JP2021531281A - 腎臓疾患のミトコンドリア増強療法 - Google Patents
腎臓疾患のミトコンドリア増強療法 Download PDFInfo
- Publication number
- JP2021531281A JP2021531281A JP2021502765A JP2021502765A JP2021531281A JP 2021531281 A JP2021531281 A JP 2021531281A JP 2021502765 A JP2021502765 A JP 2021502765A JP 2021502765 A JP2021502765 A JP 2021502765A JP 2021531281 A JP2021531281 A JP 2021531281A
- Authority
- JP
- Japan
- Prior art keywords
- mitochondria
- stem cells
- mitochondrial
- pharmaceutical composition
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000002438 mitochondrial effect Effects 0.000 title claims abstract description 145
- 208000017169 kidney disease Diseases 0.000 title claims abstract description 89
- 238000002560 therapeutic procedure Methods 0.000 title description 30
- 210000000130 stem cell Anatomy 0.000 claims abstract description 326
- 210000004027 cell Anatomy 0.000 claims abstract description 175
- 238000000034 method Methods 0.000 claims abstract description 116
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 110
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
- 208000024891 symptom Diseases 0.000 claims abstract description 35
- 201000006370 kidney failure Diseases 0.000 claims abstract description 30
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 230000004065 mitochondrial dysfunction Effects 0.000 claims abstract description 17
- 210000003470 mitochondria Anatomy 0.000 claims description 335
- 108020005196 Mitochondrial DNA Proteins 0.000 claims description 117
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims description 82
- 239000000203 mixture Substances 0.000 claims description 74
- 230000035772 mutation Effects 0.000 claims description 74
- 230000001717 pathogenic effect Effects 0.000 claims description 64
- 210000004369 blood Anatomy 0.000 claims description 63
- 239000008280 blood Substances 0.000 claims description 63
- 208000012268 mitochondrial disease Diseases 0.000 claims description 57
- 238000011282 treatment Methods 0.000 claims description 54
- 229940109239 creatinine Drugs 0.000 claims description 41
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 claims description 40
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 claims description 39
- 230000001965 increasing effect Effects 0.000 claims description 35
- 230000000694 effects Effects 0.000 claims description 34
- 230000002485 urinary effect Effects 0.000 claims description 33
- 108091093105 Nuclear DNA Proteins 0.000 claims description 32
- 108010058682 Mitochondrial Proteins Proteins 0.000 claims description 26
- 102000006404 Mitochondrial Proteins Human genes 0.000 claims description 26
- 230000037396 body weight Effects 0.000 claims description 26
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 17
- 239000011777 magnesium Substances 0.000 claims description 17
- 229910052749 magnesium Inorganic materials 0.000 claims description 17
- 208000035475 disorder Diseases 0.000 claims description 15
- 210000004698 lymphocyte Anatomy 0.000 claims description 14
- 210000004263 induced pluripotent stem cell Anatomy 0.000 claims description 13
- 102000002260 Alkaline Phosphatase Human genes 0.000 claims description 12
- 108020004774 Alkaline Phosphatase Proteins 0.000 claims description 12
- 230000000735 allogeneic effect Effects 0.000 claims description 12
- 210000003743 erythrocyte Anatomy 0.000 claims description 12
- 210000003958 hematopoietic stem cell Anatomy 0.000 claims description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 12
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 11
- 210000001778 pluripotent stem cell Anatomy 0.000 claims description 11
- 201000006328 Fanconi syndrome Diseases 0.000 claims description 10
- 201000008383 nephritis Diseases 0.000 claims description 10
- 208000026019 Fanconi renotubular syndrome Diseases 0.000 claims description 9
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 9
- 239000011591 potassium Substances 0.000 claims description 9
- 229910052700 potassium Inorganic materials 0.000 claims description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 210000002826 placenta Anatomy 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- 101000685323 Homo sapiens Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Proteins 0.000 claims description 7
- 102100023155 Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Human genes 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- 239000008103 glucose Substances 0.000 claims description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 6
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 6
- 208000024908 graft versus host disease Diseases 0.000 claims description 6
- 230000009851 immunogenic response Effects 0.000 claims description 6
- 235000014655 lactic acid Nutrition 0.000 claims description 6
- 239000004310 lactic acid Substances 0.000 claims description 6
- 210000002540 macrophage Anatomy 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 230000002407 ATP formation Effects 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 210000000601 blood cell Anatomy 0.000 claims description 5
- 210000003630 histaminocyte Anatomy 0.000 claims description 5
- 210000002901 mesenchymal stem cell Anatomy 0.000 claims description 5
- 210000005227 renal system Anatomy 0.000 claims description 5
- 238000007910 systemic administration Methods 0.000 claims description 5
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 4
- 210000003651 basophil Anatomy 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 230000002939 deleterious effect Effects 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 210000001616 monocyte Anatomy 0.000 claims description 4
- 210000001167 myeloblast Anatomy 0.000 claims description 4
- 210000000440 neutrophil Anatomy 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 230000001934 delay Effects 0.000 claims description 3
- 210000000222 eosinocyte Anatomy 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 102100030878 Cytochrome c oxidase subunit 1 Human genes 0.000 claims 1
- 101000919849 Homo sapiens Cytochrome c oxidase subunit 1 Proteins 0.000 claims 1
- 101000605122 Homo sapiens Prostaglandin G/H synthase 1 Proteins 0.000 claims 1
- 230000003833 cell viability Effects 0.000 claims 1
- 210000004940 nucleus Anatomy 0.000 claims 1
- 208000013234 Pearson syndrome Diseases 0.000 description 49
- 230000006870 function Effects 0.000 description 47
- 108010030844 2-methylcitrate synthase Proteins 0.000 description 42
- 108010071536 Citrate (Si)-synthase Proteins 0.000 description 42
- 102000006732 Citrate synthase Human genes 0.000 description 42
- 238000011534 incubation Methods 0.000 description 26
- 108090000623 proteins and genes Proteins 0.000 description 24
- 238000010257 thawing Methods 0.000 description 24
- 230000008014 freezing Effects 0.000 description 22
- 238000007710 freezing Methods 0.000 description 22
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 21
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 21
- 239000000872 buffer Substances 0.000 description 19
- 238000012360 testing method Methods 0.000 description 17
- 210000002798 bone marrow cell Anatomy 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 14
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 13
- 210000001185 bone marrow Anatomy 0.000 description 13
- 238000005119 centrifugation Methods 0.000 description 13
- 102000008100 Human Serum Albumin Human genes 0.000 description 12
- 108091006905 Human Serum Albumin Proteins 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 210000003734 kidney Anatomy 0.000 description 11
- 239000002609 medium Substances 0.000 description 9
- 102000001554 Hemoglobins Human genes 0.000 description 8
- 108010054147 Hemoglobins Proteins 0.000 description 8
- 241000282412 Homo Species 0.000 description 8
- 102000004316 Oxidoreductases Human genes 0.000 description 8
- 108090000854 Oxidoreductases Proteins 0.000 description 8
- 210000001700 mitochondrial membrane Anatomy 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 102000018832 Cytochromes Human genes 0.000 description 7
- 108010052832 Cytochromes Proteins 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000002068 genetic effect Effects 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 210000000265 leukocyte Anatomy 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 238000002617 apheresis Methods 0.000 description 6
- 238000002659 cell therapy Methods 0.000 description 6
- 230000001976 improved effect Effects 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 230000008774 maternal effect Effects 0.000 description 6
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 210000001789 adipocyte Anatomy 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 210000001671 embryonic stem cell Anatomy 0.000 description 5
- 210000004700 fetal blood Anatomy 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 230000003907 kidney function Effects 0.000 description 5
- 230000004898 mitochondrial function Effects 0.000 description 5
- 210000005259 peripheral blood Anatomy 0.000 description 5
- 239000011886 peripheral blood Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 102100029344 ATP synthase protein 8 Human genes 0.000 description 4
- 101000700892 Homo sapiens ATP synthase protein 8 Proteins 0.000 description 4
- 210000000577 adipose tissue Anatomy 0.000 description 4
- -1 coatings Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000001747 exhibiting effect Effects 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 210000002200 mouth mucosa Anatomy 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 230000036284 oxygen consumption Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000036760 body temperature Effects 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 102000054766 genetic haplotypes Human genes 0.000 description 3
- 238000005534 hematocrit Methods 0.000 description 3
- 210000005260 human cell Anatomy 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical group O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 230000007115 recruitment Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 210000003014 totipotent stem cell Anatomy 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 2
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 2
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000007798 antifreeze agent Substances 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 210000000702 aorta abdominal Anatomy 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical group C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 210000003979 eosinophil Anatomy 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000001434 glomerular Effects 0.000 description 2
- 230000024924 glomerular filtration Effects 0.000 description 2
- 230000011132 hemopoiesis Effects 0.000 description 2
- 102000044890 human EPO Human genes 0.000 description 2
- 210000003090 iliac artery Anatomy 0.000 description 2
- 210000003111 iliac vein Anatomy 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 210000000244 kidney pelvis Anatomy 0.000 description 2
- 238000009140 magnesium supplementation Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 210000000663 muscle cell Anatomy 0.000 description 2
- 210000000066 myeloid cell Anatomy 0.000 description 2
- 208000009928 nephrosis Diseases 0.000 description 2
- 231100001027 nephrosis Toxicity 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 210000004180 plasmocyte Anatomy 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 210000000512 proximal kidney tubule Anatomy 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 210000002254 renal artery Anatomy 0.000 description 2
- 230000008085 renal dysfunction Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000001082 somatic cell Anatomy 0.000 description 2
- 125000000185 sucrose group Chemical group 0.000 description 2
- 230000009469 supplementation Effects 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 108010075254 C-Peptide Proteins 0.000 description 1
- 102000013925 CD34 antigen Human genes 0.000 description 1
- 108050003733 CD34 antigen Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 101150118155 Cd34 gene Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 208000027205 Congenital disease Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010072063 Exposure to lead Diseases 0.000 description 1
- 108010000196 Factor XIIIa Proteins 0.000 description 1
- 108010057573 Flavoproteins Proteins 0.000 description 1
- 102000003983 Flavoproteins Human genes 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 101710121304 Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 1
- 206010020669 Hypermagnesaemia Diseases 0.000 description 1
- 206010055171 Hypertensive nephropathy Diseases 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 206010052641 Mitochondrial DNA mutation Diseases 0.000 description 1
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 description 1
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 description 1
- 210000004460 N cell Anatomy 0.000 description 1
- 108010045510 NADPH-Ferrihemoprotein Reductase Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000004020 Oxygenases Human genes 0.000 description 1
- 108090000417 Oxygenases Proteins 0.000 description 1
- 208000016222 Pancreatic disease Diseases 0.000 description 1
- 208000035467 Pancreatic insufficiency Diseases 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- 208000026980 Renal tubular disease Diseases 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108700017798 Type I Xanthinuria Proteins 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 208000018818 Xanthinuria type I Diseases 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 210000003486 adipose tissue brown Anatomy 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000009310 astigmatism Diseases 0.000 description 1
- 230000003416 augmentation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 238000009583 bone marrow aspiration Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000003321 cartilage cell Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007847 digital PCR Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000004205 endocrine pancreatic function Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 230000000925 erythroid effect Effects 0.000 description 1
- 230000031857 establishment of mitochondrion localization Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000004204 exocrine pancreatic function Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010185 immunofluorescence analysis Methods 0.000 description 1
- 229940099472 immunoglobulin a Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 208000037806 kidney injury Diseases 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 210000003738 lymphoid progenitor cell Anatomy 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- QCAWEPFNJXQPAN-UHFFFAOYSA-N methoxyfenozide Chemical compound COC1=CC=CC(C(=O)NN(C(=O)C=2C=C(C)C=C(C)C=2)C(C)(C)C)=C1C QCAWEPFNJXQPAN-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 108091064355 mitochondrial RNA Proteins 0.000 description 1
- 238000010852 mitochondrial transfer Methods 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 208000024691 pancreas disease Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000003169 placental 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
- 229960002169 plerixafor Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000009258 post-therapy Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 208000014318 renal tubule disease Diseases 0.000 description 1
- 210000002796 renal vein Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- NBAOBNBFGNQAEJ-UHFFFAOYSA-M tetramethylrhodamine ethyl ester perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CCOC(=O)C1=CC=CC=C1C1=C2C=CC(=[N+](C)C)C=C2OC2=CC(N(C)C)=CC=C21 NBAOBNBFGNQAEJ-UHFFFAOYSA-M 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 201000002928 xanthinuria Diseases 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 230000002034 xenobiotic effect Effects 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
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- 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
- A61K35/14—Blood; Artificial blood
- A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/18—Erythrocytes
-
- 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
- A61K35/14—Blood; Artificial blood
- A61K35/19—Platelets; Megacaryocytes
-
- 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
- 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
- A61K35/33—Fibroblasts
-
- 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
- A61K35/35—Fat tissue; Adipocytes; Stromal cells; Connective tissues
-
- 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
- A61K35/37—Digestive system
- A61K35/38—Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
-
- 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
- A61K35/48—Reproductive organs
- A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
- A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biotechnology (AREA)
- Virology (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- General Chemical & Material Sciences (AREA)
- Physiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nutrition Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
ミトコンドリアの含有量および活性を増加させるために、異なるマウス細胞を、単離されたマウスまたはヒトのミトコンドリアとともに、DMEM(24時間、37℃、5%CO2)中でインキュベートした。表1は、プロセス前の細胞のCS活性と比較した、プロセス後の細胞のCS活性の相対的な増加によって決定される、ミトコンドリア増強療法プロセスの代表的な結果を示す。
ミトコンドリアはC57/BLマウス(野生型mtDNAのドナー)の胎盤から単離された。骨髄細胞はFVB/Nマウス(ATP8にmtDNA突然変異を担持する)から単離された。FVB/N細胞は、C57/BL外因性ミトコンドリア(1×106個の細胞あたり4.4ミリユニットのミトコンドリア)をロードされ、その後、FVB/NマウスにI.V.注射で戻された。その後、FVB/Nマウスは種々の時点で屠殺され、器官の生体内分布が試験された。
ミトコンドリアは、終末C57BLマウス胎盤から単離された。12ヶ月齢のC57BLマウスの骨髄細胞が得られた。ミトコンドリアで富化された骨髄細胞(MNV−BM−PLC、1×106細胞)、骨髄細胞のみ(BM、1×106細胞)、または対照ビヒクル溶液(VEHICLE、0.9%w/vのNaCl中4.5%のアルブミン)が、実験開始時に12ヶ月齢のC57BLマウスの尾静脈にIV注射され、約15ヶ月、18ヶ月、21ヶ月齢で繰り返した。BUN血液検査が、最初のIV注射の1、3、4、および6ヶ月後に実施された。
患者1は、ピアソン症候群と診断された6.5歳の男児患者であり、mtDNAのヌクレオチド5835〜9753が欠失している。ミトコンドリア増強療法(MAT)の前の彼の体重は14.5KGであった。彼の成長は治療前の3年間大幅に遅れ、1年以上胃瘻管(G−チューブ)によって栄養補給されていたにもかかわらず、改善しなかった。患者は腎不全(GFR 22ml/分)、電解質補給を必要とする近位尿細管症、およびカルシウム補給を必要とする副甲状腺機能低下症を有した。
患者2は、ピアソン症候群と診断された7歳の女児患者であり、mtDNAの4977ヌクレオチドが欠失している。患者はまた、貧血、内分泌膵機能不全を患っており、かつ糖尿病である(ヘモグロビンA1C 7.1%)。患者は、乳酸値が高く(>25mg/dL)、体重が少なく、食事および体重増加に問題がある。患者はさらに高マグネシウム尿症(高レベルの尿中マグネシウム、低レベルの血中マグネシウム)を患っている。患者は、記憶および学習の問題、乱視があり、TMRE、ATP含有量、およびO2消費率(健康な母親と比較して)によって決定される末梢リンパ球のミトコンドリア活性が低い。
患者3は、ピアソン症候群と診断された10.5歳の女児患者であり、mtDNAのヌクレオチド12113〜14421が欠失している。患者は、貧血、および腎不全ステージ4に発展したファンコニ症候群も患っていた。患者は週に3回透析で治療された。過去2ヶ月で、患者は、重度の視力障害、視野の狭小化、および近見視力の喪失も患っていた。患者は身体活動をまったく行うことができなかった(歩くことはなく、ベビーカーに座っている)。患者の乳酸レベルは高く(>50mg/dL)、インスリンで治療された膵臓障害を有した。脳MRIは多くの病変および萎縮領域を示した。患者は、胃瘻造設術によってのみ栄養補給された。患者には記憶および学習の問題があった。患者は、テトラメチルローダミンエチルエステル(TMRE)、ATP含有量、およびO2消費率(健康な母親と比較して)試験によって決定される末梢リンパ球のミトコンドリア活性が低かった。
標題:腎臓疾患および障害を有する患者におけるミトコンドリアで富化された幹細胞の移植の安全性、生着、および治療効果を評価するための第I/II相非盲検単回投与臨床試験。
Claims (35)
- 腎臓疾患、障害、またはそれらの症状の治療を必要とするヒト患者において、かかる治療に使用するための医薬組成物であって、前記組成物が、細胞の生存能力を支援することができる薬学的に許容可能な液体培地中、前記患者の体重1キログラムあたり少なくとも105〜2×107個のヒト幹細胞を含み、前記ヒト幹細胞は、凍結−解凍した健康な機能的ヒト外因性ミトコンドリアで富化され、前記腎臓疾患または障害は、ミトコンドリアDNAの病原性突然変異によってまたはミトコンドリアタンパク質をコードする核DNAの病原性突然変異によって引き起こされる原発性ミトコンドリア病または障害ではない、医薬組成物。
- 前記富化が、百万個の細胞あたり少なくとも0.088〜最大176ミリユニットのCS活性のミトコンドリアの用量を前記幹細胞に導入することを含む、請求項1に記載の医薬組成物。
- 前記富化が、百万個の細胞あたり0.88〜最大17.6ミリユニットのCS活性のミトコンドリアの用量と前記幹細胞を接触させることを含む、請求項2に記載の医薬組成物。
- 前記健康なヒト外因性ミトコンドリアが、同系または同種異系である、請求項1〜3のいずれか一項に記載の医薬組成物。
- 前記疾患または障害が、後天性ミトコンドリア機能障害に関連している、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記疾患または障害が、後天性ミトコンドリア機能障害に関連していない、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記疾患または障害が、腎症、腎炎、ネフローゼ、腎炎症候群、ネフローゼ症候群、ファンコニ症候群、および腎不全からなる群から選択される、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記症状が、低血中アルカリホスファターゼレベル、低血中マグネシウムレベル、高血中クレアチニンレベル、低血中重炭酸塩レベル、低血中塩基過剰レベル、高尿中グルコース/クレアチニン比、高尿中塩化物/クレアチニン比、高尿中ナトリウム/クレアチニン比、高血中乳酸レベル、高尿中マグネシウム/クレアチニン比、高尿中カリウム/クレアチニン比、高尿中カルシウム/クレアチニン比、および高血中尿素レベルからなる群から選択される、請求項1〜7のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が、腎臓系に直接投与される、請求項1〜8のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が、全身投与によって投与される、請求項1〜8のいずれか一項に記載の医薬組成物。
- 前記患者の体重1キログラムあたり約106個のミトコンドリア富化ヒト幹細胞を含む、請求項10に記載の医薬組成物。
- ヒトミトコンドリアで富化された合計約5×105〜5×109個のヒト幹細胞を含む、請求項1〜9のいずれか一項に記載の医薬組成物。
- 前記ミトコンドリア富化ヒト幹細胞が、ミトコンドリア富化前の前記幹細胞における対応するレベルと比較して、
(i)増加したミトコンドリアDNA含有量、
(ii)増加したCS活性レベル、
(iii)増加したSDHAおよびCOX1から選択された少なくとも1つのミトコンドリアタンパク質の含有量、
(iv)増加したO2消費率、
(v)増加したATP産生率、または
(vi)それらの任意の組み合わせ
のうちの少なくとも1つを有する、請求項1〜12のいずれか一項に記載の医薬組成物。 - 前記ヒト幹細胞が、前記外因性ミトコンドリアで富化される前の前記患者から得られるかまたは由来する、請求項1〜13のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、前記外因性ミトコンドリアで富化される前の前記患者とは異なるドナーから得られるかまたは由来する、請求項1〜13のいずれか一項に記載の医薬組成物。
- 前記ドナーが、少なくとも部分的に前記患者とHLA適合する、請求項15に記載の医薬組成物。
- 前記ヒト幹細胞が、造血幹細胞である、請求項1〜16のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、間葉系幹細胞である、請求項1〜16のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、多能性幹細胞(PSC)または人工多能性幹細胞(iPSC)である、請求項1〜16のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、CD34+である、請求項1〜19のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、健康な機能的ヒト外因性ミトコンドリアを前記ヒト幹細胞に導入する前に、少なくとも1回の凍結−解凍サイクルを受けている、請求項2〜20のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、骨髄、脂肪組織、口腔粘膜、皮膚線維芽細胞、血液、または臍帯血の細胞から単離されるか、由来するか、または得られる、請求項1〜21のいずれか一項に記載の医薬組成物。
- 前記健康な機能的ヒト外因性ミトコンドリアが、胎盤、培養で成長させた胎盤細胞、または血液細胞から単離されるかまたは得られる、請求項1〜22のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、前記健康な機能的ヒト外因性ミトコンドリアでの富化後に、少なくとも1回の凍結−解凍サイクルを受けている、請求項1〜23のいずれか一項に記載の医薬組成物。
- 前記健康な機能的ヒト外因性ミトコンドリアが、前記ミトコンドリア富化ヒト幹細胞中の全ミトコンドリアの少なくとも3%を構成する、請求項1〜24のいずれか一項に記載の医薬組成物。
- 前記健康な機能的ヒト外因性ミトコンドリアが、前記ミトコンドリア富化ヒト幹細胞中の全ミトコンドリアの少なくとも10%を構成する、請求項25に記載の医薬組成物。
- 非富化幹細胞、巨核球、赤血球、肥満細胞、骨髄芽球、好塩基球、好中球、好酸球、単球、マクロファージ、ナチュラルキラー(NK)細胞、小リンパ球、Tリンパ球、Bリンパ球、形質細胞、細網細胞、またはそれらの任意の組み合わせをさらに含む、請求項1〜26のいずれか一項に記載の医薬組成物。
- 腎臓疾患、障害、またはそれらの症状の治療を、かかる治療を必要とするヒト患者において行う方法であって、前記方法が、前記患者に医薬組成物を非経口投与するステップを含み、前記医薬組成物が、少なくとも約5×105〜5×109個のヒト幹細胞を含み、前記ヒト幹細胞が、凍結−解凍した健康な機能的ヒト外因性ミトコンドリアで富化され、前記腎臓疾患または障害が、ミトコンドリアDNAの病原性突然変異によってまたはミトコンドリアタンパク質をコードする核DNAの病原性突然変異によって引き起こされる原発性ミトコンドリア病または障害ではない、方法。
- 前記医薬組成物の前記投与が、腎臓系に直接行われる、請求項28に記載の方法。
- 前記医薬組成物の前記投与が、全身投与によるものである、請求項28に記載の方法。
- 前記ヒト幹細胞が、前記外因性ミトコンドリアで富化される前の前記患者から得られるかまたは由来する、請求項28〜30のいずれか一項に記載の医薬組成物。
- 前記ヒト幹細胞が、前記外因性ミトコンドリアで富化される前の前記患者とは異なるドナーから得られるかまたは由来する、請求項28〜30のいずれか一項に記載の医薬組成物。
- 前記ドナーが、少なくとも部分的に前記患者とHLA適合する、請求項32に記載の医薬組成物。
- 前記患者と前記ミトコンドリア富化ヒト幹細胞との間の有害な免疫原性反応を防止、遅延、最小化、または無効化する薬剤を前記患者に投与するステップをさらに含む、請求項32または請求項33に記載の方法。
- 前記有害な免疫原性反応が、移植片対宿主病(GvHD)である、請求項34に記載の方法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862701783P | 2018-07-22 | 2018-07-22 | |
US62/701,783 | 2018-07-22 | ||
US201862753934P | 2018-11-01 | 2018-11-01 | |
US62/753,934 | 2018-11-01 | ||
PCT/IL2019/050821 WO2020021534A1 (en) | 2018-07-22 | 2019-07-22 | Mitochondrial augmentation therapy of renal diseases |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021531281A true JP2021531281A (ja) | 2021-11-18 |
JPWO2020021534A5 JPWO2020021534A5 (ja) | 2022-07-27 |
Family
ID=69180899
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021502765A Pending JP2021531281A (ja) | 2018-07-22 | 2019-07-22 | 腎臓疾患のミトコンドリア増強療法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20210275587A1 (ja) |
EP (1) | EP3823645A4 (ja) |
JP (1) | JP2021531281A (ja) |
WO (1) | WO2020021534A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI787761B (zh) * | 2020-03-20 | 2022-12-21 | 台灣粒線體應用技術股份有限公司 | 粒線體用於促進傷口修復及/或傷口癒合之用途 |
WO2022150599A1 (en) * | 2021-01-07 | 2022-07-14 | The Regents Of The University Of Michigan | Methods for preventing or treating conditions related to t cell mediated intestinal disorders |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018507690A (ja) * | 2015-02-26 | 2018-03-22 | ミノヴィア セラピューティクス リミテッド | 機能性ミトコンドリアで富化された哺乳動物細胞 |
WO2018088874A1 (ko) * | 2016-11-14 | 2018-05-17 | 주식회사 파이안바이오테크놀로지 | 외래 미토콘드리아를 세포로 전달하는 방법 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8846028B2 (en) | 2010-10-28 | 2014-09-30 | The Invention Science Fund I, Llc | Mitochondrial enhancement of cells |
WO2013035101A1 (en) | 2011-09-11 | 2013-03-14 | Minovia Therapeutics Ltd. | Compositions of functional mitochondria and uses thereof |
EP3169338A1 (en) | 2014-07-16 | 2017-05-24 | INSERM - Institut National de la Santé et de la Recherche Médicale | Methods for the intercellular transfer of isolated mitochondria in recipient cells |
WO2020021538A1 (en) * | 2018-07-22 | 2020-01-30 | Minovia Therapeutics Ltd. | Mitochondrial augmentation therapy of brain diseases |
EP3823643A4 (en) * | 2018-07-22 | 2022-06-08 | Minovia Therapeutics Ltd. | MITOCHONDRIAL AUGMENTATION THERAPY OF LIVER DISEASES |
CA3106188A1 (en) * | 2018-07-22 | 2020-01-30 | Minovia Therapeutics Ltd. | Mitochondrial augmentation therapy with stem cells enriched with functional mitochondria |
EP3823640A4 (en) * | 2018-07-22 | 2022-05-18 | Minovia Therapeutics Ltd. | MITOCHONDRIAL AUGMENTATION THERAPY OF MUSCULAR DISEASES |
MX2021000955A (es) * | 2018-07-22 | 2021-05-27 | Minovia Therapeutics Ltd | Terapia de incremento mitocondrial para enfermedades mitocondriales primarias. |
JP2021531288A (ja) * | 2018-07-22 | 2021-11-18 | ミノヴィア セラピューティクス リミテッド | 眼疾患のミトコンドリア増強療法 |
EP3823644A4 (en) * | 2018-07-22 | 2022-06-08 | Minovia Therapeutics Ltd. | MITOCHONDRIAL AUGMENTATION THERAPY OF PANCREATIC DISEASES |
-
2019
- 2019-07-22 EP EP19841655.4A patent/EP3823645A4/en active Pending
- 2019-07-22 WO PCT/IL2019/050821 patent/WO2020021534A1/en unknown
- 2019-07-22 US US17/251,666 patent/US20210275587A1/en active Pending
- 2019-07-22 JP JP2021502765A patent/JP2021531281A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018507690A (ja) * | 2015-02-26 | 2018-03-22 | ミノヴィア セラピューティクス リミテッド | 機能性ミトコンドリアで富化された哺乳動物細胞 |
WO2018088874A1 (ko) * | 2016-11-14 | 2018-05-17 | 주식회사 파이안바이오테크놀로지 | 외래 미토콘드리아를 세포로 전달하는 방법 |
Non-Patent Citations (4)
Title |
---|
AM J PHYSIOL RENAL PHYSIOL, vol. 306, JPN6023025711, 2014, pages 367 - 378, ISSN: 0005092411 * |
NORTH AMERICAN JOURNAL OF MEDICAL SCIENCES, vol. 2, no. 4, JPN6023025715, 2010, pages 170 - 173, ISSN: 0005092412 * |
ビタミン, vol. 90, no. 10, JPN6023025716, 2016, pages 502 - 507, ISSN: 0005092413 * |
日腎会誌, vol. 49, no. 2, JPN6023025717, 2007, pages 82 - 87, ISSN: 0005092414 * |
Also Published As
Publication number | Publication date |
---|---|
WO2020021534A1 (en) | 2020-01-30 |
US20210275587A1 (en) | 2021-09-09 |
EP3823645A4 (en) | 2022-04-13 |
EP3823645A1 (en) | 2021-05-26 |
WO2020021534A9 (en) | 2020-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7454548B2 (ja) | 膵臓疾患のミトコンドリア増強療法 | |
JP2021532095A (ja) | 肝臓疾患のミトコンドリア増強療法 | |
JP2021532093A (ja) | 脳疾患のミトコンドリア増強療法 | |
JP2021531288A (ja) | 眼疾患のミトコンドリア増強療法 | |
JP2021531284A (ja) | 原発性ミトコンドリア病のためのミトコンドリア増強療法 | |
US20210322485A1 (en) | Mitochondrial augmentation therapy with stem cells enriched with functional mitochondria | |
JP7458368B2 (ja) | 筋疾患のミトコンドリア増強療法 | |
JP2021531281A (ja) | 腎臓疾患のミトコンドリア増強療法 | |
US20210205368A1 (en) | Mitochondrial augmentation therapy of renal diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220719 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220719 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230616 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230627 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230927 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231127 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20240206 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20240501 |