインメントした。
ベクターのコピー数の解析
簡単に述べると、標準のプロトコールによって(例えば、QiagenのDNEasyカラムによって)細胞から全ゲノムDNAを単離した。ゲノムDNAを、ウイルスLTRおよびヒトベータアクチンに対するTaqManプローブを用いた定量的リアルタイムポリメラーゼ連鎖反応(qRT−PCR)に供した。ウイルスシグナルおよびベータアクチンシグナルについてのCt値を標準化した対照に対して正規化し、ベータアクチンのコピー当たりのウイルスコピーの数を算出した。GFPをコードするウイルス構築物を使用したところ、ベクターのコピー数と平均蛍光強度(実施例4)の間に直線関係が観察された。種々の濃度のdmPGE2を用いたベクターのコピー数(VCN)の解析についての結果を表3A〜Cに示す。
CD34+細胞のウイルスによる形質導入の促進における時間経過およびdmPGE2の用量応答
MCD−34+細胞を解凍し、SCF、TPO、FltLおよびIL3で予備刺激し、次いで、GFP+レンチウイルスを用いて感染多重度25で形質導入した。細胞を、ウイルスによる形質導入ステップ(24〜25時間の培養;24〜26時間の培養;24〜28時間の培養;または24〜48時間の培養)の間、dmPGE2に曝露させ、次いで、洗浄し、およそ1週間培養した後にフローサイトメトリーによって分析した。あるいは、細胞を、予備刺激ステップ(22〜24時間の培養;23〜24時間の培養)の間、dmPGE2に曝露させた。GFPについて陽性である細胞の百分率が表4に示されている。
dmPGE2の存在下でレンチウイルスベクターを用いてHSCに形質導入した後のベータサラセミアまたは鎌状赤血球症の調整
動員末梢血は、インフォームドコンセントを行った患者から、承認された治験審査委員会(IRB)プロトコールに従って、アフェレーシスによって収集する。フィコール勾配を用いて赤血球を取り出し、Miltenyi CliniMACS system(Miltenyi Biotec)を使用してCD34+選択した後にCD34富化細胞を得る。細胞を、ヒトSCF、FltL、TPO、およびIL3を用いて、1mL当たり細胞およそ4E6個の濃度で18〜24時間にわたって予備刺激する。次いで、細胞に、ヒトβ−グロビンA−T87Q遺伝子を有するLentiglobin GTPを感染多重度25で用い、SCF、FltL、TPO、IL3、硫酸プロタミン、およびdmPGE2の存在下で18〜24時間にわたって形質導入する。
dmPGE2の存在下でHSCにレンチウイルスベクターを用いて形質導入した後の副腎白質ジストロフィーの調整
動員末梢血は、インフォームドコンセントを行った患者から、承認された治験審査委員会(IRB)プロトコールに従って、アフェレーシスによって収集する。フィコール勾配を用いて赤血球を取り出し、Miltenyi CliniMACS system(Miltenyi Biotec)を使用してCD34+選択した後にCD34富化細胞を得る。細胞を、ヒトSCF、FltL、TPO、およびIL3を用いて、1mL当たり細胞およそ4E6個の濃度で18〜24時間にわたって予備刺激する。次いで、細胞に、ヒトABCD1遺伝子を有するLenti−D GTPを感染多重度25で用い、SCF、FltL、TPO、IL3、硫酸プロタミン、およびdmPGE2の存在下で18〜24時間にわたって形質導入する。
Claims (9)
- レンチウイルスと一緒に培養した造血幹細胞または造血前駆細胞の形質導入効率を上昇させるためのin vitro方法であって、該造血幹細胞または造血前駆細胞および該レンチウイルスを、プロスタグランジンE2(PGE2)または16,16−ジメチルPGE2を含む培養培地中で培養する工程を含む方法であって、該造血幹細胞または造血前駆細胞は、形質導入の間に、該PGE2または該16,16−ジメチルPGE2の存在下で培養される、方法。
- 形質導入の前またはその間に、前記造血幹細胞または造血前駆細胞が、前記細胞の増大を促進する1つまたは複数の増殖因子の存在下で培養される、請求項1に記載の方法。
- (a)前記造血幹細胞または造血前駆細胞の少なくとも約50%が形質導入されているか、
(b)前記造血幹細胞または造血前駆細胞の少なくとも約75%が形質導入されているか、あるいは、
(c)前記造血幹細胞または造血前駆細胞の少なくとも約90%が形質導入されている、請求項1に記載の方法。 - 前記造血幹細胞または造血前駆細胞およびレンチウイルスをヒストン脱アセチル化酵素(HDAC)阻害剤の存在下で培養する工程をさらに含み、必要に応じて、該HDAC阻害剤が、トリコスタチンA(TSA)、バルプロ酸(VPA)、酪酸ナトリウム、スベロイルアニリドヒドロキサム酸(SAHA)、フェニル酪酸ナトリウム、デプシペプチド、トラポキシン(TPX)、環状ヒドロキサム酸含有ペプチド1(CHAPl)、MS−275、LBH589、およびPXD−101からなる群から選択される、請求項1から3までのいずれか一項に記載の方法。
- (a)前記レンチウイルスが、ヒト免疫不全ウイルス(HIV)ウイルスである、および/または
(b)前記レンチウイルスが、水疱性口内炎ウイルスGタンパク質(VSV−G)エンベロープタンパク質でシュードタイピングされている
請求項1から4までのいずれか一項に記載の方法。 - 前記レンチウイルスが、
(a)左側の(5’)レンチウイルスLTRと、
(b)目的の遺伝子に作動可能に連結した発現制御配列と、
(c)右側の(3’)レンチウイルスLTRと
を含むベクターを含む、請求項1から5までのいずれか一項に記載の方法。 - (I)前記レンチウイルスが、
(a)左側の(5’)HIV−1 LTRと、
(b)プサイパッケージング配列(Ψ+)と、
(c)HIV−1セントラルポリプリントラクト/DNAフラップ(cPPT/FLAP)と、
(d)rev応答エレメント(RRE)と、
(e)目的の遺伝子に作動可能に連結したβ−グロビンプロモーターおよびβ−グロビン遺伝子座制御領域(LCR)と、
(f)
i)1つまたは複数のインスレーターエレメント、または
ii)ウサギβ−グロビンポリA配列(rβgpA)
を含む右側の(3’)レンチウイルスLTRと
を含むベクターを含む、請求項3から6までのいずれか一項に記載の方法。 - 前記レンチウイルスが、
(a)左側の(5’)HIV−1 LTRと、
(b)プサイ(Ψ)パッケージングシグナルと、
(c)cPPT/FLAPと、
(d)RREと、
(e)ヒトABCD1ポリペプチドをコードするポリヌクレオチドに作動可能に連結したMNDプロモーターと、
(f)右側の(3’)HIV−1 LTRと、
(g)ウサギβ−グロビンポリアデニル化配列と
を含むベクターを含む、請求項3から6までのいずれか一項に記載の方法。 - 前記レンチウイルスが複製欠損性である、請求項1から8までのいずれか一項に記載の方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161541736P | 2011-09-30 | 2011-09-30 | |
US61/541,736 | 2011-09-30 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014533413A Division JP6285863B2 (ja) | 2011-09-30 | 2012-09-28 | 改善されたウイルスによる形質導入のための化合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018099124A JP2018099124A (ja) | 2018-06-28 |
JP6745826B2 true JP6745826B2 (ja) | 2020-08-26 |
Family
ID=47996444
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014533413A Active JP6285863B2 (ja) | 2011-09-30 | 2012-09-28 | 改善されたウイルスによる形質導入のための化合物 |
JP2018017184A Expired - Fee Related JP6745826B2 (ja) | 2011-09-30 | 2018-02-02 | 改善されたウイルスによる形質導入のための化合物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014533413A Active JP6285863B2 (ja) | 2011-09-30 | 2012-09-28 | 改善されたウイルスによる形質導入のための化合物 |
Country Status (19)
Country | Link |
---|---|
US (4) | US9988644B2 (ja) |
EP (4) | EP4095236A1 (ja) |
JP (2) | JP6285863B2 (ja) |
KR (1) | KR102011532B1 (ja) |
CN (2) | CN103958667A (ja) |
AU (1) | AU2012315699B2 (ja) |
BR (1) | BR112014007782B1 (ja) |
CA (1) | CA2850484C (ja) |
CY (1) | CY1122654T1 (ja) |
DK (2) | DK3269802T3 (ja) |
EA (1) | EA032699B1 (ja) |
ES (3) | ES2632444T5 (ja) |
IL (2) | IL231812B (ja) |
IN (1) | IN2014CN02518A (ja) |
MX (2) | MX359398B (ja) |
PT (2) | PT2760994T (ja) |
SG (2) | SG10201602423TA (ja) |
UA (1) | UA114796C2 (ja) |
WO (1) | WO2013049615A1 (ja) |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3203374A1 (en) | 2008-11-06 | 2010-05-14 | Indiana University Research & Technology Corporation | Materials and methods to enhance hematopoietic stem cells engraftment procedures |
BR112014007782B1 (pt) | 2011-09-30 | 2021-06-01 | Bluebird Bio, Inc. | Método para aumentar a eficiência de transdução lentiviral de células progenitoras ou células-tronco hematopoiéticas cd34+, bem como usos terapêuticos de composição compreendendo as ditas células e de pge2, 16,16-dimetil pge2, ou seu análogo |
CA2880811C (en) | 2012-08-01 | 2021-12-07 | United Therapeutics Corporation | Treatment of pulmonary arterial hypertension with prostacyclin-treated endothelial progenitor cells |
JP6901823B2 (ja) | 2012-08-01 | 2021-07-14 | ユナイテッド セラピューティクス コーポレイション | 間葉系幹細胞による肺動脈性高血圧症の処置 |
US20150216903A1 (en) * | 2012-08-10 | 2015-08-06 | Bluebird Bio, Inc. | Compounds for improved viral transduction |
MX361412B (es) | 2012-11-27 | 2018-12-05 | Childrens Medical Center | Direccion de elementos reguladores distales de bcl11a para reinduccion de hemoglobina fetal. |
ES2963968T3 (es) | 2013-01-09 | 2024-04-03 | United Therapeutics Corp | Tratamiento de la vasculopatía con prostaciclina y células madre mesenquimatosas |
US10617721B2 (en) * | 2013-10-24 | 2020-04-14 | Ospedale San Raffaele S.R.L. | Methods for genetic modification of stem cells |
US20170173083A1 (en) * | 2014-03-26 | 2017-06-22 | The Brigham And Women's Hospital, Inc. | Compositions and methods for ex vivo expansion of human hematopoietic stem/progenitor cells |
EP3598984B1 (en) | 2014-04-25 | 2024-04-10 | The Children's Medical Center Corporation | Compositions and methods to treating hemoglobinopathies |
ES2835861T3 (es) | 2015-05-08 | 2021-06-23 | Childrens Medical Ct Corp | Direccionamiento de regiones funcionales del potenciador de BCL11A para la reinducción de hemoglobina fetal |
RU2630654C2 (ru) * | 2015-07-29 | 2017-09-11 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Балтийский Федеральный Университет имени Иммануила Канта" (БФУ им. И. Канта) | Способ хемогенетической регистрации и коррекции нейрогенеза на основе генетических конструкций для трансфекции астроцитов и нейронов |
CN105062979A (zh) * | 2015-08-21 | 2015-11-18 | 昆明理工大学 | 一种培养戊型肝炎病毒的方法 |
RU2021103425A (ru) * | 2016-02-12 | 2021-02-25 | Блубёрд Био, Инк. | Композиции, повышающие число копий вектора (чкв), и способы их применения |
US11326183B2 (en) | 2016-02-12 | 2022-05-10 | Bluebird Bio, Inc. | VCN enhancer compositions and methods of using the same |
US20190161530A1 (en) * | 2016-04-07 | 2019-05-30 | Bluebird Bio, Inc. | Chimeric antigen receptor t cell compositions |
US10898494B2 (en) | 2016-05-05 | 2021-01-26 | Liquidia Technologies, Inc. | Dry powder treprostinil for the treatment of pulmonary hypertension |
CA3041514A1 (en) | 2016-10-24 | 2018-05-03 | United Therapeutics Corporation | Enhancement of msc immunomodulatory properties by treprostinil |
AU2017368050A1 (en) | 2016-11-29 | 2019-06-20 | Puretech Lyt, Inc. | Exosomes for delivery of therapeutic agents |
US11261441B2 (en) | 2017-03-29 | 2022-03-01 | Bluebird Bio, Inc. | Vectors and compositions for treating hemoglobinopathies |
CA3057862A1 (en) * | 2017-03-29 | 2018-10-04 | Bluebird Bio, Inc. | Vectors and compositions for treating hemoglobinopathies |
US11788087B2 (en) | 2017-05-25 | 2023-10-17 | The Children's Medical Center Corporation | BCL11A guide delivery |
CN111247149A (zh) * | 2017-09-15 | 2020-06-05 | 威斯康星州医药大学股份有限公司 | 肾脏靶向的环氧二十碳三烯酸(eet)类似物 |
FR3074189A1 (fr) * | 2017-11-30 | 2019-05-31 | Assistance Publique - Hopitaux De Paris | Methode de generation de greffons de cellules souches hematopoietiques |
WO2019196816A1 (zh) * | 2018-04-13 | 2019-10-17 | 诺未科技(北京)有限公司 | 丁酸钠的用途及含有丁酸钠的培养体系 |
CN109207427B (zh) * | 2018-09-17 | 2020-12-08 | 诺未科技(银川)有限公司 | 一种将人造血祖细胞转变为造血干细胞的方法 |
EP3784695B1 (en) * | 2018-04-27 | 2023-08-09 | The Medical College of Wisconsin, Inc. | Use of lentivector-transduced t-rapa cells for amelioration of lysosomal storage disorders |
US20220389448A1 (en) * | 2019-06-28 | 2022-12-08 | The Children's Hospital Of Philadelphia | Compositions and methods for treating anemia |
EP4045666A4 (en) * | 2019-10-16 | 2023-11-15 | Orchard Therapeutics (Europe) Limited | COMPOSITIONS AND METHODS FOR MODIFYING EUKARYOTIC CELLS |
CN113106098B (zh) * | 2021-04-21 | 2022-04-01 | 贵州医科大学 | 一种在红系细胞中特异表达人β珠蛋白的重组序列及其应用 |
AU2021202658A1 (en) | 2021-04-28 | 2022-11-17 | Fondazione Telethon | Gene therapy |
CN113336833A (zh) * | 2021-06-04 | 2021-09-03 | 广州伯尼兹生物科技有限公司 | 一种高效分泌表达猪流行性腹泻病毒s1蛋白的生产方法 |
WO2023133595A2 (en) | 2022-01-10 | 2023-07-13 | Sana Biotechnology, Inc. | Methods of ex vivo dosing and administration of lipid particles or viral vectors and related systems and uses |
GB202206346D0 (en) | 2022-04-29 | 2022-06-15 | Ospedale San Raffaele Srl | Gene therapy |
WO2024033802A2 (en) | 2022-08-11 | 2024-02-15 | Fondazione Telethon Ets | Gene therapy |
WO2024079644A1 (en) | 2022-10-11 | 2024-04-18 | Fondazione Telethon Ets | 3d cell culture methods |
WO2024081820A1 (en) | 2022-10-13 | 2024-04-18 | Sana Biotechnology, Inc. | Viral particles targeting hematopoietic stem cells |
WO2024119157A1 (en) | 2022-12-02 | 2024-06-06 | Sana Biotechnology, Inc. | Lipid particles with cofusogens and methods of producing and using the same |
Family Cites Families (74)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US568159A (en) | 1896-06-26 | 1896-09-22 | Veneering-machine | |
FR901228A (fr) | 1943-01-16 | 1945-07-20 | Deutsche Edelstahlwerke Ag | Système d'aimant à entrefer annulaire |
US4873192A (en) | 1987-02-17 | 1989-10-10 | The United States Of America As Represented By The Department Of Health And Human Services | Process for site specific mutagenesis without phenotypic selection |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
US5399493A (en) | 1989-06-15 | 1995-03-21 | The Regents Of The University Of Michigan | Methods and compositions for the optimization of human hematopoietic progenitor cell cultures |
US5725871A (en) | 1989-08-18 | 1998-03-10 | Danbiosyst Uk Limited | Drug delivery compositions comprising lysophosphoglycerolipid |
US5707644A (en) | 1989-11-04 | 1998-01-13 | Danbiosyst Uk Limited | Small particle compositions for intranasal drug delivery |
US5061620A (en) | 1990-03-30 | 1991-10-29 | Systemix, Inc. | Human hematopoietic stem cell |
US5466468A (en) | 1990-04-03 | 1995-11-14 | Ciba-Geigy Corporation | Parenterally administrable liposome formulation comprising synthetic lipids |
US5635387A (en) | 1990-04-23 | 1997-06-03 | Cellpro, Inc. | Methods and device for culturing human hematopoietic cells and their precursors |
US5399363A (en) | 1991-01-25 | 1995-03-21 | Eastman Kodak Company | Surface modified anticancer nanoparticles |
US5756353A (en) | 1991-12-17 | 1998-05-26 | The Regents Of The University Of California | Expression of cloned genes in the lung by aerosol-and liposome-based delivery |
US5460964A (en) | 1992-04-03 | 1995-10-24 | Regents Of The University Of Minnesota | Method for culturing hematopoietic cells |
DE69312487T2 (de) | 1992-05-18 | 1997-11-27 | Minnesota Mining & Mfg | Einrichtung zur transmucosalen wirkstoffabgabe |
CA2165679A1 (en) | 1993-06-21 | 1995-01-05 | Tim M. Townes | Anti-sickling hemoglobin |
US5543158A (en) | 1993-07-23 | 1996-08-06 | Massachusetts Institute Of Technology | Biodegradable injectable nanoparticles |
US5409813A (en) | 1993-09-30 | 1995-04-25 | Systemix, Inc. | Method for mammalian cell separation from a mixture of cell populations |
US5869039A (en) | 1993-10-15 | 1999-02-09 | Institut National De La Sante Et De La Recherche Medicale | X-linked adrenoleukodystrophy gene and corresponding protein |
WO1996009385A1 (en) | 1994-09-19 | 1996-03-28 | Massachusetts Institute Of Technology | Anti-sickling beta-globin protein, compositions and methods for treating sickle cell disease |
US5677136A (en) | 1994-11-14 | 1997-10-14 | Systemix, Inc. | Methods of obtaining compositions enriched for hematopoietic stem cells, compositions derived therefrom and methods of use thereof |
IE80468B1 (en) | 1995-04-04 | 1998-07-29 | Elan Corp Plc | Controlled release biodegradable nanoparticles containing insulin |
CA2233316C (en) * | 1995-09-29 | 2010-12-14 | Indiana University Foundation | Methods for enhanced virus-mediated dna transfer using molecules with virus- and cell-binding domains |
US6013516A (en) | 1995-10-06 | 2000-01-11 | The Salk Institute For Biological Studies | Vector and method of use for nucleic acid delivery to non-dividing cells |
US6057117A (en) | 1996-04-04 | 2000-05-02 | Chiron Corporation | Identification and use of selective inhibitors of glycogen synthase kinase 3 |
EP0915975A2 (en) | 1996-07-03 | 1999-05-19 | Chiron Corporation | Methods for administration of recombinant gene delivery vehicles for treatment of hemophilia |
US5994136A (en) | 1997-12-12 | 1999-11-30 | Cell Genesys, Inc. | Method and means for producing high titer, safe, recombinant lentivirus vectors |
FR2777909B1 (fr) | 1998-04-24 | 2002-08-02 | Pasteur Institut | Utilisation de sequences d'adn de structure triplex pour le tranfert de sequences de nucleotides dans des cellules, vecteurs recombinants contenant ces sequences triplex |
JP2002527101A (ja) | 1998-10-16 | 2002-08-27 | ノバルティス アクチエンゲゼルシャフト | ヒストンデアセチラーゼ阻害剤による造血幹細胞への遺伝子形質導入の改良及び自己再生の促進 |
AU2183900A (en) | 1998-12-24 | 2000-07-31 | Alcon Laboratories, Inc. | Ep4 receptor agonists for treatment of dry eye |
US7015037B1 (en) | 1999-08-05 | 2006-03-21 | Regents Of The University Of Minnesota | Multiponent adult stem cells and methods for isolation |
EP1219600A4 (en) | 1999-08-13 | 2004-11-03 | Taisho Pharmaceutical Co Ltd | PROSTAGLANDIN DERIVATIVES |
AU784195B2 (en) | 1999-11-12 | 2006-02-16 | Baxter Biotech Technology S.A.R.L. | Reduced side-effect hemoglobin compositions |
CN1272328C (zh) | 1999-12-17 | 2006-08-30 | 希龙公司 | 糖元合成酶激酶3的基于吡嗪的抑制剂 |
DK1132086T3 (da) | 2000-01-31 | 2006-08-28 | Pfizer Prod Inc | Anvendelse af prostaglandin (PGE2) selektive receptor 4 (EP4) agonister til behandling af akut og kronisk nyresvigt |
US20020013294A1 (en) | 2000-03-31 | 2002-01-31 | Delong Mitchell Anthony | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
DE60234824D1 (de) | 2001-05-01 | 2010-02-04 | Ca Nat Research Council | Induzierbares expressionssystem in eukaryotischen zellen |
AU2002347563A1 (en) | 2001-12-06 | 2003-06-17 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Use of cd34+ hematopoietic progenitor cells for the treatment of cns disorders |
WO2003056019A1 (en) | 2001-12-24 | 2003-07-10 | Es Cell International Pte Ltd | Method of transducing es cells |
WO2003065871A2 (en) | 2002-02-04 | 2003-08-14 | Millennium Pharmaceuticals Inc. | Methods and compositions for treating hematological disorders |
EP1539754A4 (en) | 2002-08-23 | 2009-02-25 | Novartis Vaccines & Diagnostic | BENZIMIDAZOLE QUINOLINONES AND USES THEREOF |
US7119200B2 (en) | 2002-09-04 | 2006-10-10 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
DE60333487D1 (de) | 2002-12-13 | 2010-09-02 | Genetix Pharmaceuticals Inc | Therapeutische retrovirus-vektoren für gentherapie |
EP1613742A2 (en) | 2003-04-08 | 2006-01-11 | YEDA RESEARCH AND DEVELOPMENT Co. LTD. | Stem cells having increased sensitivity to a chemoattractant and methods of generating and using same |
WO2004098531A2 (en) * | 2003-05-05 | 2004-11-18 | Virxsys Corporation | Increased transduction using abc transporter substrates and/or inhibitors |
US6747037B1 (en) | 2003-06-06 | 2004-06-08 | Allergan, Inc. | Piperidinyl prostaglandin E analogs |
IL158868A0 (en) | 2003-11-13 | 2004-05-12 | Yeda Res & Dev | Methods of generating and using stem cells enriched with immature primitive progenitor |
EP1760071A4 (en) | 2004-06-23 | 2008-03-05 | Ono Pharmaceutical Co | COMPOUND WITH S1P RECEPTOR BINDING ABILITY AND USE THEREOF |
EP1805139A2 (en) | 2004-10-26 | 2007-07-11 | Allergan, Inc. | Therapeutic and delivery methods of prostaglandin ep4 agonists |
US20080021078A1 (en) | 2006-07-18 | 2008-01-24 | Horizon Therapeutics, Inc. | Methods and medicaments for administration of ibuprofen |
WO2007041511A2 (en) | 2005-09-30 | 2007-04-12 | New York University | Hematopoietic progenitor kinase 1 for modulation of an immune response |
US8076315B2 (en) | 2005-10-14 | 2011-12-13 | The Board Of Trustees Of The University Of Illinois | Pharmacological treatments for sleep disorders (apnoe) with prostanoid receptor antagonists |
DE102005062741A1 (de) | 2005-12-22 | 2007-06-28 | Bayer Schering Pharma Ag | Fluorene und Carbazole als Liganden des EP2 Rezeptors |
CA2647201C (en) | 2006-03-24 | 2016-03-08 | Children's Medical Center Corporation | Method to modulate hematopoietic stem cell growth |
EP2021534B1 (en) * | 2006-04-27 | 2011-12-28 | Université de Montréal | Assessment and reduction of risk of graft-versus-host disease |
WO2007148332A1 (en) | 2006-06-22 | 2007-12-27 | Yeda Resaerch And Development Co. Ltd | Catecholamine receptor modulation |
JP5426389B2 (ja) | 2006-10-20 | 2014-02-26 | チルドレンズ メディカル センター コーポレーション | 組織の再生を亢進するための方法 |
EP2094839B1 (en) | 2006-12-08 | 2020-02-05 | University of Rochester | Expansion of hematopoietic stem cells |
ES2703592T3 (es) | 2007-03-07 | 2019-03-11 | Mei Pharma Inc | Combinación de agente anticancerígeno de bencimidazol y un segundo agente anticancerígeno |
WO2008126932A2 (en) | 2007-04-09 | 2008-10-23 | Riken | Epigenetical regulation of brain plasticity |
CA3203374A1 (en) * | 2008-11-06 | 2010-05-14 | Indiana University Research & Technology Corporation | Materials and methods to enhance hematopoietic stem cells engraftment procedures |
WO2010108028A2 (en) | 2009-03-19 | 2010-09-23 | Fate Therapeutics, Inc. | Compositions comprising cyclic amp enhancers and/or ep ligands, and methods of preparing and using the same |
JP6037836B2 (ja) * | 2009-11-15 | 2016-12-07 | インディアナ・ユニバーシティ・リサーチ・アンド・テクノロジー・コーポレーション | 特異的プロスタグランジンe2受容体の特定を含む幹細胞の送達及び生着を高めるための方法 |
BR112014007782B1 (pt) * | 2011-09-30 | 2021-06-01 | Bluebird Bio, Inc. | Método para aumentar a eficiência de transdução lentiviral de células progenitoras ou células-tronco hematopoiéticas cd34+, bem como usos terapêuticos de composição compreendendo as ditas células e de pge2, 16,16-dimetil pge2, ou seu análogo |
WO2014015318A1 (en) * | 2012-07-19 | 2014-01-23 | Bluebird Bio, Inc. | Soluble compounds for improved gene therapy methods |
US20150216903A1 (en) * | 2012-08-10 | 2015-08-06 | Bluebird Bio, Inc. | Compounds for improved viral transduction |
US9943545B2 (en) * | 2013-03-15 | 2018-04-17 | Fate Therapeutics, Inc. | Stem cell culture media and methods of enhancing cell survival |
US10617721B2 (en) * | 2013-10-24 | 2020-04-14 | Ospedale San Raffaele S.R.L. | Methods for genetic modification of stem cells |
CN103937743B (zh) * | 2014-04-27 | 2017-12-01 | 浙江大学 | 一种利用三维诱导系统获得造血干细胞的方法 |
EP3313420B1 (en) * | 2015-06-25 | 2024-03-13 | The Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance |
JP2018520688A (ja) * | 2015-07-21 | 2018-08-02 | ザ チルドレンズ メディカル センター コーポレーション | Pd−l1発現造血幹細胞およびその使用 |
US11326183B2 (en) * | 2016-02-12 | 2022-05-10 | Bluebird Bio, Inc. | VCN enhancer compositions and methods of using the same |
RU2021103425A (ru) * | 2016-02-12 | 2021-02-25 | Блубёрд Био, Инк. | Композиции, повышающие число копий вектора (чкв), и способы их применения |
GB201706394D0 (en) * | 2017-04-21 | 2017-06-07 | Ospedale San Raffaele Srl | Gene Therapy |
FR3074189A1 (fr) * | 2017-11-30 | 2019-05-31 | Assistance Publique - Hopitaux De Paris | Methode de generation de greffons de cellules souches hematopoietiques |
-
2012
- 2012-09-28 BR BR112014007782-7A patent/BR112014007782B1/pt not_active IP Right Cessation
- 2012-09-28 CN CN201280056851.7A patent/CN103958667A/zh active Pending
- 2012-09-28 DK DK17173567.3T patent/DK3269802T3/da active
- 2012-09-28 SG SG10201602423TA patent/SG10201602423TA/en unknown
- 2012-09-28 CN CN201810168851.5A patent/CN108220246B/zh active Active
- 2012-09-28 DK DK12836507.9T patent/DK2760994T4/da active
- 2012-09-28 PT PT128365079T patent/PT2760994T/pt unknown
- 2012-09-28 ES ES12836507T patent/ES2632444T5/es active Active
- 2012-09-28 CA CA2850484A patent/CA2850484C/en active Active
- 2012-09-28 EP EP22161134.6A patent/EP4095236A1/en not_active Withdrawn
- 2012-09-28 MX MX2014003923A patent/MX359398B/es active IP Right Grant
- 2012-09-28 SG SG11201401077PA patent/SG11201401077PA/en unknown
- 2012-09-28 US US14/348,572 patent/US9988644B2/en active Active
- 2012-09-28 ES ES17173567T patent/ES2769270T3/es active Active
- 2012-09-28 AU AU2012315699A patent/AU2012315699B2/en not_active Ceased
- 2012-09-28 WO PCT/US2012/057987 patent/WO2013049615A1/en active Application Filing
- 2012-09-28 KR KR1020147011495A patent/KR102011532B1/ko active IP Right Grant
- 2012-09-28 EP EP17173567.3A patent/EP3269802B1/en active Active
- 2012-09-28 EP EP19204363.6A patent/EP3656848B1/en active Active
- 2012-09-28 ES ES19204363T patent/ES2913633T3/es active Active
- 2012-09-28 UA UAA201403867A patent/UA114796C2/uk unknown
- 2012-09-28 EP EP12836507.9A patent/EP2760994B2/en active Active
- 2012-09-28 JP JP2014533413A patent/JP6285863B2/ja active Active
- 2012-09-28 EA EA201490627A patent/EA032699B1/ru unknown
- 2012-09-28 PT PT171735673T patent/PT3269802T/pt unknown
- 2012-09-28 IN IN2518CHN2014 patent/IN2014CN02518A/en unknown
-
2014
- 2014-03-30 IL IL231812A patent/IL231812B/en active IP Right Grant
- 2014-03-31 MX MX2018011791A patent/MX2018011791A/es unknown
-
2018
- 2018-02-02 JP JP2018017184A patent/JP6745826B2/ja not_active Expired - Fee Related
- 2018-06-04 US US15/997,643 patent/US10501759B2/en active Active
-
2019
- 2019-10-28 US US16/665,892 patent/US10907177B2/en active Active
-
2020
- 2020-01-22 CY CY20201100056T patent/CY1122654T1/el unknown
- 2020-12-17 US US17/125,930 patent/US11834668B2/en active Active
-
2021
- 2021-02-23 IL IL281045A patent/IL281045B/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6745826B2 (ja) | 改善されたウイルスによる形質導入のための化合物 | |
JP2019504635A (ja) | Vcnエンハンサー組成物およびその使用方法 | |
US20150216903A1 (en) | Compounds for improved viral transduction | |
US11326183B2 (en) | VCN enhancer compositions and methods of using the same | |
WO2014015318A1 (en) | Soluble compounds for improved gene therapy methods | |
US20190284533A1 (en) | Vcn enhancer compositions and methods of using the same | |
US20240229070A1 (en) | Compounds for improved viral transduction | |
NZ623341B2 (en) | Compounds for improved viral transduction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180202 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190107 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190405 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190607 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A132 Effective date: 20191127 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200227 |
|
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: 20200709 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200804 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6745826 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |