JP2018535988A - 小分子カクテルによるヒトグリア細胞からニューロンへの化学的リプログラミング - Google Patents
小分子カクテルによるヒトグリア細胞からニューロンへの化学的リプログラミング Download PDFInfo
- Publication number
- JP2018535988A JP2018535988A JP2018527791A JP2018527791A JP2018535988A JP 2018535988 A JP2018535988 A JP 2018535988A JP 2018527791 A JP2018527791 A JP 2018527791A JP 2018527791 A JP2018527791 A JP 2018527791A JP 2018535988 A JP2018535988 A JP 2018535988A
- Authority
- JP
- Japan
- Prior art keywords
- cri
- flu
- pfd
- cer
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 210000002569 neuron Anatomy 0.000 title claims abstract description 76
- 210000004498 neuroglial cell Anatomy 0.000 title claims abstract description 38
- 150000003384 small molecules Chemical class 0.000 title description 15
- 239000000126 substance Substances 0.000 title description 8
- 230000008672 reprogramming Effects 0.000 title description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 108
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims abstract description 62
- 229960003073 pirfenidone Drugs 0.000 claims abstract description 62
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims abstract description 54
- 229930003268 Vitamin C Natural products 0.000 claims abstract description 54
- 235000019154 vitamin C Nutrition 0.000 claims abstract description 54
- 239000011718 vitamin C Substances 0.000 claims abstract description 54
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000002146 L01XE16 - Crizotinib Substances 0.000 claims abstract description 24
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 claims abstract description 24
- 229960005061 crizotinib Drugs 0.000 claims abstract description 24
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229960002390 flurbiprofen Drugs 0.000 claims abstract description 24
- 229960001602 ceritinib Drugs 0.000 claims abstract description 16
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 208000024827 Alzheimer disease Diseases 0.000 claims description 12
- 230000004770 neurodegeneration Effects 0.000 claims description 10
- 210000000278 spinal cord Anatomy 0.000 claims description 7
- 208000028389 Nerve injury Diseases 0.000 claims description 6
- 230000008764 nerve damage Effects 0.000 claims description 6
- 206010018341 Gliosis Diseases 0.000 claims description 5
- 230000032683 aging Effects 0.000 claims description 4
- 210000005171 mammalian brain Anatomy 0.000 claims description 4
- 208000004141 microcephaly Diseases 0.000 claims description 4
- 206010010904 Convulsion Diseases 0.000 claims description 3
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 3
- 206010061431 Glial scar Diseases 0.000 claims description 2
- 208000029028 brain injury Diseases 0.000 claims description 2
- 230000000302 ischemic effect Effects 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 230000004766 neurogenesis Effects 0.000 abstract description 24
- 239000000203 mixture Substances 0.000 abstract description 21
- 210000005036 nerve Anatomy 0.000 abstract description 4
- 210000000653 nervous system Anatomy 0.000 abstract description 4
- 230000001737 promoting effect Effects 0.000 abstract description 3
- 230000008929 regeneration Effects 0.000 abstract description 2
- 238000011069 regeneration method Methods 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 27
- 210000001130 astrocyte Anatomy 0.000 description 19
- 241000699670 Mus sp. Species 0.000 description 18
- 101000720704 Homo sapiens Neuronal migration protein doublecortin Proteins 0.000 description 16
- 102100025929 Neuronal migration protein doublecortin Human genes 0.000 description 16
- 238000007917 intracranial administration Methods 0.000 description 16
- 210000004556 brain Anatomy 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 101001092197 Homo sapiens RNA binding protein fox-1 homolog 3 Proteins 0.000 description 13
- 102100035530 RNA binding protein fox-1 homolog 3 Human genes 0.000 description 13
- 239000003550 marker Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 210000001320 hippocampus Anatomy 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 230000001537 neural effect Effects 0.000 description 9
- 229940124602 FDA-approved drug Drugs 0.000 description 8
- 210000001947 dentate gyrus Anatomy 0.000 description 8
- 229940073577 lithium chloride Drugs 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000012744 immunostaining Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000004445 quantitative analysis Methods 0.000 description 6
- 210000000130 stem cell Anatomy 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 238000000692 Student's t-test Methods 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 235000015872 dietary supplement Nutrition 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 230000015654 memory Effects 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 239000005022 packaging material Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- 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
- 102000006941 Amino Acid Transport System X-AG Human genes 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- 102000001267 GSK3 Human genes 0.000 description 2
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 2
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 2
- 108091006151 Glutamate transporters Proteins 0.000 description 2
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 2
- 101000979001 Homo sapiens Methionine aminopeptidase 2 Proteins 0.000 description 2
- 101000969087 Homo sapiens Microtubule-associated protein 2 Proteins 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
- 102100021118 Microtubule-associated protein 2 Human genes 0.000 description 2
- 101150041420 Slc1a2 gene Proteins 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000003855 cell nucleus Anatomy 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 230000002518 glial effect Effects 0.000 description 2
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 239000005414 inactive ingredient Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 210000000274 microglia Anatomy 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003955 neuronal function Effects 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- -1 2 μM Chemical compound 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 229940125373 Gamma-Secretase Inhibitor Drugs 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 208000037875 astrocytosis Diseases 0.000 description 1
- 230000007341 astrogliosis Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 239000003540 gamma secretase inhibitor Substances 0.000 description 1
- 210000001362 glutamatergic neuron Anatomy 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000007787 long-term memory Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000007992 neural conversion Effects 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000002856 peripheral neuron Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 210000001202 rhombencephalon Anatomy 0.000 description 1
- 238000013515 script Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 208000037974 severe injury Diseases 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 230000006403 short-term memory Effects 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 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 1
- 230000009466 transformation Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000003612 virological 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
- 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
- C12N5/0618—Cells of the nervous system
- C12N5/0619—Neurons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
- A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- C12N2500/00—Specific components of cell culture medium
- C12N2500/05—Inorganic components
- C12N2500/10—Metals; Metal chelators
- C12N2500/12—Light metals, i.e. alkali, alkaline earth, Be, Al, Mg
-
- 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
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/38—Vitamins
-
- 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
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/10—Growth factors
-
- 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
- C12N2501/10—Growth factors
- C12N2501/15—Transforming growth factor beta (TGF-β)
-
- 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
- C12N2501/40—Regulators of development
- C12N2501/42—Notch; Delta; Jagged; Serrate
-
- 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
- C12N2501/70—Enzymes
- C12N2501/72—Transferases [EC 2.]
- C12N2501/727—Kinases (EC 2.7.)
-
- 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
- C12N2501/70—Enzymes
- C12N2501/73—Hydrolases (EC 3.)
- C12N2501/734—Proteases (EC 3.4.)
-
- 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
- C12N2501/999—Small molecules not provided for elsewhere
-
- 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
- C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
- C12N2506/08—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from cells of the nervous system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Inorganic Chemistry (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Cell Biology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Toxicology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
本出願は、2015年12月4日出願の米国特許仮出願第62/263,353号に対して優先権を主張するものであり、その開示は、参照によって本明細書に援用されている。
本実施例は、本明細書に記載のFDA認可済み薬物群が、ヒトグリア細胞をニューロンへin vitroで変換できることを実証する。
本実施例は、成体マウス及びアルツハイマー病のトランスジェニックマウスモデルに、化合物の群を頭蓋内投与を用いることによって、本開示の態様である、in vivoでの実施態様の非限定的な例を提示する。特に、図3Aは、新生ニューロンマーカーダブルコルチン(DCX、緑色(green))及び細胞増殖マーカーKi67(赤色(red))の免疫染色によって明らかなように、クリゾチニブ50μM、フルルビプロフェン0.2mM、ピルフェニドン2μM、ビタミンC10mg/ml、及びLiCl0.4Mを含む小分子カクテル2μlを3ヶ月のWTマウスの海馬に頭蓋内注射することによって、成体神経発生が促進されたことを示す。図3B。DCX陽性の新たなニューロン及びKi67陽性増殖細胞の数の増加によって支持されるように、1歳の成体WTマウスの海馬に小分子カクテルを頭蓋内注射することによって、歯状回(DG)の成体神経発生が有意に促進された。図3C。5ヶ月の、アルツハイマー病のトランスジェニックマウスモデルの海馬に小分子カクテルを頭蓋内注射することによって、DGのDCX陽性の新たなニューロンの数が有意に増加した。図3D。GFAP::GFPマウスにおいて、星状細胞はGFPによって標識される。系列追跡分析によれば、DCX+の新たなニューロンが、小分子カクテルによってGFP標識星状細胞から誘発された。図3E、図3F、及び図3Gは、DCX+の新たなニューロンの数が、3ヶ月のWTマウス(図3E)、1歳の成体WTマウス(図3F)、及び5ヶ月のアルツハイマー病のトランスジェニックマウスモデル(図3G)の海馬に小分子カクテルを頭蓋内注射することによって増加したことを示す定量解析を表す。スチューデントt検定、*P<0.05、**P<0.01、1群あたりn=3マウス。
本実施例は、本明細書に記載のFDA認可済み薬物群の腹腔内注射することによって、マウス脳の成体神経発生を増やすこともできることの実証を提示する。特に、図4A及び図4Bは、ビヒクル対照(図4A、20%Captisol)、又はクリゾチニブ50μM、フルルビプロフェン0.2mM、ピルフェニドン2μM、ビタミンC10mg/ml、及びLiCl0.4Mを含む化合物の群カクテル(図4B)を腹腔内注射した後の(投与量0.1ml/10g重量、1ヶ月間毎日注射された3ヶ月のWTマウス)、海馬の歯状回の成体神経発生を示す代表的な画像を提示する。化学的処置の7日後、マウスを屠殺して、新生ニューロンマーカーDCXの免疫染色を用いて調べた(図4C)。定量解析によれば、FDA認可済み薬物カクテルで処理されたDCX+ニューロンの数が増加したことが明らかになった。スチューデントt検定、*P<0.05、n=2ペア。
Claims (20)
- グリア細胞をクリゾチニブ(Cri)、フルルビプロフェン(Flu)、塩化リチウム(Li)、ビタミンC(VC)、セリチニブ(Cer)、及びピルフェニドン(PFD)のうちの少なくとも3種の組み合わせを含む化合物の群と接触させることを含む、ニューロンを発生させるための方法。
- 前記群が、前記化合物のうちの4種を含む、請求項1に記載の方法。
- 前記群が、前記化合物のうちの5種を含む、請求項1に記載の方法。
- 前記群が、前記化合物のうちの4種のみからなる、請求項1に記載の方法。
- 前記群が、前記化合物のうちの5種のみからなる、請求項1に記載の方法。
- 前記群が、i)Cer/Cri/Li/Flu/VC、ii)PFD/Cri/Li/Flu/VC、iii)Cer/Cri/Li/Flu、又はiv)PFD/Cri/Li/Fluを含む、請求項1に記載の方法。
- 前記群が、i)Cer/Cri/Li/Flu/VC、ii)PFD/Cri/Li/Flu/VC、iii)Cer/Cri/Li/Flu、又はiv)PFD/Cri/Li/Fluのみからなる、請求項1に記載の方法。
- 前記グリア細胞が、哺乳動物の脳、又は脊髄、又は末梢神経系に存在する、請求項1から7のいずれか一項に記載の方法。
- 前記群が、Cri/Flu/PFD/VC/Liを含む、請求項8に記載の方法。
- 前記群が、前記Cri/Flu/PFD/VC/Liのみからなる、請求項9に記載の方法。
- 前記群が、ニューロンの欠損及び/又はグリア性瘢痕及び/又は神経傷害、及び/又は加齢、又は神経変性、又は小頭症、又は重篤な発作を含む状態のために、前記ニューロンを必要とする個体に投与される、請求項8に記載の方法。
- 前記個体が、虚血性脳損傷のために前記ニューロンを必要とする、請求項8に記載の方法。
- 前記個体が、アルツハイマー病と診断されたか、又はアルツハイマー病を患っていると疑われる、請求項8に記載の方法。
- クリゾチニブ(Cri)、フルルビプロフェン(Flu)、塩化リチウム(Li)、ならびにビタミンC(VC)、セリチニブ(Cer)、及びピルフェニドン(PFD)から選択される少なくとも1種の追加の化合物を含む化合物の群を含む医薬組成物。
- 前記群が、i)Cer/Cri/Li/Flu/VC、ii)PFD/Cri/Li/Flu/VC、iii)Cer/Cri/Li/Flu、又はiv)PFD/Cri/Li/Fluを含む、請求項14に記載の医薬組成物。
- 前記群が、Cri/Flu/PFD/VC/Liを含む、請求項14に記載の医薬組成物。
- 前記群が、前記Cri/Flu/PFD/VC/Liのみからなる、請求項15に記載の医薬組成物。
- クリゾチニブ(Cri)、フルルビプロフェン(Flu)、塩化リチウム(Li)、ビタミンC(VC)、セリチニブ(Cer)、及びピルフェニドン(PFD)のうちの少なくとも3種を含む化合物の群を含む医薬組成物を含む製品であって、前記化合物の群が、機能性ニューロンの必要性に関連する状態を処置するのに使用されるという指示を示す印刷物をさらに含む、製品。
- 群が、i)Cer/Cri/Li/Flu/VC、ii)PFD/Cri/Li/Flu/VC、iii)Cer/Cri/Li/Flu、又はiv)PFD/Cri/Li/Fluを含む、請求項18に記載の製品。
- 前記群が、Cri/Flu/PFD/VC/Liを含む、請求項18に記載の製品。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562263353P | 2015-12-04 | 2015-12-04 | |
US62/263,353 | 2015-12-04 | ||
PCT/US2016/064553 WO2017096123A1 (en) | 2015-12-04 | 2016-12-02 | Chemical reprogramming of human glial cells into neurons with small molecule cocktail |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018535988A true JP2018535988A (ja) | 2018-12-06 |
JP6951336B2 JP6951336B2 (ja) | 2021-10-20 |
Family
ID=58797771
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018527791A Active JP6951336B2 (ja) | 2015-12-04 | 2016-12-02 | 小分子カクテルによるヒトグリア細胞からニューロンへの化学的リプログラミング |
Country Status (10)
Country | Link |
---|---|
US (2) | US9885015B2 (ja) |
EP (2) | EP3795147B1 (ja) |
JP (1) | JP6951336B2 (ja) |
KR (2) | KR102444438B1 (ja) |
CN (2) | CN108430582B (ja) |
AU (1) | AU2016364845B2 (ja) |
CA (1) | CA3007116A1 (ja) |
HK (1) | HK1256307A1 (ja) |
SG (1) | SG11201804440XA (ja) |
WO (1) | WO2017096123A1 (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT201800001168A1 (it) * | 2018-01-17 | 2019-07-17 | Fond Per Listituto Oncologico Di Ricerca Ior | Nuovi farmaci senolitici inibitori alk |
AU2020257262A1 (en) * | 2019-04-18 | 2021-11-18 | Brown University | Neurogenesis |
EP4065091A4 (en) * | 2019-11-25 | 2023-11-29 | The Penn State Research Foundation | COMPOSITION AND METHOD FOR CONVERTING HUMAN GLIA CELLS INTO NEURONS |
WO2021195706A1 (en) * | 2020-03-31 | 2021-10-07 | Children's Medical Research Institute | New dynamin inhibitors and uses |
WO2022095057A1 (zh) * | 2020-11-09 | 2022-05-12 | 深圳先进技术研究院 | 一种医药组合物及其医药用途 |
CN113244236B (zh) * | 2021-06-01 | 2023-02-03 | 上海市第一人民医院 | 色瑞替尼在制备治疗甲状腺相关眼病的药物中的应用 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2379149A1 (en) | 1999-07-09 | 2001-01-18 | Ortho-Mcneil Pharmaceutical, Inc. | Neurotrophic pyrrolidines and piperidines, and related compositions and methods |
GB0316882D0 (en) * | 2003-07-18 | 2003-08-20 | Consejo Superior Investigacion | Reversible immortalization of OEG from human olfactory bulbs as a tool to promote spinal cord regeneration |
JP2009538279A (ja) | 2006-03-09 | 2009-11-05 | ユニバーシティー オブ ロチェスター | 末梢および神経の炎症性クロストーク |
CN101732255A (zh) | 2010-01-07 | 2010-06-16 | 同济大学 | 一种氟比洛芬脂质体及其制备方法 |
EP2577318B1 (en) | 2010-05-25 | 2019-06-26 | Memorial Sloan-Kettering Cancer Center | Method of nociceptor differentiantion of human embryonic stem cells and uses thereof |
CN114601937A (zh) * | 2012-07-19 | 2022-06-10 | 宾夕法尼亚州研究基金会 | 再生用于在神经系统中治疗疾病和损伤的功能性神经元 |
EP3881857A1 (en) * | 2016-02-18 | 2021-09-22 | The Penn State Research Foundation | Generating gabaergic neurons in brains |
WO2020263639A1 (en) * | 2019-06-28 | 2020-12-30 | The Penn State Research Foundation | Methods and materials for treating huntington's disease |
-
2016
- 2016-12-02 US US15/367,382 patent/US9885015B2/en active Active
- 2016-12-02 WO PCT/US2016/064553 patent/WO2017096123A1/en active Application Filing
- 2016-12-02 CN CN201680077502.1A patent/CN108430582B/zh active Active
- 2016-12-02 CN CN202010064422.0A patent/CN111184739B/zh active Active
- 2016-12-02 KR KR1020207010846A patent/KR102444438B1/ko active IP Right Grant
- 2016-12-02 CA CA3007116A patent/CA3007116A1/en active Pending
- 2016-12-02 EP EP20207658.4A patent/EP3795147B1/en active Active
- 2016-12-02 KR KR1020187019038A patent/KR102102837B1/ko active IP Right Grant
- 2016-12-02 JP JP2018527791A patent/JP6951336B2/ja active Active
- 2016-12-02 SG SG11201804440XA patent/SG11201804440XA/en unknown
- 2016-12-02 AU AU2016364845A patent/AU2016364845B2/en active Active
- 2016-12-02 EP EP16871554.8A patent/EP3383495B1/en active Active
-
2017
- 2017-12-01 US US15/828,652 patent/US10253293B2/en active Active
-
2018
- 2018-11-30 HK HK18115373.5A patent/HK1256307A1/zh unknown
Also Published As
Publication number | Publication date |
---|---|
SG11201804440XA (en) | 2018-06-28 |
KR102102837B1 (ko) | 2020-04-22 |
CN111184739B (zh) | 2022-06-24 |
EP3383495A1 (en) | 2018-10-10 |
KR102444438B1 (ko) | 2022-09-19 |
EP3795147A1 (en) | 2021-03-24 |
CN108430582A (zh) | 2018-08-21 |
CA3007116A1 (en) | 2017-06-08 |
EP3383495B1 (en) | 2021-01-20 |
CN108430582B (zh) | 2020-02-21 |
US20170159013A1 (en) | 2017-06-08 |
EP3795147B1 (en) | 2023-08-30 |
EP3383495A4 (en) | 2019-09-04 |
US20180148688A1 (en) | 2018-05-31 |
CN111184739A (zh) | 2020-05-22 |
US9885015B2 (en) | 2018-02-06 |
KR20180081824A (ko) | 2018-07-17 |
US10253293B2 (en) | 2019-04-09 |
HK1256307A1 (zh) | 2019-09-20 |
AU2016364845A1 (en) | 2018-06-21 |
JP6951336B2 (ja) | 2021-10-20 |
KR20200043503A (ko) | 2020-04-27 |
WO2017096123A1 (en) | 2017-06-08 |
AU2016364845B2 (en) | 2022-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6951336B2 (ja) | 小分子カクテルによるヒトグリア細胞からニューロンへの化学的リプログラミング | |
US20220071929A1 (en) | Application of r-ketamine and salt thereof as pharmaceuticals | |
Johnson et al. | Pharmacotherapy for amyotrophic lateral sclerosis: a review of approved and upcoming agents | |
ES2938546T3 (es) | Método de tratamiento de la esclerosis lateral amiotrófica con pridopidina | |
CN105209036B (zh) | 氧杂双环庚烷和氧杂双环庚烯的配制品 | |
Ouyang et al. | Brain‐Penetration and Neuron‐Targeting DNA Nanoflowers Co‐Delivering miR‐124 and Rutin for Synergistic Therapy of Alzheimer's Disease | |
CA2688327A1 (en) | Methods and compositions for stimulating cells | |
Jann | Implications for atypical antipsychotics in the treatment of schizophrenia: neurocognition effects and a neuroprotective hypothesis | |
Ahmad et al. | Evolving therapeutic interventions for the management and treatment of Alzheimer’s disease | |
El Ganainy et al. | Stereotaxic-assisted gene therapy in Alzheimer’s and Parkinson’s diseases: therapeutic potentials and clinical frontiers | |
Chen et al. | Metabolic reprogramming: a new option for the treatment of spinal cord injury | |
Samim et al. | Pathophysiology and Management Approaches for Parkinson’s Disease | |
US20220395483A1 (en) | Composition and method for converting human gilial cells into neurons | |
Jain | Check for Pathophysiology and Management Approaches in Alzheimer's Disease Shreshta Jain, Divya Goel, Sheikh Sana Nazir, Vaishali Yadav, and Divya Vohora | |
Wang et al. | Advances in Neuroprotection in Glaucoma: Pharmacological Strategies and Emerging Technologies | |
WO2021245315A1 (es) | Prevención y/o tratamiento del deterioro cognitivo asociado a síndromes de demencia | |
Di Franco | Development and characterization of a new therapeutic approach of the Down Syndrome targeting the type-1 cannabinoid receptor | |
Boyadjieva | TEACHING PHARMACOLOGY IN THE MEDICAL FACULTY OF MEDICAL UNIVERSITY IN SOFIA | |
Chao | Investigation on Alternative Treatment Approaches in the Unilateral 6-OHDA Lesion Rat Model of Parkinson's Disease | |
Martinez-Fernandez et al. | Chorea: A Surgical Approach | |
Higgins | Targeting Trends |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190723 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200630 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200918 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210202 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210426 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210511 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210706 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210804 |
|
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: 20210831 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210924 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6951336 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |