JP6920062B2 - 子宮内膜病変における幹細胞治療 - Google Patents
子宮内膜病変における幹細胞治療 Download PDFInfo
- Publication number
- JP6920062B2 JP6920062B2 JP2016573587A JP2016573587A JP6920062B2 JP 6920062 B2 JP6920062 B2 JP 6920062B2 JP 2016573587 A JP2016573587 A JP 2016573587A JP 2016573587 A JP2016573587 A JP 2016573587A JP 6920062 B2 JP6920062 B2 JP 6920062B2
- Authority
- JP
- Japan
- Prior art keywords
- endometrial
- bmdsc
- subject
- composition
- autologous
- 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.)
- Active
Links
- 230000002357 endometrial effect Effects 0.000 title description 74
- 238000009168 stem cell therapy Methods 0.000 title description 9
- 238000009580 stem-cell therapy Methods 0.000 title description 8
- 230000003902 lesion Effects 0.000 title description 6
- 102100040120 Prominin-1 Human genes 0.000 claims description 81
- 208000002777 Gynatresia Diseases 0.000 claims description 44
- 210000000130 stem cell Anatomy 0.000 claims description 32
- 238000011282 treatment Methods 0.000 claims description 32
- 206010051909 Endometrial atrophy Diseases 0.000 claims description 25
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 24
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 24
- 210000000685 uterine artery Anatomy 0.000 claims description 22
- 210000001185 bone marrow Anatomy 0.000 claims description 21
- 238000002617 apheresis Methods 0.000 claims description 16
- 210000002565 arteriole Anatomy 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 210000005259 peripheral blood Anatomy 0.000 claims description 12
- 239000011886 peripheral blood Substances 0.000 claims description 12
- 230000032692 embryo implantation Effects 0.000 claims description 8
- 230000003054 hormonal effect Effects 0.000 claims description 8
- 230000001483 mobilizing effect Effects 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 description 54
- 210000004027 cell Anatomy 0.000 description 44
- 210000004696 endometrium Anatomy 0.000 description 40
- 238000011069 regeneration method Methods 0.000 description 29
- 230000008929 regeneration Effects 0.000 description 28
- 238000002659 cell therapy Methods 0.000 description 16
- 210000004204 blood vessel Anatomy 0.000 description 13
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 10
- 230000001939 inductive effect Effects 0.000 description 10
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002955 isolation Methods 0.000 description 9
- 238000002604 ultrasonography Methods 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 229940011871 estrogen Drugs 0.000 description 8
- 239000000262 estrogen Substances 0.000 description 8
- 238000002657 hormone replacement therapy Methods 0.000 description 8
- 238000002513 implantation Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 230000002175 menstrual effect Effects 0.000 description 8
- 230000027758 ovulation cycle Effects 0.000 description 8
- 230000007115 recruitment Effects 0.000 description 8
- 238000002399 angioplasty Methods 0.000 description 7
- 210000001367 artery Anatomy 0.000 description 7
- 239000002346 layers by function Substances 0.000 description 7
- 230000005906 menstruation Effects 0.000 description 7
- 210000000754 myometrium Anatomy 0.000 description 7
- 239000013641 positive control Substances 0.000 description 7
- 230000035935 pregnancy Effects 0.000 description 7
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 6
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 6
- 208000037093 Menstruation Disturbances Diseases 0.000 description 6
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 6
- 210000004291 uterus Anatomy 0.000 description 6
- 201000000736 Amenorrhea Diseases 0.000 description 5
- 206010001928 Amenorrhoea Diseases 0.000 description 5
- 231100000540 amenorrhea Toxicity 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000000981 epithelium Anatomy 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 201000010260 leiomyoma Diseases 0.000 description 5
- 230000003836 peripheral circulation Effects 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000007619 statistical method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 206010046798 Uterine leiomyoma Diseases 0.000 description 4
- 238000011130 autologous cell therapy Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 208000021267 infertility disease Diseases 0.000 description 4
- 210000001161 mammalian embryo Anatomy 0.000 description 4
- 210000002741 palatine tonsil Anatomy 0.000 description 4
- 230000000306 recurrent effect Effects 0.000 description 4
- 230000001850 reproductive effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 208000000995 spontaneous abortion Diseases 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 206010000234 Abortion spontaneous Diseases 0.000 description 3
- 102000052030 Aldehyde Dehydrogenase 1 Family Human genes 0.000 description 3
- 101710196131 Aldehyde dehydrogenase 1 Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010021033 Hypomenorrhoea Diseases 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 206010041660 Splenomegaly Diseases 0.000 description 3
- 210000004504 adult stem cell Anatomy 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000002583 angiography Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000010102 embolization Effects 0.000 description 3
- 201000006828 endometrial hyperplasia Diseases 0.000 description 3
- 230000000762 glandular Effects 0.000 description 3
- 230000002055 immunohistochemical effect Effects 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 208000000509 infertility Diseases 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 231100000535 infertility Toxicity 0.000 description 3
- 238000001361 intraarterial administration Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 208000015994 miscarriage Diseases 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 239000000186 progesterone Substances 0.000 description 3
- 229960003387 progesterone Drugs 0.000 description 3
- 238000007634 remodeling Methods 0.000 description 3
- 238000002660 stem cell treatment Methods 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 208000006379 syphilis Diseases 0.000 description 3
- 108010005465 AC133 Antigen Proteins 0.000 description 2
- 102000005908 AC133 Antigen Human genes 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 206010008805 Chromosomal abnormalities Diseases 0.000 description 2
- 208000031404 Chromosome Aberrations Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 206010055690 Foetal death Diseases 0.000 description 2
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 101150017554 LGR5 gene Proteins 0.000 description 2
- 206010027339 Menstruation irregular Diseases 0.000 description 2
- 208000035175 Oligomenorrhea Diseases 0.000 description 2
- 206010030295 Oligomenorrhoea Diseases 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 241000270295 Serpentes Species 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 206010000210 abortion Diseases 0.000 description 2
- 231100000176 abortion Toxicity 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 210000002257 embryonic structure Anatomy 0.000 description 2
- 210000005168 endometrial cell Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 210000004392 genitalia Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 210000003090 iliac artery Anatomy 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 230000029849 luteinization Effects 0.000 description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 2
- 210000004967 non-hematopoietic stem cell Anatomy 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000035752 proliferative phase Effects 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 210000000603 stem cell niche Anatomy 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000000472 traumatic effect Effects 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 1
- 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 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 208000028685 Asherman syndrome Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100037904 CD9 antigen Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000008899 Habitual abortion Diseases 0.000 description 1
- 101000738354 Homo sapiens CD9 antigen Proteins 0.000 description 1
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000035002 Pregnancy of unknown location Diseases 0.000 description 1
- 208000002500 Primary Ovarian Insufficiency Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 206010046764 Uterine atrophy Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 201000001389 adhesions of uterus Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000010108 arterial embolization Effects 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 102000049842 cholesterol binding protein Human genes 0.000 description 1
- 108010011793 cholesterol binding protein Proteins 0.000 description 1
- 208000030373 chronic endometritis Diseases 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004246 corpus luteum Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000003511 ectopic pregnancy Diseases 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 206010016629 fibroma Diseases 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000005283 ground state Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 238000011575 immunodeficient mouse model Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000002697 interventional radiology Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical compound [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 description 1
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 1
- 206010024378 leukocytosis Diseases 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 231100000544 menstrual irregularity Toxicity 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000037211 monthly cycles Effects 0.000 description 1
- 229940031182 nanoparticles iron oxide Drugs 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 208000015124 ovarian disease Diseases 0.000 description 1
- 201000004535 ovarian dysfunction Diseases 0.000 description 1
- 231100000543 ovarian dysfunction Toxicity 0.000 description 1
- 230000011599 ovarian follicle development Effects 0.000 description 1
- 238000010831 paired-sample T-test Methods 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 208000016685 primary ovarian failure Diseases 0.000 description 1
- 229960003351 prussian blue Drugs 0.000 description 1
- 239000013225 prussian blue Substances 0.000 description 1
- 208000034213 recurrent susceptibility to 1 pregnancy loss Diseases 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000009589 serological test Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000001988 somatic stem cell Anatomy 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 231100001042 uterine atrophy Toxicity 0.000 description 1
- 208000010579 uterine corpus leiomyoma Diseases 0.000 description 1
- 201000007954 uterine fibroid Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- 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
- C12N2320/00—Applications; Uses
- C12N2320/30—Special therapeutic applications
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Developmental Biology & Embryology (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Cell Biology (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Thermotherapy And Cooling Therapy Devices (AREA)
Description
本出願は、2014年6月17日に出願された米国仮特許出願第62/013,121の35U.S.C§119(e)の下での利益を主張し、当該出願の内容全体が、ここで参考として援用される。
本発明は、一般に、子宮内膜再生を誘導し、アッシャーマン症候群および子宮内膜萎縮のような子宮内膜病変を処置するための自己由来CD133+骨髄幹細胞(BMDSC)の使用に関する。
生殖可能年齢の女性において、子宮内膜のうちの2層は、区別され得る:(i)子宮腔に隣接する機能的層、および(ii)子宮筋層に隣接しかつ上記機能的層の下にある基底層。上記機能的な層は、以前の月経周期の第1の部分の間の、月経の終了の後に構築される。増殖は、エストロゲンによって誘導され(月経周期の卵胞期)、この層における後の変化は、黄体に由来するプロゲステロンによって生じる(黄体期)。それは、胚の着床および成長に最適な環境を提供するように適応される。この層は、月経の間に完全に脱落する。対照的に、上記基底層は、上記月経周期の間のいかなるときにも脱落しない。各月経周期における全身性の卵巣ステロイド変化の下でのヒト子宮内膜の再生は、その主要な機能のためのこの器官の準備(すなわち、着床しつつある胚盤胞を迎え入れる(host)ための子宮内膜の着床ウインドウを発生させ、妊娠が起こることを可能にする)に必須である。従って、各月経周期に伴う子宮内膜機能的層の全ての細胞区画の補充は、正常な生殖機能に必須である。
本開示は、少なくとも部分的に、自己由来CD133+骨髄由来幹細胞(BMDSC)が自己由来の機能的子宮内膜の新規生成をもたらす血管形成を再生し得るという発見に関する。よって、本開示の局面は、子宮内膜再生を誘導するための方法を提供する。いくつかの実施形態において、上記方法は、自己由来CD133+骨髄由来幹細胞(BMDSC)の有効量を、子宮内膜再生が必要な被験体の子宮動脈へと投与して、子宮内膜再生を誘導することを包含する。
本発明は、例えば、以下の項目を提供する。
(項目1)
子宮内膜再生を誘導するための方法であって、該方法は、
自己由来CD133 + 骨髄由来幹細胞(BMDSC)の有効量を、子宮内膜再生が必要な被験体の子宮動脈へと投与して、子宮内膜再生を誘導すること
を包含する、方法。
(項目2)
前記被験体は、アッシャーマン症候群もしくは子宮内膜萎縮を有することが既知である、項目1に記載の方法。
(項目3)
前記被験体は、ホルモン処置に抵抗性である子宮内膜萎縮を有する、項目2に記載の方法。
(項目4)
前記被験体は、1回もしくはこれより多く、胚着床に以前失敗したことがある、項目1〜3のいずれか1項に記載の方法。
(項目5)
前記自己由来CD133 + BMDSCは、
前記被験体に、該被験体の骨髄から末梢血へとBMDSCを動員するための薬剤を投与すること;および
CD133 + BMDSCを該被験体の末梢血から単離すること、
によって調製される、項目1〜4のいずれか1項に記載の方法。
(項目6)
BMDSCを動員するための前記薬剤は、顆粒球コロニー刺激因子(G−CSF)である、項目1〜5のいずれか1項に記載の方法。
(項目7)
前記自己由来CD133 + BMDSCは、抗CD133抗体を使用するアフェレーシスによって前記被験体の末梢循環から単離される、項目5〜6のいずれか1項に記載の方法。
(項目8)
前記CD133 + BMDSCは、カテーテルを介して前記子宮動脈へと投与される、項目1〜8のいずれか1項に記載の方法。
(項目9)
前記CD133 + BMDSCは、前記被験体の子宮螺旋細動脈へと投与される、項目1〜8のいずれか1項に記載の方法。
(項目10)
子宮内膜再生を誘導するための方法であって、該方法は、
自己由来CD133 + 骨髄由来幹細胞(BMDSC)を、子宮内膜再生が必要な被験体から単離すること;および
該単離されたCD133 + BMDSCの有効量を、該被験体の子宮動脈へと投与して、子宮内膜再生を誘導すること
を包含する方法。
(項目11)
顆粒球コロニー刺激因子(G−CSF)は、前記自己由来BMDSCを単離する前に前記被験体へと投与される、項目10に記載の方法。
(項目12)
前記自己由来CD133 + BMDSCは、抗CD133抗体を使用するアフェレーシスによって前記被験体の末梢循環から単離される、項目10〜11のいずれか1項に記載の方法。
(項目13)
前記CD133 + BMDSCは、カテーテルを介して前記子宮動脈へと投与される、項目10〜12のいずれか1項に記載の方法。
(項目14)
前記CD133 + BMDSCは、前記被験体の子宮螺旋細動脈へと投与される、項目10〜13のいずれか1項に記載の方法。
(項目15)
前記被験体は、アッシャーマン症候群もしくは子宮内膜萎縮を有することが既知である、項目10〜14のいずれか1項に記載の方法。
(項目16)
前記被験体は、ホルモン処置に抵抗性である子宮内膜萎縮を有する、項目15に記載の方法。
(項目17)
前記被験体は、1回もしくはこれより多く、胚着床に以前失敗したことがある、項目10〜16のいずれか1項に記載の方法。
本発明は、少なくとも部分的に、自己由来幹細胞治療を使用して子宮内膜再生を誘導する新たな治療アプローチの発見に基づく。特に、本出願は、自己由来CD133+骨髄由来幹細胞(BMDSC)が自己由来機能的子宮内膜の新規生成をもたらす血管形成を再生し得るという知見に基づく。BMDSCは、種々の子宮内膜細胞区画(間質、腺上皮、および内腔上皮)における非造血細胞の供給源であることが公知であったものの、BMDSCの亜集団(複数可)が子宮内膜の修復を促進することは公知ではなかった。本出願は、子宮内膜再生を誘導し、アッシャーマン症候群および子宮内膜萎縮のような子宮内膜変性と関連する病変を処置するために安全かつ有効な細胞ベースの治療を提供する。
・上記CD133+BMSC幹細胞処置後の月経の再開;
・子宮内膜厚の増大;(子宮内膜厚は、子宮内膜腔の底において子宮筋層の上限から下限までの長さとして測定される)。例えば、上記増大は、子宮底において長軸方向の膣超音波によって測定される、ホルモン補充療法(HRT)でこれまで得られた最大厚の50%の増大であり得る(4〜6mmのvgr);
・新規子宮内膜形成の子宮鏡検査によるおよび組織学的な証拠;ならびに/または
・これら患者における胚配置(embryo placement)後の生児出生率(live−birth rate)、妊娠および着床率に関する再構築された子宮内膜の機能性。
(材料および方法)
(デザイン)
以下は、Hospital Clinico de Valencia(Spain)のIRBによって承認され、Spanish Ministry of Healthによって資金援助(Ref EC 11−299)された、難治性ASを有する16名の患者における実験的な非対照研究である。BMDSC動員を、顆粒球−CSF(G−CSF)(4日間の間に5mg/kg/12時間 sc)を使用して行った。7日後に、末梢血アフェレーシスとCD133+細胞の単離を、行った。次いで、自己由来CD133+細胞を、非侵襲性放射線医学介入によって、2.5 Fマイクロカテーテルを使用して子宮動脈を介して、螺旋細動脈へと送達した。子宮内膜腔状態を、幹細胞介入の前、ならびに該介入の3ヶ月後、6ヶ月後および9ヶ月後に、子宮鏡検査、膣超音波、および組織学を介して評価した。
(患者および方法)
(包含基準)
(排除基準)
(方法論)
(1.骨髄幹細胞(BMSC)動員)
・上記患者に、上記手順について情報を与え、上記動員の少なくとも24時間前に同意書を与えた。
・相当する医学的評価を、関連する補完的触診(exploration)とともに行い、BMSC再収集に責任のある医師が確認した。
・関連する血清学的試験結果(HIV、HBcAg、HBsAg、HCV、梅毒)を利用可能になった。
・静脈を評価して上記手順に彼らが適切であることを決定した。
次いで、末梢血へのBMSC動員を、G−CSF(5mcg/kg sc 12時間ごと)によって4日間誘導した。
(2.BMSC再収集)
(3.動脈内カテーテル法による子宮螺旋細動脈へのCD133+細胞移植)
(応答基準)
・月経転帰。月経は、上記CD133+BMSC処置の後に再開しなければならない。
・子宮内膜厚の増大。これまでHRTで得られた最大厚のうちの最小50%が、子宮底において縦軸方向の(longitudinal axis)膣超音波によって測定された(4〜6mmのvgr)。
・形成される新規子宮内膜の子宮鏡検査によるおよび組織学の証拠。
・これら患者における胚移植(embryo replacement)後の生児出生率、妊娠および着床率に関する上記再構築された子宮内膜の機能性。
(結果)
(実施例2)
(研究参加者)
(BMDSC動員および単離)
(BMDSCの送達)
(追跡)
(子宮内膜免疫組織化学)
(統計分析)
(結果)
(考察)
Claims (8)
- アッシャーマン症候群または子宮内膜萎縮の処置を必要とする被験体におけるアッシャーマン症候群または子宮内膜萎縮の処置において使用するための、単離された自己由来CD133+骨髄由来幹細胞(BMDSC)を含む組成物であって、前記組成物が前記被験体の子宮動脈へと投与されることを特徴とし、前記被験体がホルモン処置に抵抗性である子宮内膜委縮を有する、組成物。
- 前記被験体が1回またはこれより多く、胚着床に以前失敗したことがある、請求項1に記載の使用のための組成物。
- 前記単離された自己由来CD133+BMDSCは、前記被験体の骨髄から末梢血へとBMDSCを動員するための薬剤を前記被験体に投与した後に前記被験体の末梢血から単離される、請求項1または2に記載の使用のための組成物。
- BMDSCを動員するための前記薬剤が顆粒球コロニー刺激因子(G−CSF)である、請求項3に記載の使用のための組成物。
- 前記組成物がカテーテルを介して子宮動脈へと投与されることを特徴とする、請求項1〜4のいずれか一項に記載の使用のための組成物。
- 前記組成物が前記被験体の子宮螺旋細動脈へと投与されることを特徴とする、請求項1〜5のいずれか一項に記載の使用のための組成物。
- 前記自己由来CD133+BMDSCはアフェレーシスによって、前記被験体の前記末梢血から単離され、前記アフェレーシスは抗CD133抗体を使用して行われる、請求項3〜6のいずれか一項に記載の使用のための組成物。
- 前記組成物が少なくとも4500万個のCD133+BMDSCを含む、請求項1〜7のいずれか一項に記載の使用のための組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462013121P | 2014-06-17 | 2014-06-17 | |
US62/013,121 | 2014-06-17 | ||
PCT/IB2015/001715 WO2015193737A1 (en) | 2014-06-17 | 2015-06-05 | Stem cell therapy in endometrial pathologies |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020102340A Division JP2020138984A (ja) | 2014-06-17 | 2020-06-12 | 子宮内膜病変における幹細胞治療 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017522288A JP2017522288A (ja) | 2017-08-10 |
JP2017522288A5 JP2017522288A5 (ja) | 2018-07-12 |
JP6920062B2 true JP6920062B2 (ja) | 2021-08-18 |
Family
ID=54329860
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016573587A Active JP6920062B2 (ja) | 2014-06-17 | 2015-06-05 | 子宮内膜病変における幹細胞治療 |
JP2020102340A Pending JP2020138984A (ja) | 2014-06-17 | 2020-06-12 | 子宮内膜病変における幹細胞治療 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020102340A Pending JP2020138984A (ja) | 2014-06-17 | 2020-06-12 | 子宮内膜病変における幹細胞治療 |
Country Status (21)
Country | Link |
---|---|
US (1) | US11129851B2 (ja) |
EP (3) | EP4012023B1 (ja) |
JP (2) | JP6920062B2 (ja) |
CN (2) | CN107073040A (ja) |
AU (1) | AU2015275798B2 (ja) |
BR (1) | BR112016029558A2 (ja) |
CA (1) | CA2952559C (ja) |
CY (2) | CY1122615T1 (ja) |
DK (2) | DK3158057T3 (ja) |
ES (2) | ES2910306T3 (ja) |
HR (3) | HRP20240798T1 (ja) |
HU (2) | HUE058328T2 (ja) |
LT (2) | LT3569697T (ja) |
MX (1) | MX2016016756A (ja) |
PL (3) | PL3569697T3 (ja) |
PT (2) | PT3569697T (ja) |
RS (3) | RS63093B1 (ja) |
RU (1) | RU2725006C2 (ja) |
SI (2) | SI3158057T1 (ja) |
TR (1) | TR201910410T4 (ja) |
WO (1) | WO2015193737A1 (ja) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010010201A1 (es) | 2008-07-22 | 2010-01-28 | Equipo Ivi Investigacion Sl | Perfil de expresion genetica como marcador de la receptividad endometrial |
JP6386450B2 (ja) | 2012-06-06 | 2018-09-05 | フンダシオ、インスティトゥト、デ、レセルカ、ビオメディカ(イエレベ、バルセロナ)Fundacio Institut De Recerca Biomedica (Irb Barcelona) | 肺がん転移の診断、予後診断および処置のための方法 |
US10119171B2 (en) | 2012-10-12 | 2018-11-06 | Inbiomotion S.L. | Method for the diagnosis, prognosis and treatment of prostate cancer metastasis |
DK2906718T3 (da) | 2012-10-12 | 2019-07-01 | Inbiomotion Sl | Fremgangsmåde til diagnose, prognose og behandling af prostatakræftmetastase under anvendelse af c-maf |
EP3272880B1 (en) | 2013-03-15 | 2020-11-25 | Fundació Institut de Recerca Biomèdica (IRB Barcelona) | Method for the diagnosis, prognosis and treatment of metastatic cancer |
PT3569697T (pt) | 2014-06-17 | 2022-05-02 | Asherman Therapy S L | Terapia de células estaminais em patologias endometriais |
EP3474866A4 (en) * | 2016-06-23 | 2020-02-26 | Tithon Biotech, Inc. | CELLS EXPRESSING THE PARATHYROID HORMONE RECEPTOR 1 AND USES THEREOF |
RU2699029C1 (ru) * | 2018-12-10 | 2019-09-03 | Частное образовательное учреждение дополнительного профессионального образования "Академия медицинского образования имени Федора Ивановича Иноземцева" (ЧОУ ДПО "Академия медицинского образования им. Ф.И. Иноземцева") | Способ использования мезенхимальных стволовых клеток для улучшения состояния рубца на матке |
RU2741621C1 (ru) * | 2020-09-25 | 2021-01-28 | Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии имени академика В.И. Кулакова" Министерства здравоохранения Российской Федерации | Способ лечения внутриматочных синехий |
CN117979980A (zh) | 2021-07-23 | 2024-05-03 | 车医科学大学校产学协力团 | 用于预防或治疗阿谢曼综合征的包含分离的线粒体作为活性成分的药物组合物 |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR920700648A (ko) | 1989-05-05 | 1992-08-10 | 오닐 크리스토퍼 | 가임성 향상 |
US6979533B2 (en) | 1992-06-12 | 2005-12-27 | The Trustees Of The University Of Pennsylvania | Determination of endometrial receptivity toward embryo implantation |
CA2203718A1 (en) | 1997-04-25 | 1998-10-25 | University Of British Columbia | Cadherin-11 as an indicator of viable pregnancy |
IL127896A0 (en) | 1998-12-31 | 1999-10-28 | Gail Laster | A novel treatment for preeclampsia and related diseases |
WO2001066786A1 (en) | 2000-03-08 | 2001-09-13 | Kliman Harvey J | Methods of diagnosing and monitoring endometrial glandular development |
AU2001264900A1 (en) | 2000-05-24 | 2001-12-03 | Schering Aktiengesellschaft | Pharmaceutical use of fibulin-1 |
US6780594B2 (en) | 2000-09-25 | 2004-08-24 | Schering Aktiengesellschaft | Method for in vitro diagnosis of endometriosis |
AUPR673001A0 (en) | 2001-07-31 | 2001-08-23 | Prince Henry's Institute Of Medical Research | Pregnancy-related enzyme activity |
DE10139874A1 (de) | 2001-08-10 | 2003-04-30 | Schering Ag | Humane Mater-Proteine |
GB0201284D0 (en) | 2002-01-21 | 2002-03-06 | Isis Innovation | Screening methods for contraceptive and fertility agents |
US20030186300A1 (en) | 2002-03-20 | 2003-10-02 | Ali Akoum | Methods and products for modulation of reproductive processes and for diagnosis, prognostication and treatment of related conditions |
WO2004061074A2 (en) | 2002-05-14 | 2004-07-22 | The Board Of Trustees Of The Leland Stanford Junior University | Endometrial genes in endometrial disorders |
AU2003255355A1 (en) | 2002-08-02 | 2004-02-25 | Schering Aktiengesellschaft | Progesterone receptor modulators having an increased antigonadotropic activity for use in female fertility testing and hormone replacement therapy |
DE10236405A1 (de) | 2002-08-02 | 2004-02-19 | Schering Ag | Progesteronrezeptormodulatoren mit erhöhter antigonadotroper Aktivität für die weibliche Fertilitätskontrolle und Hormonersatztherapie |
WO2004058999A2 (de) | 2002-12-21 | 2004-07-15 | Universität Leipzig | Verfahren und mittel zur bestimmung von bestimmten zuständen bzw. veränderungen im uterusepithel und im epithel anderer organe |
WO2005018796A1 (en) | 2003-08-21 | 2005-03-03 | Pamgene B.V. | Microarray support for bioprobe synthesis |
CN1863905A (zh) | 2003-09-08 | 2006-11-15 | 得克萨斯系统大学董事会 | 通过用前列腺素或前列腺素类似物补充培养基加强体外胚发育的方法以及组合物 |
WO2005026324A2 (en) | 2003-09-08 | 2005-03-24 | The Board Of Regents Of The University Of Texas System | Method and composition for enhancing in vitro embryo development by supplementing culture medium with prostaglandin or a prostaglandin analog |
AU2004303448A1 (en) | 2003-12-23 | 2005-07-07 | Mount Sinai Hospital | Methods for detecting markers associated with endometrial disease or phase |
JP2008501035A (ja) | 2004-05-28 | 2008-01-17 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | 妊孕性関連障害の治療におけるil−17の使用 |
RU2434645C2 (ru) * | 2006-03-31 | 2011-11-27 | Конинклейке Филипс Электроникс, Н.В. | Системы и методы измерения клеток, использующие ультракороткую т2*-релаксометрию |
JP2007278750A (ja) | 2006-04-04 | 2007-10-25 | Ono Pharmaceut Co Ltd | プロスタグランジン類及びその類縁体の定量方法 |
WO2008036374A2 (en) * | 2006-09-21 | 2008-03-27 | Medistem Laboratories, Inc. | Allogeneic stem cell transplants in non-conditioned recipients |
GB0703683D0 (en) * | 2007-02-26 | 2007-04-04 | Ark Therapeutics Ltd | The treatment of complications in pregnancy |
US9259233B2 (en) * | 2007-04-06 | 2016-02-16 | Hologic, Inc. | Method and device for distending a gynecological cavity |
WO2009143633A1 (en) | 2008-05-30 | 2009-12-03 | Institut De Recherches Cliniques De Montreal | Pcsk9 inhibitors and methods of use thereof |
WO2010010201A1 (es) | 2008-07-22 | 2010-01-28 | Equipo Ivi Investigacion Sl | Perfil de expresion genetica como marcador de la receptividad endometrial |
WO2013166281A1 (en) * | 2012-05-02 | 2013-11-07 | Cedars-Sinai Medical Center | Bi-functional compositions for targeting cells to diseased tissues and methods of using same |
EP2348318A1 (en) | 2010-01-21 | 2011-07-27 | Equipo Ivi Investigación, S.L. | Diagnostic method for endometrial receptivity |
PT2768976T (pt) | 2011-10-21 | 2018-04-05 | Inst Nat Sante Rech Med | Métodos para avaliar a receptividade endométrica de uma paciente após hiperestimulação ovárica controlada |
WO2013081554A1 (en) | 2011-11-30 | 2013-06-06 | Agency For Science, Technology And Research | Gm1 ganglioside to annexin v microparticle polypeptide ratio for biological monitoring |
EP2867670B1 (en) | 2012-06-27 | 2018-05-30 | Roche Diagnostics GmbH | MEANS AND METHODS APPLYING sFlt-1/PlGF OR ENDOGLIN/PlGF RATIO TO RULE-OUT ONSET OF PREECLAMPSIA WITHIN A CERTAIN TIME PERIOD |
RU2515475C1 (ru) * | 2012-11-15 | 2014-05-10 | Федеральное государственное бюджетное учреждение науки ИНСТИТУТ ЦИТОЛОГИИ РОССИЙСКОЙ АКАДЕМИИ НАУК | Способ стимуляции образования децидуальной оболочки эндометрия в эксперименте |
CN106662589B (zh) | 2014-03-21 | 2019-07-30 | 艾基诺米公司 | 先兆子痫的早期检测 |
PT3569697T (pt) | 2014-06-17 | 2022-05-02 | Asherman Therapy S L | Terapia de células estaminais em patologias endometriais |
-
2015
- 2015-06-05 PT PT191693092T patent/PT3569697T/pt unknown
- 2015-06-05 RU RU2017101147A patent/RU2725006C2/ru active
- 2015-06-05 BR BR112016029558A patent/BR112016029558A2/pt not_active Application Discontinuation
- 2015-06-05 MX MX2016016756A patent/MX2016016756A/es active IP Right Grant
- 2015-06-05 AU AU2015275798A patent/AU2015275798B2/en active Active
- 2015-06-05 RS RS20220339A patent/RS63093B1/sr unknown
- 2015-06-05 US US15/318,825 patent/US11129851B2/en active Active
- 2015-06-05 SI SI201530822T patent/SI3158057T1/sl unknown
- 2015-06-05 RS RS20240690A patent/RS65719B1/sr unknown
- 2015-06-05 LT LTEP19169309.2T patent/LT3569697T/lt unknown
- 2015-06-05 DK DK15781411.2T patent/DK3158057T3/da active
- 2015-06-05 HR HRP20240798TT patent/HRP20240798T1/hr unknown
- 2015-06-05 JP JP2016573587A patent/JP6920062B2/ja active Active
- 2015-06-05 PL PL19169309T patent/PL3569697T3/pl unknown
- 2015-06-05 PL PL15781411T patent/PL3158057T3/pl unknown
- 2015-06-05 CN CN201580043147.1A patent/CN107073040A/zh active Pending
- 2015-06-05 ES ES19169309T patent/ES2910306T3/es active Active
- 2015-06-05 HR HRP20220419TT patent/HRP20220419T1/hr unknown
- 2015-06-05 SI SI201531822T patent/SI3569697T1/sl unknown
- 2015-06-05 EP EP22150013.5A patent/EP4012023B1/en active Active
- 2015-06-05 HU HUE19169309A patent/HUE058328T2/hu unknown
- 2015-06-05 RS RSP20190913 patent/RS59210B1/sr unknown
- 2015-06-05 PT PT15781411T patent/PT3158057T/pt unknown
- 2015-06-05 HU HUE15781411 patent/HUE044823T2/hu unknown
- 2015-06-05 PL PL22150013.5T patent/PL4012023T3/pl unknown
- 2015-06-05 LT LTEP15781411.2T patent/LT3158057T/lt unknown
- 2015-06-05 DK DK19169309.2T patent/DK3569697T3/da active
- 2015-06-05 CN CN202310575540.1A patent/CN116747241A/zh active Pending
- 2015-06-05 ES ES15781411T patent/ES2736117T3/es active Active
- 2015-06-05 CA CA2952559A patent/CA2952559C/en active Active
- 2015-06-05 EP EP15781411.2A patent/EP3158057B1/en active Active
- 2015-06-05 EP EP19169309.2A patent/EP3569697B8/en active Active
- 2015-06-05 TR TR2019/10410T patent/TR201910410T4/tr unknown
- 2015-06-05 WO PCT/IB2015/001715 patent/WO2015193737A1/en active Application Filing
-
2019
- 2019-07-11 HR HRP20191240 patent/HRP20191240T1/hr unknown
- 2019-07-16 CY CY20191100753T patent/CY1122615T1/el unknown
-
2020
- 2020-06-12 JP JP2020102340A patent/JP2020138984A/ja active Pending
-
2022
- 2022-04-05 CY CY20221100258T patent/CY1125938T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6920062B2 (ja) | 子宮内膜病変における幹細胞治療 | |
Puente Gonzalo et al. | Intrauterine infusion of platelet-rich plasma for severe Asherman syndrome: a cutting-edge approach | |
CN112870228B (zh) | 一种多功能微环境保护外泌体水凝胶及其制备方法和应用 | |
US11931383B2 (en) | Bioactive renal cells for the treatment of chronic kidney disease | |
Santamaria et al. | Should we consider alternative therapies to operative hysteroscopy for the treatment of Asherman syndrome? | |
Pandey et al. | Intrauterine instillation of autologous platelet-rich plasma in infertile females with thin endometrium undergoing intrauterine insemination: an open-label randomized controlled trial | |
Hu et al. | Cyclical endometrial repair and regeneration: Molecular mechanisms, diseases, and therapeutic interventions | |
TW201836635A (zh) | 不孕症之處置所用的醫藥組成物及其製造方法 | |
Wallach et al. | Hysterectomy: Exploring your options | |
Bereza et al. | Vascular structure of outer myometrial uterine leiomyomata: a preliminary sem and immunohistochemical study | |
Patel et al. | Birth of a healthy infant after bone marrow-derived cell therapy | |
Amer et al. | Organic Tissue Grafts Following Intrauterine Adhesiolysis | |
Arya | Viva practice for the FRCS (Urol) examination | |
Nicolaiciuc et al. | Abdominal radical trachelectomy as a method of preserving fertility in patients with cervical cancer | |
Dige et al. | of Injection | |
Santamaria et al. | Hysteroscopy and Stem Cell Therapy to Approach Refractory Asherman’s Syndrome | |
Delis | AMD3100 Administration for the Treatment of Asherman’s Syndrome in a Murine Model | |
Sampietro et al. | A retrospective comparison of Calistar A versus the second-generation light-weight Calistar S for treating anterior and apical pelvic organ prolapse | |
Peng et al. | Preventive Management of Hypertriglycer-idemia in Pregnancy | |
Lassiter et al. | MP52-07 EXTENDED PHARMACOLOGICAL THROMBOPROPHYLAXIS POST ROBOTIC PROSTATECTOMY WITH PELVIC LYMPH NODE DISSECTION | |
Wang et al. | MP52-06 IMMEDIATE RADICAL PROSTATECTOMY AFTER INTRAOPERATIVE CONFIRMED DIAGNOSIS OF PROSTATE CANCER BY FROZEN SECTION OF SPECIMEN FROM TARGETED BIOPSY-INVESTIGATION OF A NOVEL STRATEGY | |
Almogahed et al. | Vesicovaginal Fistula and Hydronephrosis Post-radiation for Cervical Cancer: Challenges and Strategies in Management | |
HASEGAN et al. | Pringle maneuver during open partial nephrectomy for renal tumors | |
Tomasini et al. | Report of initial experience with a novel extracellular matrix material derived from porcine urinary bladder to treat patients with vesico-vaginal fistula | |
Balci et al. | The treatment of Cesarean Scar Pregnancies with Foley Catheter Application following Suction Curettage |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170613 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180604 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180604 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190604 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190902 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20191101 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20200213 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200612 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20200612 |
|
C11 | Written invitation by the commissioner to file amendments |
Free format text: JAPANESE INTERMEDIATE CODE: C11 Effective date: 20200624 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20200709 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20200806 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20200807 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20201016 |
|
C211 | Notice of termination of reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C211 Effective date: 20201020 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20210325 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20210407 |
|
C23 | Notice of termination of proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C23 Effective date: 20210528 |
|
C03 | Trial/appeal decision taken |
Free format text: JAPANESE INTERMEDIATE CODE: C03 Effective date: 20210624 |
|
C30A | Notification sent |
Free format text: JAPANESE INTERMEDIATE CODE: C3012 Effective date: 20210624 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210726 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6920062 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |