CA2758120C - Engineered mesenchymal stem cells and method of using same to treat tumors - Google Patents
Engineered mesenchymal stem cells and method of using same to treat tumors Download PDFInfo
- Publication number
- CA2758120C CA2758120C CA2758120A CA2758120A CA2758120C CA 2758120 C CA2758120 C CA 2758120C CA 2758120 A CA2758120 A CA 2758120A CA 2758120 A CA2758120 A CA 2758120A CA 2758120 C CA2758120 C CA 2758120C
- Authority
- CA
- Canada
- Prior art keywords
- genetically modified
- mesenchymal stem
- stem cells
- tumor
- promoter
- 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
- 210000002901 mesenchymal stem cell Anatomy 0.000 title claims abstract description 254
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 149
- 238000000034 method Methods 0.000 title abstract description 26
- 231100000433 cytotoxic Toxicity 0.000 claims abstract description 47
- 230000001472 cytotoxic effect Effects 0.000 claims abstract description 47
- 239000003623 enhancer Substances 0.000 claims abstract description 34
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 34
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 34
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 34
- 239000003145 cytotoxic factor Substances 0.000 claims abstract description 31
- 210000004027 cell Anatomy 0.000 claims description 115
- 108090000623 proteins and genes Proteins 0.000 claims description 73
- 210000000130 stem cell Anatomy 0.000 claims description 70
- 210000001519 tissue Anatomy 0.000 claims description 47
- 230000003612 virological effect Effects 0.000 claims description 46
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 claims description 41
- 229960002963 ganciclovir Drugs 0.000 claims description 39
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 37
- 201000002528 pancreatic cancer Diseases 0.000 claims description 37
- 208000009889 Herpes Simplex Diseases 0.000 claims description 31
- 230000037396 body weight Effects 0.000 claims description 31
- 239000013598 vector Substances 0.000 claims description 29
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims description 26
- 108020004440 Thymidine kinase Proteins 0.000 claims description 26
- 102000006601 Thymidine Kinase Human genes 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 24
- 239000003550 marker Substances 0.000 claims description 20
- 230000001177 retroviral effect Effects 0.000 claims description 19
- 230000001105 regulatory effect Effects 0.000 claims description 18
- 230000004913 activation Effects 0.000 claims description 15
- 229940104230 thymidine Drugs 0.000 claims description 14
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims description 13
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 13
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 13
- 102000004169 proteins and genes Human genes 0.000 claims description 13
- 238000004806 packaging method and process Methods 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 11
- 208000026310 Breast neoplasm Diseases 0.000 claims description 11
- 230000010415 tropism Effects 0.000 claims description 10
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 9
- 102000018697 Membrane Proteins Human genes 0.000 claims description 8
- 108010052285 Membrane Proteins Proteins 0.000 claims description 8
- 239000012212 insulator Substances 0.000 claims description 8
- 230000003211 malignant effect Effects 0.000 claims description 7
- 230000001394 metastastic effect Effects 0.000 claims description 7
- 230000003115 biocidal effect Effects 0.000 claims description 6
- 206010018338 Glioma Diseases 0.000 claims description 5
- 206010025323 Lymphomas Diseases 0.000 claims description 5
- 230000001566 pro-viral effect Effects 0.000 claims description 5
- 238000009877 rendering Methods 0.000 claims description 5
- 201000003076 Angiosarcoma Diseases 0.000 claims description 4
- 206010003571 Astrocytoma Diseases 0.000 claims description 4
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 108010080611 Cytosine Deaminase Proteins 0.000 claims description 4
- 206010014733 Endometrial cancer Diseases 0.000 claims description 4
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 4
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 201000010915 Glioblastoma multiforme Diseases 0.000 claims description 4
- 208000001258 Hemangiosarcoma Diseases 0.000 claims description 4
- 208000018142 Leiomyosarcoma Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010029260 Neuroblastoma Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 4
- 206010057644 Testis cancer Diseases 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 201000003914 endometrial carcinoma Diseases 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 4
- 201000005296 lung carcinoma Diseases 0.000 claims description 4
- 208000030883 malignant astrocytoma Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 201000008968 osteosarcoma Diseases 0.000 claims description 4
- 208000023958 prostate neoplasm Diseases 0.000 claims description 4
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 4
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 4
- 206010042863 synovial sarcoma Diseases 0.000 claims description 4
- 201000003120 testicular cancer Diseases 0.000 claims description 4
- 208000024719 uterine cervix neoplasm Diseases 0.000 claims description 4
- 102000000311 Cytosine Deaminase Human genes 0.000 claims description 3
- 108091000080 Phosphotransferase Proteins 0.000 claims description 3
- 102000020233 phosphotransferase Human genes 0.000 claims description 3
- 230000014509 gene expression Effects 0.000 description 46
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 32
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 30
- 108010054624 red fluorescent protein Proteins 0.000 description 22
- 241000699670 Mus sp. Species 0.000 description 21
- 238000002347 injection Methods 0.000 description 18
- 239000007924 injection Substances 0.000 description 18
- 206010027476 Metastases Diseases 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 17
- 230000004614 tumor growth Effects 0.000 description 17
- 241000700584 Simplexvirus Species 0.000 description 12
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 12
- 208000008443 pancreatic carcinoma Diseases 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 11
- 102000004127 Cytokines Human genes 0.000 description 10
- 108090000695 Cytokines Proteins 0.000 description 10
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 10
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 10
- 108700008625 Reporter Genes Proteins 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 239000005090 green fluorescent protein Substances 0.000 description 10
- 230000002757 inflammatory effect Effects 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 239000003981 vehicle Substances 0.000 description 10
- 108700019146 Transgenes Proteins 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 230000001939 inductive effect Effects 0.000 description 9
- 230000007115 recruitment Effects 0.000 description 9
- 210000002845 virion Anatomy 0.000 description 9
- 210000001185 bone marrow Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000006698 induction Effects 0.000 description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 8
- 210000002536 stromal cell Anatomy 0.000 description 8
- 238000011740 C57BL/6 mouse Methods 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 238000001415 gene therapy Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 210000000496 pancreas Anatomy 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 210000004303 peritoneum Anatomy 0.000 description 7
- 210000000952 spleen Anatomy 0.000 description 7
- 108010012236 Chemokines Proteins 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 210000002950 fibroblast Anatomy 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 102000019034 Chemokines Human genes 0.000 description 5
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 5
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 5
- 229930189065 blasticidin Natural products 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 238000003364 immunohistochemistry Methods 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 238000007809 Boyden Chamber assay Methods 0.000 description 4
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 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 4
- 101000958041 Homo sapiens Musculin Proteins 0.000 description 4
- 241000713666 Lentivirus Species 0.000 description 4
- 101710172711 Structural protein Proteins 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 239000008121 dextrose Substances 0.000 description 4
- 108700004025 env Genes Proteins 0.000 description 4
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 4
- 238000012239 gene modification Methods 0.000 description 4
- 230000005017 genetic modification Effects 0.000 description 4
- 235000013617 genetically modified food Nutrition 0.000 description 4
- 102000046949 human MSC Human genes 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 230000005012 migration Effects 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 238000000729 Fisher's exact test Methods 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 102100034349 Integrase Human genes 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101150003725 TK gene Proteins 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 210000000651 myofibroblast Anatomy 0.000 description 3
- 238000002559 palpation Methods 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 239000013603 viral vector Substances 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 102100022524 Alpha-1-antichymotrypsin Human genes 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241001663880 Gammaretrovirus Species 0.000 description 2
- 241000713813 Gibbon ape leukemia virus Species 0.000 description 2
- 101100118916 Gibbon ape leukemia virus env gene Proteins 0.000 description 2
- 101000678026 Homo sapiens Alpha-1-antichymotrypsin Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 2
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 2
- 108010029973 Lymphocytic choriomeningitis virus glycoprotein peptide Proteins 0.000 description 2
- 206010027457 Metastases to liver Diseases 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 102100040247 Tumor necrosis factor Human genes 0.000 description 2
- 241000711975 Vesicular stomatitis virus Species 0.000 description 2
- 108700005077 Viral Genes Proteins 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 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
- 230000033228 biological regulation Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000002224 dissection Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 239000005550 inflammation mediator Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000001617 migratory effect Effects 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 108020001162 nitroreductase Proteins 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 2
- 210000003668 pericyte Anatomy 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 230000003836 peripheral circulation Effects 0.000 description 2
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 2
- 230000008569 process Effects 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
- 230000010076 replication Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 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 2
- 238000002054 transplantation Methods 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- 210000005166 vasculature Anatomy 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- 230000005730 ADP ribosylation Effects 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 1
- 241001664176 Alpharetrovirus Species 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 102100022718 Atypical chemokine receptor 2 Human genes 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 1
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 1
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 1
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 1
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 description 1
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 1
- 101710186200 CCAAT/enhancer-binding protein Proteins 0.000 description 1
- 108700013048 CCL2 Proteins 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 102000000018 Chemokine CCL2 Human genes 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 102000001327 Chemokine CCL5 Human genes 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 101710121417 Envelope glycoprotein Proteins 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 206010071602 Genetic polymorphism Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 101000678892 Homo sapiens Atypical chemokine receptor 2 Proteins 0.000 description 1
- 101000777558 Homo sapiens C-C chemokine receptor type 10 Proteins 0.000 description 1
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 1
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 description 1
- 101001027631 Homo sapiens Kinesin-like protein KIF20B Proteins 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 102100037691 Kinesin-like protein KIF20B Human genes 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 241000283923 Marmota monax Species 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 206010051676 Metastases to peritoneum Diseases 0.000 description 1
- 206010051682 Metastases to spleen Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 101710101148 Probable 6-oxopurine nucleoside phosphorylase Proteins 0.000 description 1
- 239000004792 Prolene Substances 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 102000030764 Purine-nucleoside phosphorylase Human genes 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- 102000008579 Transposases Human genes 0.000 description 1
- 108010020764 Transposases Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 101900150902 Varicella-zoster virus Thymidine kinase Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 101150005187 acm gene Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000000981 bystander Effects 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 125000002250 eicosanoid group Chemical group 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 108700004026 gag Genes Proteins 0.000 description 1
- 108010062699 gamma-Glutamyl Hydrolase Proteins 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 238000003197 gene knockdown Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 101150106093 gpt gene Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000005099 host tropism Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000037456 inflammatory mechanism Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003716 mesoderm Anatomy 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000010232 migration assay Methods 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000012758 nuclear staining Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- -1 olive oil Chemical compound 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 108700004029 pol Genes Proteins 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000007112 pro inflammatory response Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 210000001350 reed-sternberg cell Anatomy 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- TUFFYSFVSYUHPA-UHFFFAOYSA-M rhodamine 123 Chemical compound [Cl-].COC(=O)C1=CC=CC=C1C1=C(C=CC(N)=C2)C2=[O+]C2=C1C=CC(N)=C2 TUFFYSFVSYUHPA-UHFFFAOYSA-M 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229940030325 tumor cell vaccine Drugs 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
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
- 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
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0662—Stem cells
- C12N5/0663—Bone marrow mesenchymal stem cells (BM-MSC)
-
- 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
-
- 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
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
-
- 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
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0662—Stem 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- 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
- 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
- C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
- C12N2740/15041—Use of virus, viral particle or viral elements as a vector
- C12N2740/15043—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
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/001—Vector systems having a special element relevant for transcription controllable enhancer/promoter combination
- C12N2830/002—Vector systems having a special element relevant for transcription controllable enhancer/promoter combination inducible enhancer/promoter combination, e.g. hypoxia, iron, transcription factor
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Developmental Biology & Embryology (AREA)
- General Health & Medical Sciences (AREA)
- Cell Biology (AREA)
- Immunology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Hematology (AREA)
- Virology (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Plant Pathology (AREA)
- Oncology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16878709P | 2009-04-13 | 2009-04-13 | |
| US61/168,787 | 2009-04-13 | ||
| PCT/EP2010/054844 WO2010119039A1 (en) | 2009-04-13 | 2010-04-13 | Engineered mesenchymal stem cells and method of using same to treat tumors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2758120A1 CA2758120A1 (en) | 2010-10-21 |
| CA2758120C true CA2758120C (en) | 2014-08-19 |
Family
ID=42270435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2758120A Expired - Fee Related CA2758120C (en) | 2009-04-13 | 2010-04-13 | Engineered mesenchymal stem cells and method of using same to treat tumors |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US9434925B2 (enExample) |
| EP (1) | EP2419113B1 (enExample) |
| JP (1) | JP5727458B2 (enExample) |
| KR (1) | KR20120088542A (enExample) |
| CN (1) | CN102695517B (enExample) |
| AU (1) | AU2010237130B2 (enExample) |
| BR (1) | BRPI1013771A2 (enExample) |
| CA (1) | CA2758120C (enExample) |
| IL (1) | IL215581A0 (enExample) |
| RU (1) | RU2539099C2 (enExample) |
| SG (1) | SG175127A1 (enExample) |
| WO (1) | WO2010119039A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12053493B2 (en) | 2016-11-03 | 2024-08-06 | Exostem Biotec Ltd. | Mesenchymal stem cells populations, their products, and use thereof |
Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010045659A1 (en) | 2008-10-17 | 2010-04-22 | American Gene Technologies International Inc. | Safe lentiviral vectors for targeted delivery of multiple therapeutic molecules |
| US20130171115A1 (en) * | 2011-12-30 | 2013-07-04 | Gang Li | Cell-mediated gene therapy for cancer using mesenchymal stem cells expressing a suicide gene |
| US20140369979A1 (en) * | 2012-02-01 | 2014-12-18 | Postech Academy-Industry Foundation | Vector simultaneously expressing dodecameric trail and hsv-tk suicide genes, and anticancer stem cell therapeutic agent using same |
| US20130203166A1 (en) * | 2012-02-06 | 2013-08-08 | Protobios Llc | Stimulation of multipotency of mesenchymal stem cells by chemokine ccl5 |
| GB201202319D0 (en) | 2012-02-10 | 2012-03-28 | Orbsen Therapeutics Ltd | Stromal stem cells |
| US20140065110A1 (en) | 2012-08-31 | 2014-03-06 | The Regents Of The University Of California | Genetically modified msc and therapeutic methods |
| ES2748662T3 (es) * | 2012-11-05 | 2020-03-17 | Institute For Res In Biomedicine Irb | Roedores inmunodeficientes modificados genéticamente y métodos de uso de los mismos |
| US10472647B2 (en) | 2012-12-21 | 2019-11-12 | The Administrators Of The Tulane Educational Fund | Primary mesenchymal stem cells as a vaccine platform |
| WO2015100268A1 (en) * | 2013-12-23 | 2015-07-02 | The Regents Of The University Of California | Mesenchymal stem cells for targeted cancer therapy |
| JP2017506884A (ja) * | 2014-01-17 | 2017-03-16 | ウェイク・フォレスト・ユニヴァーシティ・ヘルス・サイエンシズ | 活性薬の送達を増強するための方法 |
| CA2956987C (en) | 2014-08-18 | 2023-03-21 | Apceth Gmbh & Co. Kg | Genetically modified mesenchymal stem cells expressing an immune response-stimulating cytokine to attract and/or activate immune cells |
| RU2716821C2 (ru) * | 2014-10-24 | 2020-03-17 | Калиди Биотерапьютикс, Инк. | Комбинированный иммунотерапевтический подход к лечению рака |
| CN104622903B (zh) * | 2015-01-20 | 2018-10-09 | 奥思达干细胞有限公司 | 抗恶性黑色素瘤的干细胞制剂及其制备方法 |
| JP6734283B2 (ja) | 2015-01-21 | 2020-08-05 | フレッド ハッチンソン キャンサー リサーチ センター | 遺伝子治療用ポイントオブケア及び／又はポータブルプラットフォーム |
| US20180037868A1 (en) * | 2015-02-27 | 2018-02-08 | Apceth Gmbh & Co. Kg | Genetically modified mesenchymal stem cell expressing klotho |
| US10618944B2 (en) | 2015-02-27 | 2020-04-14 | Saint Louis University | Tumor suppressor SALL1 as a therapeutic agent for treating cancer |
| WO2016146819A1 (en) * | 2015-03-18 | 2016-09-22 | Apceth Gmbh & Co. Kg | Hypoxia-induced expression of therapeutic proteins in mesenchymal stem cells |
| EP3319631A4 (en) | 2015-07-08 | 2019-01-09 | American Gene Technologies International Inc. | HIV PREMUNICATION AND IMMUNOTHERAPY |
| EA201800148A1 (ru) | 2015-08-11 | 2019-01-31 | Калиди Биотерапьютикс, Инк. | Оспенная вакцина для лечения рака |
| WO2017036925A1 (en) * | 2015-08-28 | 2017-03-09 | Apceth Gmbh & Co. Kg | Mesenchymal stem cells for the treatment of metastatic liver disease |
| CA3011529A1 (en) | 2016-01-15 | 2017-07-20 | American Gene Technologies International Inc. | Methods and compositions for the activation of gamma-delta t-cells |
| US10137144B2 (en) | 2016-01-15 | 2018-11-27 | American Gene Technologies International Inc. | Methods and compositions for the activation of gamma-delta T-cells |
| US10888613B2 (en) | 2016-02-08 | 2021-01-12 | American Gene Technologies International Inc. | Method of producing cells resistant to HIV infection |
| ES2911448T3 (es) | 2016-03-09 | 2022-05-19 | American Gene Tech Int Inc | Vectores combinados y métodos para el tratamiento del cáncer |
| CN109561691A (zh) * | 2016-06-07 | 2019-04-02 | 太平洋心肺血研究所 | 用于治疗癌症的组合物和方法 |
| EP3468617A4 (en) | 2016-06-08 | 2020-01-22 | American Gene Technologies International Inc. | INTEGRATED VIRAL ADMINISTRATION SYSTEM AND RELATED METHODS |
| IL300730A (en) | 2016-07-08 | 2023-04-01 | American Gene Tech Int Inc | Pre-HIV vaccine and immunotherapy |
| JP7176756B2 (ja) | 2016-07-21 | 2022-11-22 | アメリカン ジーン テクノロジーズ インターナショナル インコーポレイテッド | パーキンソン病を処置するためのウイルスベクター |
| US11820999B2 (en) | 2017-04-03 | 2023-11-21 | American Gene Technologies International Inc. | Compositions and methods for treating phenylketonuria |
| SG10202111394XA (en) | 2017-04-13 | 2021-12-30 | Senti Biosciences Inc | Combinatorial cancer immunotherapy |
| WO2019195142A1 (en) | 2018-04-03 | 2019-10-10 | The Board Of Trustees Of The Leland Stanford Junior University | Mesenchymal stem cells comprising a chimeric antigen receptor (car) for treating inflammatory and autoimmune diseases |
| US11505782B2 (en) | 2018-06-04 | 2022-11-22 | Calidi Biotherapeutics, Inc. | Cell-based vehicles for potentiation of viral therapy |
| CA3103423A1 (en) * | 2018-06-14 | 2019-12-19 | Loma Linda University | Engineered hematopoietic stem cells for the treatment of acute myeloid leukemia |
| US11419898B2 (en) | 2018-10-17 | 2022-08-23 | Senti Biosciences, Inc. | Combinatorial cancer immunotherapy |
| AU2019359890B2 (en) | 2018-10-17 | 2024-10-24 | Senti Biosciences, Inc. | Combinatorial cancer immunotherapy |
| WO2020097049A1 (en) * | 2018-11-05 | 2020-05-14 | American Gene Technologies International Inc. | Vector system for expressing regulatory rna |
| AU2019377141B2 (en) | 2018-11-06 | 2024-06-06 | Calidi Biotherapeutics (Nevada), Inc. | Enhanced systems for cell-mediated oncolytic viral therapy |
| US20220241337A1 (en) * | 2019-02-22 | 2022-08-04 | The Trustees Of Columbia University In The City Of Newyork | Preparing tissues for delivery of therapeutic and diagnostic agents and delivering the agents |
| SG10201902002SA (en) * | 2019-03-06 | 2020-10-29 | Nat Univ Singapore | Non-viral modification of mesenchymal stem cells |
| EP4017512B1 (en) * | 2019-08-23 | 2025-04-02 | Orbsen Therapeutics Limited | Compositions for monocyte and macrophage polarization and methods of use |
| EP3995130A1 (en) | 2020-11-06 | 2022-05-11 | JunctuCell Biomed Manufacturing GmbH | A composition comprising extra-cellular vesicles from mesenchymal stem cells and alpha-1 antitrypsin for the treatment of viral infections |
| AU2021375735A1 (en) | 2020-11-06 | 2023-06-08 | Aatec Medical Gmbh | A composition comprising extra-cellular vesicles from mesenchymal stem cells and alpha-1 antitrypsin for the treatment of viral infections |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6265564B1 (en) * | 1996-08-02 | 2001-07-24 | Regeneron Pharmaceuticals, Inc. | Expressed ligand-vascular intercellular signalling molecule |
| US7098185B2 (en) * | 1998-05-18 | 2006-08-29 | University College London | Polypeptide hormone phosphatonin |
| WO2001091802A1 (en) * | 2000-05-30 | 2001-12-06 | Baylor College Of Medicine | Chimeric viral vectors for gene therapy |
| WO2002069953A1 (en) * | 2001-03-01 | 2002-09-12 | The Board Of Regents Of The University Of Texas System | Methods of treating lung inflammation |
| US20030165579A1 (en) * | 2002-02-27 | 2003-09-04 | Chih-Hui Lin | Euphorbia antiquorum extract, a pharmaceutical composition containing the same and methods for treatment of cancers |
| ATE386748T1 (de) * | 2003-12-19 | 2008-03-15 | Charite Universitaetsmedizin | Verwendung von liganden von cd52 antigen zur behandlung von soliden tumoren und von knochenkrebserkrankungen |
| JP2006194752A (ja) * | 2005-01-14 | 2006-07-27 | Sumitomo Metal Mining Co Ltd | Ｘ線回折測定における試料固定方法および試料固定具 |
| KR101022401B1 (ko) * | 2005-09-29 | 2011-03-15 | 아주대학교산학협력단 | 자살유전자를 발현하는 중간엽 줄기세포를 포함하는 암치료용 조성물 |
| BRPI0811906A2 (pt) * | 2007-05-24 | 2014-11-18 | Apceth Gmbh & Co Kg | Composições e métodos relacionados a célula-tronco cd34 |
-
2010
- 2010-04-13 KR KR1020117026918A patent/KR20120088542A/ko not_active Ceased
- 2010-04-13 BR BRPI1013771A patent/BRPI1013771A2/pt not_active IP Right Cessation
- 2010-04-13 CA CA2758120A patent/CA2758120C/en not_active Expired - Fee Related
- 2010-04-13 EP EP10713933.9A patent/EP2419113B1/en not_active Not-in-force
- 2010-04-13 US US13/264,084 patent/US9434925B2/en not_active Expired - Fee Related
- 2010-04-13 AU AU2010237130A patent/AU2010237130B2/en not_active Ceased
- 2010-04-13 RU RU2011146048/10A patent/RU2539099C2/ru not_active IP Right Cessation
- 2010-04-13 SG SG2011073418A patent/SG175127A1/en unknown
- 2010-04-13 WO PCT/EP2010/054844 patent/WO2010119039A1/en not_active Ceased
- 2010-04-13 JP JP2012505149A patent/JP5727458B2/ja active Active
- 2010-04-13 CN CN201080026333.1A patent/CN102695517B/zh not_active Expired - Fee Related
-
2011
- 2011-10-06 IL IL215581A patent/IL215581A0/en unknown
-
2016
- 2016-08-31 US US15/253,353 patent/US20170015976A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12053493B2 (en) | 2016-11-03 | 2024-08-06 | Exostem Biotec Ltd. | Mesenchymal stem cells populations, their products, and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US20170015976A1 (en) | 2017-01-19 |
| JP5727458B2 (ja) | 2015-06-03 |
| WO2010119039A1 (en) | 2010-10-21 |
| RU2539099C2 (ru) | 2015-01-10 |
| IL215581A0 (en) | 2011-12-29 |
| US9434925B2 (en) | 2016-09-06 |
| AU2010237130A1 (en) | 2011-11-03 |
| CA2758120A1 (en) | 2010-10-21 |
| JP2012523243A (ja) | 2012-10-04 |
| KR20120088542A (ko) | 2012-08-08 |
| CN102695517A (zh) | 2012-09-26 |
| EP2419113B1 (en) | 2017-05-10 |
| RU2011146048A (ru) | 2013-05-20 |
| SG175127A1 (en) | 2011-11-28 |
| BRPI1013771A2 (pt) | 2016-04-05 |
| AU2010237130B2 (en) | 2015-01-29 |
| EP2419113A1 (en) | 2012-02-22 |
| US20120087901A1 (en) | 2012-04-12 |
| CN102695517B (zh) | 2015-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2758120C (en) | Engineered mesenchymal stem cells and method of using same to treat tumors | |
| Oggu et al. | Gene delivery approaches for mesenchymal stem cell therapy: strategies to increase efficiency and specificity | |
| Bajetto et al. | Cross talk between mesenchymal and glioblastoma stem cells: Communication beyond controversies | |
| CN106659742B (zh) | 表达免疫应答刺激细胞因子以吸引和/或激活免疫细胞的基因修饰间充质干细胞 | |
| Zischek et al. | Targeting tumor stroma using engineered mesenchymal stem cells reduces the growth of pancreatic carcinoma | |
| EP3498846B1 (en) | Manipulated immunoregulatory element and immunity altered thereby | |
| Hagenhoff et al. | Harnessing mesenchymal stem cell homing as an anticancer therapy | |
| US20230105186A1 (en) | Nanoparticle Modification of Human Adipose-Derived Mesenchymal Stem Cells for Treating Brain Cancer and Other Neurological Diseases | |
| Leblond et al. | Developing cell therapy techniques for respiratory disease: intratracheal delivery of genetically engineered stem cells in a murine model of airway injury | |
| Namba et al. | Use of genetically engineered stem cells for glioma therapy | |
| Li et al. | Integrin β1 increases stem cell survival and cardiac function after myocardial infarction | |
| KR20220140542A (ko) | 제핵 세포의 생체공학적 제조를 위한 방법 및 용도 | |
| Benabdallah et al. | Natural killer cells prevent the formation of teratomas derived from human induced pluripotent stem cells | |
| CN116801890A (zh) | 用于增强治疗性免疫细胞功效的方法和组合物 | |
| Bahrambeigi et al. | Genetically modified murine adipose-derived mesenchymal stem cells producing interleukin-2 favor B16F10 melanoma cell proliferation | |
| Pereboeva et al. | Cellular vehicles for cancer gene therapy: current status and future potential | |
| Maliha et al. | The role of mesenchymal stem cells in oncology and regenerative medicine | |
| Ebrahimi et al. | Drug delivery using genetically modified mesenchymal stem cells: a promising targeted-delivery method | |
| Fukutani et al. | Human iPSC-derived NK cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D complex enhance anti-solid tumor activity | |
| Annese et al. | Endothelial progenitor cells from bench to antitumor therapy and diagnostic imaging | |
| Kerrigan et al. | Mesenchymal Stem/Stromal Cell Recruitment by Central Nervous System Tumors | |
| Stagg et al. | Properties of mesenchymal stem cells to consider for cancer cell therapy | |
| da Silva | Genetic engineering of Mesenchymal Stromal Cells to express anti-cancer proteins | |
| Chen et al. | Recent advances in CAR-MSCs: the new engine of cellular immunotherapy evolution | |
| Lee | Engineering Macrophages for Cell-Based Therapies |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20130529 |
|
| MKLA | Lapsed |
Effective date: 20180413 |