JP6823167B2 - ミオスタチン阻害剤の使用および併用療法 - Google Patents
ミオスタチン阻害剤の使用および併用療法 Download PDFInfo
- Publication number
- JP6823167B2 JP6823167B2 JP2019517209A JP2019517209A JP6823167B2 JP 6823167 B2 JP6823167 B2 JP 6823167B2 JP 2019517209 A JP2019517209 A JP 2019517209A JP 2019517209 A JP2019517209 A JP 2019517209A JP 6823167 B2 JP6823167 B2 JP 6823167B2
- Authority
- JP
- Japan
- Prior art keywords
- myostatin
- muscle
- smn
- sma
- subject
- 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
- 108010056852 Myostatin Proteins 0.000 title claims description 403
- 239000003112 inhibitor Substances 0.000 title claims description 202
- 102000004472 Myostatin Human genes 0.000 title claims 28
- 238000002648 combination therapy Methods 0.000 title description 46
- 210000003205 muscle Anatomy 0.000 claims description 288
- 102100021947 Survival motor neuron protein Human genes 0.000 claims description 201
- 208000002320 spinal muscular atrophy Diseases 0.000 claims description 185
- 239000003607 modifier Substances 0.000 claims description 170
- 238000011282 treatment Methods 0.000 claims description 94
- 239000003795 chemical substances by application Substances 0.000 claims description 81
- 230000007659 motor function Effects 0.000 claims description 79
- 238000002560 therapeutic procedure Methods 0.000 claims description 78
- 238000000034 method Methods 0.000 claims description 75
- 230000001965 increasing effect Effects 0.000 claims description 40
- 239000000427 antigen Substances 0.000 claims description 38
- 108091007433 antigens Proteins 0.000 claims description 38
- 102000036639 antigens Human genes 0.000 claims description 38
- 201000000585 muscular atrophy Diseases 0.000 claims description 35
- 230000014509 gene expression Effects 0.000 claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 31
- 150000003384 small molecules Chemical class 0.000 claims description 29
- 206010028289 Muscle atrophy Diseases 0.000 claims description 27
- 230000020763 muscle atrophy Effects 0.000 claims description 25
- 230000004913 activation Effects 0.000 claims description 22
- 238000001415 gene therapy Methods 0.000 claims description 22
- 210000002569 neuron Anatomy 0.000 claims description 21
- 210000000577 adipose tissue Anatomy 0.000 claims description 20
- 230000014616 translation Effects 0.000 claims description 20
- 238000007918 intramuscular administration Methods 0.000 claims description 17
- 239000003623 enhancer Substances 0.000 claims description 13
- 238000011156 evaluation Methods 0.000 claims description 12
- 101150113275 Smn gene Proteins 0.000 claims description 9
- 230000007423 decrease Effects 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000012153 long-term therapy Methods 0.000 claims description 6
- 238000009256 replacement therapy Methods 0.000 claims description 5
- 238000010253 intravenous injection Methods 0.000 claims description 4
- 229940124272 protein stabilizer Drugs 0.000 claims description 4
- 238000010254 subcutaneous injection Methods 0.000 claims description 4
- 239000007929 subcutaneous injection Substances 0.000 claims description 4
- 238000013518 transcription Methods 0.000 claims description 4
- 230000035897 transcription Effects 0.000 claims description 4
- 108020005544 Antisense RNA Proteins 0.000 claims description 3
- 239000003184 complementary RNA Substances 0.000 claims description 3
- 230000003698 anagen phase Effects 0.000 claims 1
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 description 376
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 107
- 230000000694 effects Effects 0.000 description 82
- 201000010099 disease Diseases 0.000 description 73
- 230000006870 function Effects 0.000 description 69
- 230000005764 inhibitory process Effects 0.000 description 64
- 210000002161 motor neuron Anatomy 0.000 description 64
- 241000699670 Mus sp. Species 0.000 description 58
- 208000021642 Muscular disease Diseases 0.000 description 56
- 239000003814 drug Substances 0.000 description 56
- 230000001195 anabolic effect Effects 0.000 description 55
- 201000009623 Myopathy Diseases 0.000 description 53
- 230000008901 benefit Effects 0.000 description 45
- 238000012360 testing method Methods 0.000 description 42
- 230000001537 neural effect Effects 0.000 description 39
- 230000011664 signaling Effects 0.000 description 36
- 101000617738 Homo sapiens Survival motor neuron protein Proteins 0.000 description 35
- 229940124597 therapeutic agent Drugs 0.000 description 35
- 210000004027 cell Anatomy 0.000 description 34
- 230000004220 muscle function Effects 0.000 description 34
- 108090000623 proteins and genes Proteins 0.000 description 34
- 210000001519 tissue Anatomy 0.000 description 33
- 208000035475 disorder Diseases 0.000 description 32
- 206010003694 Atrophy Diseases 0.000 description 30
- 230000037444 atrophy Effects 0.000 description 30
- 230000006378 damage Effects 0.000 description 29
- 210000002027 skeletal muscle Anatomy 0.000 description 28
- 210000001087 myotubule Anatomy 0.000 description 27
- 239000012634 fragment Substances 0.000 description 26
- 241001465754 Metazoa Species 0.000 description 24
- 230000002232 neuromuscular Effects 0.000 description 24
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 23
- 230000036961 partial effect Effects 0.000 description 23
- 239000003102 growth factor Substances 0.000 description 22
- 210000005036 nerve Anatomy 0.000 description 22
- 238000009097 single-agent therapy Methods 0.000 description 22
- 102100040898 Growth/differentiation factor 11 Human genes 0.000 description 21
- 230000009467 reduction Effects 0.000 description 21
- 230000001225 therapeutic effect Effects 0.000 description 21
- 101000893545 Homo sapiens Growth/differentiation factor 11 Proteins 0.000 description 20
- 230000002638 denervation Effects 0.000 description 20
- 239000000835 fiber Substances 0.000 description 20
- 230000004044 response Effects 0.000 description 20
- 208000027418 Wounds and injury Diseases 0.000 description 19
- 208000014674 injury Diseases 0.000 description 19
- 230000035772 mutation Effects 0.000 description 18
- 208000018360 neuromuscular disease Diseases 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 210000002966 serum Anatomy 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- 229940079593 drug Drugs 0.000 description 17
- 108020004999 messenger RNA Proteins 0.000 description 17
- 230000037257 muscle growth Effects 0.000 description 17
- 230000001771 impaired effect Effects 0.000 description 16
- 102000004169 proteins and genes Human genes 0.000 description 16
- 230000006872 improvement Effects 0.000 description 15
- 206010006895 Cachexia Diseases 0.000 description 14
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 14
- 239000003550 marker Substances 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- 230000003442 weekly effect Effects 0.000 description 14
- 230000001976 improved effect Effects 0.000 description 13
- 238000001243 protein synthesis Methods 0.000 description 13
- 208000029578 Muscle disease Diseases 0.000 description 12
- 239000000090 biomarker Substances 0.000 description 12
- 230000030214 innervation Effects 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 230000003387 muscular Effects 0.000 description 12
- 230000002265 prevention Effects 0.000 description 12
- 230000001737 promoting effect Effects 0.000 description 12
- 208000011580 syndromic disease Diseases 0.000 description 12
- 239000003981 vehicle Substances 0.000 description 12
- WWFDJIVIDXJAQR-FFWSQMGZSA-N 1-[(2R,3R,4R,5R)-4-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[(2R,3R,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-sulfanylphosphoryl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(hydroxymethyl)-3-(2-methoxyethoxy)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound COCCO[C@@H]1[C@H](O)[C@@H](COP(O)(=S)O[C@@H]2[C@@H](COP(S)(=O)O[C@@H]3[C@@H](COP(O)(=S)O[C@@H]4[C@@H](COP(O)(=S)O[C@@H]5[C@@H](COP(O)(=S)O[C@@H]6[C@@H](COP(O)(=S)O[C@@H]7[C@@H](COP(O)(=S)O[C@@H]8[C@@H](COP(O)(=S)O[C@@H]9[C@@H](COP(O)(=S)O[C@@H]%10[C@@H](COP(O)(=S)O[C@@H]%11[C@@H](COP(O)(=S)O[C@@H]%12[C@@H](COP(O)(=S)O[C@@H]%13[C@@H](COP(O)(=S)O[C@@H]%14[C@@H](COP(O)(=S)O[C@@H]%15[C@@H](COP(O)(=S)O[C@@H]%16[C@@H](COP(O)(=S)O[C@@H]%17[C@@H](COP(O)(=S)O[C@@H]%18[C@@H](CO)O[C@H]([C@@H]%18OCCOC)n%18cc(C)c(=O)[nH]c%18=O)O[C@H]([C@@H]%17OCCOC)n%17cc(C)c(N)nc%17=O)O[C@H]([C@@H]%16OCCOC)n%16cnc%17c(N)ncnc%16%17)O[C@H]([C@@H]%15OCCOC)n%15cc(C)c(N)nc%15=O)O[C@H]([C@@H]%14OCCOC)n%14cc(C)c(=O)[nH]c%14=O)O[C@H]([C@@H]%13OCCOC)n%13cc(C)c(=O)[nH]c%13=O)O[C@H]([C@@H]%12OCCOC)n%12cc(C)c(=O)[nH]c%12=O)O[C@H]([C@@H]%11OCCOC)n%11cc(C)c(N)nc%11=O)O[C@H]([C@@H]%10OCCOC)n%10cnc%11c(N)ncnc%10%11)O[C@H]([C@@H]9OCCOC)n9cc(C)c(=O)[nH]c9=O)O[C@H]([C@@H]8OCCOC)n8cnc9c(N)ncnc89)O[C@H]([C@@H]7OCCOC)n7cnc8c(N)ncnc78)O[C@H]([C@@H]6OCCOC)n6cc(C)c(=O)[nH]c6=O)O[C@H]([C@@H]5OCCOC)n5cnc6c5nc(N)[nH]c6=O)O[C@H]([C@@H]4OCCOC)n4cc(C)c(N)nc4=O)O[C@H]([C@@H]3OCCOC)n3cc(C)c(=O)[nH]c3=O)O[C@H]([C@@H]2OCCOC)n2cnc3c2nc(N)[nH]c3=O)O[C@H]1n1cnc2c1nc(N)[nH]c2=O WWFDJIVIDXJAQR-FFWSQMGZSA-N 0.000 description 11
- 229950001015 nusinersen Drugs 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 230000036982 action potential Effects 0.000 description 10
- 210000000593 adipose tissue white Anatomy 0.000 description 10
- 239000000074 antisense oligonucleotide Substances 0.000 description 10
- 238000012230 antisense oligonucleotides Methods 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 230000018109 developmental process Effects 0.000 description 10
- 239000013603 viral vector Substances 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- 101150081851 SMN1 gene Proteins 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 9
- 230000007547 defect Effects 0.000 description 9
- 230000008021 deposition Effects 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000004927 fusion Effects 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 210000001596 intra-abdominal fat Anatomy 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 201000006938 muscular dystrophy Diseases 0.000 description 9
- 238000001356 surgical procedure Methods 0.000 description 9
- 230000009885 systemic effect Effects 0.000 description 9
- 238000001262 western blot Methods 0.000 description 9
- 206010061818 Disease progression Diseases 0.000 description 8
- 206010020880 Hypertrophy Diseases 0.000 description 8
- 241000282567 Macaca fascicularis Species 0.000 description 8
- 102000035195 Peptidases Human genes 0.000 description 8
- 108091005804 Peptidases Proteins 0.000 description 8
- 239000004365 Protease Substances 0.000 description 8
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 8
- 210000003486 adipose tissue brown Anatomy 0.000 description 8
- 230000002411 adverse Effects 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 230000005750 disease progression Effects 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 235000019419 proteases Nutrition 0.000 description 8
- 230000000638 stimulation Effects 0.000 description 8
- 230000005062 synaptic transmission Effects 0.000 description 8
- 206010001497 Agitation Diseases 0.000 description 7
- 206010028311 Muscle hypertrophy Diseases 0.000 description 7
- 102000005604 Myosin Heavy Chains Human genes 0.000 description 7
- 108010084498 Myosin Heavy Chains Proteins 0.000 description 7
- 108010029485 Protein Isoforms Proteins 0.000 description 7
- 102000001708 Protein Isoforms Human genes 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- 230000000692 anti-sense effect Effects 0.000 description 7
- 230000009286 beneficial effect Effects 0.000 description 7
- 210000003169 central nervous system Anatomy 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 230000002068 genetic effect Effects 0.000 description 7
- 230000004190 glucose uptake Effects 0.000 description 7
- 210000001352 masseter muscle Anatomy 0.000 description 7
- 230000004060 metabolic process Effects 0.000 description 7
- 238000010172 mouse model Methods 0.000 description 7
- 230000012042 muscle hypertrophy Effects 0.000 description 7
- 230000007170 pathology Effects 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
- 230000017854 proteolysis Effects 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 208000020431 spinal cord injury Diseases 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 210000004291 uterus Anatomy 0.000 description 7
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 6
- 241000282693 Cercopithecidae Species 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 208000028389 Nerve injury Diseases 0.000 description 6
- 108091034117 Oligonucleotide Proteins 0.000 description 6
- 230000035508 accumulation Effects 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 6
- 210000000988 bone and bone Anatomy 0.000 description 6
- 230000001413 cellular effect Effects 0.000 description 6
- 230000007812 deficiency Effects 0.000 description 6
- 230000006866 deterioration Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000007913 intrathecal administration Methods 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 230000008764 nerve damage Effects 0.000 description 6
- 108020004707 nucleic acids Proteins 0.000 description 6
- 102000039446 nucleic acids Human genes 0.000 description 6
- 150000007523 nucleic acids Chemical group 0.000 description 6
- 230000003285 pharmacodynamic effect Effects 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000013598 vector Substances 0.000 description 6
- 230000009184 walking Effects 0.000 description 6
- 206010064571 Gene mutation Diseases 0.000 description 5
- 206010022489 Insulin Resistance Diseases 0.000 description 5
- 102000016267 Leptin Human genes 0.000 description 5
- 108010092277 Leptin Proteins 0.000 description 5
- 101100437153 Rattus norvegicus Acvr2b gene Proteins 0.000 description 5
- 101150015954 SMN2 gene Proteins 0.000 description 5
- 102100036202 Serum amyloid P-component Human genes 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 108010031318 Vitronectin Proteins 0.000 description 5
- 102100035140 Vitronectin Human genes 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 201000011474 congenital myopathy Diseases 0.000 description 5
- 230000002354 daily effect Effects 0.000 description 5
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 5
- 229960003957 dexamethasone Drugs 0.000 description 5
- 230000002708 enhancing effect Effects 0.000 description 5
- 238000010448 genetic screening Methods 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 229940088597 hormone Drugs 0.000 description 5
- 239000005556 hormone Substances 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 201000008319 inclusion body myositis Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 229940039781 leptin Drugs 0.000 description 5
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 5
- 230000033001 locomotion Effects 0.000 description 5
- 210000003141 lower extremity Anatomy 0.000 description 5
- 238000012423 maintenance Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 230000004898 mitochondrial function Effects 0.000 description 5
- 238000010606 normalization Methods 0.000 description 5
- 239000000902 placebo Substances 0.000 description 5
- 229940068196 placebo Drugs 0.000 description 5
- 230000002980 postoperative effect Effects 0.000 description 5
- 238000011002 quantification Methods 0.000 description 5
- 230000004043 responsiveness Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 210000001364 upper extremity Anatomy 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 102000004506 Blood Proteins Human genes 0.000 description 4
- 108010017384 Blood Proteins Proteins 0.000 description 4
- 102100032752 C-reactive protein Human genes 0.000 description 4
- 102100024154 Cadherin-13 Human genes 0.000 description 4
- 102100038196 Chitinase-3-like protein 1 Human genes 0.000 description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 4
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 102100037241 Endoglin Human genes 0.000 description 4
- 108010036395 Endoglin Proteins 0.000 description 4
- 206010017076 Fracture Diseases 0.000 description 4
- 102100040892 Growth/differentiation factor 2 Human genes 0.000 description 4
- 101000942118 Homo sapiens C-reactive protein Proteins 0.000 description 4
- 101000893585 Homo sapiens Growth/differentiation factor 2 Proteins 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 201000002481 Myositis Diseases 0.000 description 4
- 208000010316 Myotonia congenita Diseases 0.000 description 4
- 108010045517 Serum Amyloid P-Component Proteins 0.000 description 4
- 229920000147 Styrene maleic anhydride Polymers 0.000 description 4
- 102100024554 Tetranectin Human genes 0.000 description 4
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 4
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 description 4
- 210000001789 adipocyte Anatomy 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 230000008335 axon cargo transport Effects 0.000 description 4
- 229960000074 biopharmaceutical Drugs 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000001925 catabolic effect Effects 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 210000001723 extracellular space Anatomy 0.000 description 4
- 210000003414 extremity Anatomy 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 230000008595 infiltration Effects 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- 238000011221 initial treatment Methods 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 238000002595 magnetic resonance imaging Methods 0.000 description 4
- 230000010120 metabolic dysregulation Effects 0.000 description 4
- 230000004118 muscle contraction Effects 0.000 description 4
- 230000003955 neuronal function Effects 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 208000022074 proximal spinal muscular atrophy Diseases 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 229960003604 testosterone Drugs 0.000 description 4
- 230000028973 vesicle-mediated transport Effects 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 108010059616 Activins Proteins 0.000 description 3
- 102100037320 Apolipoprotein A-IV Human genes 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 102000019034 Chemokines Human genes 0.000 description 3
- 108010012236 Chemokines Proteins 0.000 description 3
- 102000004381 Complement C2 Human genes 0.000 description 3
- 108090000955 Complement C2 Proteins 0.000 description 3
- 102100025877 Complement component C1q receptor Human genes 0.000 description 3
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 3
- 206010010356 Congenital anomaly Diseases 0.000 description 3
- 208000034656 Contusions Diseases 0.000 description 3
- 102100035233 Furin Human genes 0.000 description 3
- 108090001126 Furin Proteins 0.000 description 3
- 101000762243 Homo sapiens Cadherin-13 Proteins 0.000 description 3
- 101000933665 Homo sapiens Complement component C1q receptor Proteins 0.000 description 3
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 3
- 206010061598 Immunodeficiency Diseases 0.000 description 3
- 208000029462 Immunodeficiency disease Diseases 0.000 description 3
- 208000026350 Inborn Genetic disease Diseases 0.000 description 3
- 102100026818 Inhibin beta E chain Human genes 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 102000004883 Insulin-like growth factor-binding protein 6 Human genes 0.000 description 3
- 108090001014 Insulin-like growth factor-binding protein 6 Proteins 0.000 description 3
- 102100032114 Lumican Human genes 0.000 description 3
- 108010076371 Lumican Proteins 0.000 description 3
- 238000012307 MRI technique Methods 0.000 description 3
- 201000002169 Mitochondrial myopathy Diseases 0.000 description 3
- 102000008934 Muscle Proteins Human genes 0.000 description 3
- 108010074084 Muscle Proteins Proteins 0.000 description 3
- 102100040557 Osteopontin Human genes 0.000 description 3
- 208000032225 Proximal spinal muscular atrophy type 1 Diseases 0.000 description 3
- -1 SMN-C2 Chemical compound 0.000 description 3
- 101710168942 Sphingosine-1-phosphate phosphatase 1 Proteins 0.000 description 3
- 102100029219 Thrombospondin-4 Human genes 0.000 description 3
- 102100030742 Transforming growth factor beta-1 proprotein Human genes 0.000 description 3
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 3
- 102100039662 Xaa-Pro dipeptidase Human genes 0.000 description 3
- 210000000579 abdominal fat Anatomy 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000000488 activin Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 108010073614 apolipoprotein A-IV Proteins 0.000 description 3
- 210000003050 axon Anatomy 0.000 description 3
- 230000002457 bidirectional effect Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 230000009519 contusion Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000002716 delivery method Methods 0.000 description 3
- 201000001981 dermatomyositis Diseases 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 230000005021 gait Effects 0.000 description 3
- 230000009395 genetic defect Effects 0.000 description 3
- 208000016361 genetic disease Diseases 0.000 description 3
- 230000002414 glycolytic effect Effects 0.000 description 3
- 210000004247 hand Anatomy 0.000 description 3
- 238000003119 immunoblot Methods 0.000 description 3
- 230000007813 immunodeficiency Effects 0.000 description 3
- 238000010166 immunofluorescence Methods 0.000 description 3
- 208000023692 inborn mitochondrial myopathy Diseases 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000004717 laryngeal muscle Anatomy 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- 230000003137 locomotive effect Effects 0.000 description 3
- 238000007726 management method Methods 0.000 description 3
- 230000002438 mitochondrial effect Effects 0.000 description 3
- 230000037230 mobility Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 206010028417 myasthenia gravis Diseases 0.000 description 3
- 230000032405 negative regulation of neuron apoptotic process Effects 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- 210000000715 neuromuscular junction Anatomy 0.000 description 3
- 230000003957 neurotransmitter release Effects 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 230000000717 retained effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 210000000278 spinal cord Anatomy 0.000 description 3
- 239000000021 stimulant Substances 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 230000002123 temporal effect Effects 0.000 description 3
- 238000011287 therapeutic dose Methods 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- 208000032471 type 1 spinal muscular atrophy Diseases 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 210000001260 vocal cord Anatomy 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- STWTUEAWRAIWJG-UHFFFAOYSA-N 5-(1H-pyrazol-4-yl)-2-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol Chemical compound C1C(C)(C)NC(C)(C)CC1OC1=CC=C(C=2C(=CC(=CC=2)C2=CNN=C2)O)N=N1 STWTUEAWRAIWJG-UHFFFAOYSA-N 0.000 description 2
- HFDKKNHCYWNNNQ-YOGANYHLSA-N 75976-10-2 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@@H](NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)N)C(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 HFDKKNHCYWNNNQ-YOGANYHLSA-N 0.000 description 2
- 102100022980 ADAMTS-like protein 4 Human genes 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- 102000003966 Alpha-1-microglobulin Human genes 0.000 description 2
- 101800001761 Alpha-1-microglobulin Proteins 0.000 description 2
- 102100033312 Alpha-2-macroglobulin Human genes 0.000 description 2
- 208000031713 Autosomal recessive spastic paraplegia type 20 Diseases 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 102100028726 Bone morphogenetic protein 10 Human genes 0.000 description 2
- 102100036849 C-C motif chemokine 24 Human genes 0.000 description 2
- 108010075254 C-Peptide Proteins 0.000 description 2
- 108091033409 CRISPR Proteins 0.000 description 2
- 102100037988 Cartilage acidic protein 1 Human genes 0.000 description 2
- 206010007733 Catabolic state Diseases 0.000 description 2
- 102100035882 Catalase Human genes 0.000 description 2
- 108010053835 Catalase Proteins 0.000 description 2
- 102100032219 Cathepsin D Human genes 0.000 description 2
- 108010066813 Chitinase-3-Like Protein 1 Proteins 0.000 description 2
- 102100029057 Coagulation factor XIII A chain Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010053085 Complement Factor H Proteins 0.000 description 2
- 102100035432 Complement factor H Human genes 0.000 description 2
- 102100024340 Contactin-4 Human genes 0.000 description 2
- 102100032323 Corticosteroid-binding globulin Human genes 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 108010009900 Endothelial Protein C Receptor Proteins 0.000 description 2
- 102000009839 Endothelial Protein C Receptor Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000001690 Factor VIII Human genes 0.000 description 2
- 108010054218 Factor VIII Proteins 0.000 description 2
- 102000030914 Fatty Acid-Binding Human genes 0.000 description 2
- 102100031752 Fibrinogen alpha chain Human genes 0.000 description 2
- 101710137044 Fibrinogen alpha chain Proteins 0.000 description 2
- 102000002090 Fibronectin type III Human genes 0.000 description 2
- 108050009401 Fibronectin type III Proteins 0.000 description 2
- 102000016970 Follistatin Human genes 0.000 description 2
- 108010014612 Follistatin Proteins 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- 208000002705 Glucose Intolerance Diseases 0.000 description 2
- 108010009202 Growth Factor Receptors Proteins 0.000 description 2
- 102000009465 Growth Factor Receptors Human genes 0.000 description 2
- 102100027772 Haptoglobin-related protein Human genes 0.000 description 2
- 101710122541 Haptoglobin-related protein Proteins 0.000 description 2
- 102100027685 Hemoglobin subunit alpha Human genes 0.000 description 2
- 108091005902 Hemoglobin subunit alpha Proteins 0.000 description 2
- 206010020100 Hip fracture Diseases 0.000 description 2
- 101000975058 Homo sapiens ADAMTS-like protein 4 Proteins 0.000 description 2
- 101000695367 Homo sapiens Bone morphogenetic protein 10 Proteins 0.000 description 2
- 101000869010 Homo sapiens Cathepsin D Proteins 0.000 description 2
- 101000883515 Homo sapiens Chitinase-3-like protein 1 Proteins 0.000 description 2
- 101000918352 Homo sapiens Coagulation factor XIII A chain Proteins 0.000 description 2
- 101000868967 Homo sapiens Corticosteroid-binding globulin Proteins 0.000 description 2
- 101001054832 Homo sapiens Inhibin beta C chain Proteins 0.000 description 2
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 2
- 101000615933 Homo sapiens Phosphoserine aminotransferase Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 101000626163 Homo sapiens Tenascin-X Proteins 0.000 description 2
- 101000626125 Homo sapiens Tetranectin Proteins 0.000 description 2
- 101000633617 Homo sapiens Thrombospondin-4 Proteins 0.000 description 2
- 101000606589 Homo sapiens Xaa-Pro dipeptidase Proteins 0.000 description 2
- 206010021639 Incontinence Diseases 0.000 description 2
- 102100026812 Inhibin beta C chain Human genes 0.000 description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 2
- 102000004371 Insulin-like growth factor binding protein 5 Human genes 0.000 description 2
- 108090000961 Insulin-like growth factor binding protein 5 Proteins 0.000 description 2
- 102000003810 Interleukin-18 Human genes 0.000 description 2
- 108090000171 Interleukin-18 Proteins 0.000 description 2
- 102000004125 Interleukin-1alpha Human genes 0.000 description 2
- 108010082786 Interleukin-1alpha Proteins 0.000 description 2
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 2
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 2
- 102100026236 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 208000026492 Isaac syndrome Diseases 0.000 description 2
- 208000000209 Isaacs syndrome Diseases 0.000 description 2
- 102100033467 L-selectin Human genes 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- 102000004856 Lectins Human genes 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000004318 Matrilysin Human genes 0.000 description 2
- 108090000855 Matrilysin Proteins 0.000 description 2
- 108010076497 Matrix Metalloproteinase 10 Proteins 0.000 description 2
- 102000000424 Matrix Metalloproteinase 2 Human genes 0.000 description 2
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 2
- 102000001776 Matrix metalloproteinase-9 Human genes 0.000 description 2
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 2
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 2
- 102100022465 Methanethiol oxidase Human genes 0.000 description 2
- 108700021757 Minicore Myopathy with External Ophthalmoplegia Proteins 0.000 description 2
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 description 2
- 102100029820 Mitochondrial brown fat uncoupling protein 1 Human genes 0.000 description 2
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 2
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 2
- 102100023346 Multimerin-2 Human genes 0.000 description 2
- 102000003505 Myosin Human genes 0.000 description 2
- 108060008487 Myosin Proteins 0.000 description 2
- 206010068871 Myotonic dystrophy Diseases 0.000 description 2
- 102100031900 Neogenin Human genes 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 102000007072 Nerve Growth Factors Human genes 0.000 description 2
- 206010072359 Neuromyotonia Diseases 0.000 description 2
- 102100026747 Osteomodulin Human genes 0.000 description 2
- 102000004264 Osteopontin Human genes 0.000 description 2
- 108010081689 Osteopontin Proteins 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 102000018886 Pancreatic Polypeptide Human genes 0.000 description 2
- 102100020749 Pantetheinase Human genes 0.000 description 2
- 102000003982 Parathyroid hormone Human genes 0.000 description 2
- 108090000445 Parathyroid hormone Proteins 0.000 description 2
- 229940122344 Peptidase inhibitor Drugs 0.000 description 2
- 102100029324 Peptidase inhibitor 16 Human genes 0.000 description 2
- 101710081388 Peptidase inhibitor 16 Proteins 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 102000003867 Phospholipid Transfer Proteins Human genes 0.000 description 2
- 108090000216 Phospholipid Transfer Proteins Proteins 0.000 description 2
- 102100021768 Phosphoserine aminotransferase Human genes 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 108010015078 Pregnancy-Associated alpha 2-Macroglobulins Proteins 0.000 description 2
- 102000006437 Proprotein Convertases Human genes 0.000 description 2
- 108010044159 Proprotein Convertases Proteins 0.000 description 2
- 102100023087 Protein S100-A4 Human genes 0.000 description 2
- 208000033522 Proximal spinal muscular atrophy type 2 Diseases 0.000 description 2
- 208000033526 Proximal spinal muscular atrophy type 3 Diseases 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- 108010085149 S100 Calcium-Binding Protein A4 Proteins 0.000 description 2
- 102100028848 Stromelysin-2 Human genes 0.000 description 2
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 2
- 102100038836 Superoxide dismutase [Cu-Zn] Human genes 0.000 description 2
- 101000983124 Sus scrofa Pancreatic prohormone precursor Proteins 0.000 description 2
- 102100024549 Tenascin-X Human genes 0.000 description 2
- 102100026966 Thrombomodulin Human genes 0.000 description 2
- 108010079274 Thrombomodulin Proteins 0.000 description 2
- 102100036034 Thrombospondin-1 Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 102100024944 Tropomyosin alpha-4 chain Human genes 0.000 description 2
- 201000003397 Troyer syndrome Diseases 0.000 description 2
- 108010042352 Urokinase Plasminogen Activator Receptors Proteins 0.000 description 2
- 102000004504 Urokinase Plasminogen Activator Receptors Human genes 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 102100028885 Vitamin K-dependent protein S Human genes 0.000 description 2
- 208000005248 Vocal Cord Paralysis Diseases 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 108010023082 activin A Proteins 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 108010075843 alpha-2-HS-Glycoprotein Proteins 0.000 description 2
- 102000012005 alpha-2-HS-Glycoprotein Human genes 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003712 anti-aging effect Effects 0.000 description 2
- 102000015736 beta 2-Microglobulin Human genes 0.000 description 2
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 2
- 230000008236 biological pathway Effects 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000007012 clinical effect Effects 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 230000008472 epithelial growth Effects 0.000 description 2
- 108091022862 fatty acid binding Proteins 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000007446 glucose tolerance test Methods 0.000 description 2
- 108010092206 glutathione S-transferase alpha Proteins 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 229940099472 immunoglobulin a Drugs 0.000 description 2
- 238000007901 in situ hybridization Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 210000003127 knee Anatomy 0.000 description 2
- 239000002523 lectin Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 210000003784 masticatory muscle Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004630 mental health Effects 0.000 description 2
- 230000007102 metabolic function Effects 0.000 description 2
- 230000037323 metabolic rate Effects 0.000 description 2
- 238000010603 microCT Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000037023 motor activity Effects 0.000 description 2
- 230000029712 muscle cell homeostasis Effects 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 230000001114 myogenic effect Effects 0.000 description 2
- 230000007372 neural signaling Effects 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 230000006764 neuronal dysfunction Effects 0.000 description 2
- 230000006576 neuronal survival Effects 0.000 description 2
- 239000003900 neurotrophic factor Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 229950009805 onasemnogene abeparvovec Drugs 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 108010078960 osteoadherin Proteins 0.000 description 2
- 239000000199 parathyroid hormone Substances 0.000 description 2
- 229960001319 parathyroid hormone Drugs 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000009038 pharmacological inhibition Effects 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 210000000229 preadipocyte Anatomy 0.000 description 2
- 201000009104 prediabetes syndrome Diseases 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 238000010966 qNMR Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 210000002235 sarcomere Anatomy 0.000 description 2
- 208000037974 severe injury Diseases 0.000 description 2
- 230000009528 severe injury Effects 0.000 description 2
- 230000003584 silencer Effects 0.000 description 2
- 238000011947 six minute walk test Methods 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 230000001148 spastic effect Effects 0.000 description 2
- 230000009192 sprinting Effects 0.000 description 2
- 210000003699 striated muscle Anatomy 0.000 description 2
- 230000021966 synaptic vesicle transport Effects 0.000 description 2
- 108010013645 tetranectin Proteins 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 208000032521 type II spinal muscular atrophy Diseases 0.000 description 2
- 208000032527 type III spinal muscular atrophy Diseases 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Chemical compound OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- UQIHHGNTYLFRNX-ALKRTJFJSA-N (2s)-5-[[(2r)-1-(carboxymethylamino)-1-oxo-3-sulfanylpropan-2-yl]amino]-2-(2-hydroxypropanoylamino)-5-oxopentanoic acid Chemical compound CC(O)C(=O)N[C@H](C(O)=O)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O UQIHHGNTYLFRNX-ALKRTJFJSA-N 0.000 description 1
- ZACWYYKZMLGOTG-UHFFFAOYSA-N 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1CN(CC)CCC1C1=CN2C(=O)C=C(C3=NN4C=C(C)N=C(C)C4=C3)N=C2C(C)=C1 ZACWYYKZMLGOTG-UHFFFAOYSA-N 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
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- ZKRFOXLVOKTUTA-KQYNXXCUSA-N 9-(5-phosphoribofuranosyl)-6-mercaptopurine Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=S)=C2N=C1 ZKRFOXLVOKTUTA-KQYNXXCUSA-N 0.000 description 1
- 101150101604 ACVR1B gene Proteins 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 102100036664 Adenosine deaminase Human genes 0.000 description 1
- 102100025683 Alkaline phosphatase, tissue-nonspecific isozyme Human genes 0.000 description 1
- 101710161969 Alkaline phosphatase, tissue-nonspecific isozyme Proteins 0.000 description 1
- 102100022463 Alpha-1-acid glycoprotein 1 Human genes 0.000 description 1
- 102100022460 Alpha-1-acid glycoprotein 2 Human genes 0.000 description 1
- 102100022524 Alpha-1-antichymotrypsin Human genes 0.000 description 1
- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 description 1
- 102000016893 Amine Oxidase (Copper-Containing) Human genes 0.000 description 1
- 102100034608 Angiopoietin-2 Human genes 0.000 description 1
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 description 1
- 102100036597 Basement membrane-specific heparan sulfate proteoglycan core protein Human genes 0.000 description 1
- 108010081589 Becaplermin Proteins 0.000 description 1
- 102000000119 Beta-lactoglobulin Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102100036845 C-C motif chemokine 22 Human genes 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 238000010354 CRISPR gene editing Methods 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 102100038518 Calcitonin Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 101710196749 Cartilage acidic protein 1 Proteins 0.000 description 1
- 108010072135 Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 102100024649 Cell adhesion molecule 1 Human genes 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 108010083701 Chemokine CCL22 Proteins 0.000 description 1
- 108010083647 Chemokine CCL24 Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 102100029058 Coagulation factor XIII B chain Human genes 0.000 description 1
- 102100031519 Collagen alpha-1(VI) chain Human genes 0.000 description 1
- 102100024338 Collagen alpha-3(VI) chain Human genes 0.000 description 1
- 108010028780 Complement C3 Proteins 0.000 description 1
- 102000016918 Complement C3 Human genes 0.000 description 1
- 108010027644 Complement C9 Proteins 0.000 description 1
- 102100031037 Complement component C9 Human genes 0.000 description 1
- 208000004117 Congenital Myasthenic Syndromes Diseases 0.000 description 1
- 101710107714 Contactin-4 Proteins 0.000 description 1
- 108010071840 Cytosol nonspecific dipeptidase Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 108700022150 Designed Ankyrin Repeat Proteins Proteins 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 101710158332 Diuretic hormone Proteins 0.000 description 1
- 101710204261 Diuretic hormone class 2 Proteins 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 108010061932 Factor VIIIa Proteins 0.000 description 1
- 108010074105 Factor Va Proteins 0.000 description 1
- 108010071289 Factor XIII Proteins 0.000 description 1
- 102100030431 Fatty acid-binding protein, adipocyte Human genes 0.000 description 1
- 102100037738 Fatty acid-binding protein, heart Human genes 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 101150027875 Ftl1 gene Proteins 0.000 description 1
- 206010018276 Gingival bleeding Diseases 0.000 description 1
- 208000024283 Gingival haemorrhages Diseases 0.000 description 1
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 1
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 208000032007 Glycogen storage disease due to acid maltase deficiency Diseases 0.000 description 1
- 206010053185 Glycogen storage disease type II Diseases 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 101710194452 Growth/differentiation factor 11 Proteins 0.000 description 1
- 108010066705 H-cadherin Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 102000014702 Haptoglobin Human genes 0.000 description 1
- 108050005077 Haptoglobin Proteins 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 102100032813 Hepatocyte growth factor-like protein Human genes 0.000 description 1
- 101000678195 Homo sapiens Alpha-1-acid glycoprotein 1 Proteins 0.000 description 1
- 101000678191 Homo sapiens Alpha-1-acid glycoprotein 2 Proteins 0.000 description 1
- 101000924533 Homo sapiens Angiopoietin-2 Proteins 0.000 description 1
- 101000732617 Homo sapiens Angiotensinogen Proteins 0.000 description 1
- 101000713078 Homo sapiens C-C motif chemokine 24 Proteins 0.000 description 1
- 101000741445 Homo sapiens Calcitonin Proteins 0.000 description 1
- 101000932890 Homo sapiens Calcitonin gene-related peptide 1 Proteins 0.000 description 1
- 101000878940 Homo sapiens Cartilage acidic protein 1 Proteins 0.000 description 1
- 101000918350 Homo sapiens Coagulation factor XIII B chain Proteins 0.000 description 1
- 101000941581 Homo sapiens Collagen alpha-1(VI) chain Proteins 0.000 description 1
- 101000909506 Homo sapiens Collagen alpha-3(VI) chain Proteins 0.000 description 1
- 101000909504 Homo sapiens Contactin-4 Proteins 0.000 description 1
- 101001062864 Homo sapiens Fatty acid-binding protein, adipocyte Proteins 0.000 description 1
- 101001027663 Homo sapiens Fatty acid-binding protein, heart Proteins 0.000 description 1
- 101000886562 Homo sapiens Growth/differentiation factor 8 Proteins 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- 101001066435 Homo sapiens Hepatocyte growth factor-like protein Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 101001004946 Homo sapiens Lactoylglutathione lyase Proteins 0.000 description 1
- 101000694615 Homo sapiens Membrane primary amine oxidase Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 101000822604 Homo sapiens Methanethiol oxidase Proteins 0.000 description 1
- 101001114675 Homo sapiens Multimerin-2 Proteins 0.000 description 1
- 101000636823 Homo sapiens Neogenin Proteins 0.000 description 1
- 101000854777 Homo sapiens Pantetheinase Proteins 0.000 description 1
- 101001090065 Homo sapiens Peroxiredoxin-2 Proteins 0.000 description 1
- 101000609255 Homo sapiens Plasminogen activator inhibitor 1 Proteins 0.000 description 1
- 101000596046 Homo sapiens Plastin-2 Proteins 0.000 description 1
- 101000577619 Homo sapiens Profilin-1 Proteins 0.000 description 1
- 101000869693 Homo sapiens Protein S100-A9 Proteins 0.000 description 1
- 101000964691 Homo sapiens Protein Z-dependent protease inhibitor Proteins 0.000 description 1
- 101100203485 Homo sapiens SMN2 gene Proteins 0.000 description 1
- 101000880431 Homo sapiens Serine/threonine-protein kinase 4 Proteins 0.000 description 1
- 101001092910 Homo sapiens Serum amyloid P-component Proteins 0.000 description 1
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 1
- 101001131204 Homo sapiens Sulfhydryl oxidase 1 Proteins 0.000 description 1
- 101000762938 Homo sapiens TOX high mobility group box family member 4 Proteins 0.000 description 1
- 101000659879 Homo sapiens Thrombospondin-1 Proteins 0.000 description 1
- 101000837639 Homo sapiens Thyroxine-binding globulin Proteins 0.000 description 1
- 101000635938 Homo sapiens Transforming growth factor beta-1 proprotein Proteins 0.000 description 1
- 101000830781 Homo sapiens Tropomyosin alpha-4 chain Proteins 0.000 description 1
- 101000638161 Homo sapiens Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 101000577630 Homo sapiens Vitamin K-dependent protein S Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 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 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 208000015580 Increased body weight Diseases 0.000 description 1
- 208000011327 Increased bone mineral density Diseases 0.000 description 1
- 102000014429 Insulin-like growth factor Human genes 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 102100026019 Interleukin-6 Human genes 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 108010060630 Lactoglobulins Proteins 0.000 description 1
- 102100026004 Lactoylglutathione lyase Human genes 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 201000009342 Limb-girdle muscular dystrophy Diseases 0.000 description 1
- 208000035967 Long Term Adverse Effects Diseases 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 108091027974 Mature messenger RNA Proteins 0.000 description 1
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 1
- 206010068836 Metabolic myopathy Diseases 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- 101710134383 Methanethiol oxidase Proteins 0.000 description 1
- 101710130571 Multimerin-2 Proteins 0.000 description 1
- 101100203487 Mus musculus Smn1 gene Proteins 0.000 description 1
- 101100148113 Mus musculus Snrpn gene Proteins 0.000 description 1
- 206010056720 Muscle mass Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 102100038610 Myeloperoxidase Human genes 0.000 description 1
- 108090000235 Myeloperoxidases Proteins 0.000 description 1
- 102100030856 Myoglobin Human genes 0.000 description 1
- 108010062374 Myoglobin Proteins 0.000 description 1
- 206010028629 Myoglobinuria Diseases 0.000 description 1
- 208000023137 Myotoxicity Diseases 0.000 description 1
- 108091061960 Naked DNA Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 102000003683 Neurotrophin-4 Human genes 0.000 description 1
- 108090000099 Neurotrophin-4 Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000007542 Paresis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102100037499 Parkinson disease protein 7 Human genes 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 102100034763 Peroxiredoxin-2 Human genes 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 1
- 102000011195 Profilin Human genes 0.000 description 1
- 108050001408 Profilin Proteins 0.000 description 1
- 102100028857 Profilin-1 Human genes 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 102100024952 Protein CBFA2T1 Human genes 0.000 description 1
- 108010032428 Protein Deglycase DJ-1 Proteins 0.000 description 1
- 108010066124 Protein S Proteins 0.000 description 1
- 102100032420 Protein S100-A9 Human genes 0.000 description 1
- 102100040790 Protein Z-dependent protease inhibitor Human genes 0.000 description 1
- 208000033550 Proximal spinal muscular atrophy type 4 Diseases 0.000 description 1
- 241000269435 Rana <genus> Species 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102000013674 S-100 Human genes 0.000 description 1
- 108700021018 S100 Proteins 0.000 description 1
- 101000849522 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 40S ribosomal protein S13 Proteins 0.000 description 1
- 101000721481 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) Succinyl-diaminopimelate desuccinylase Proteins 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 101710132826 Selenium-binding protein 1 Proteins 0.000 description 1
- 108010089417 Sex Hormone-Binding Globulin Proteins 0.000 description 1
- 102100030758 Sex hormone-binding globulin Human genes 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 208000026214 Skeletal muscle atrophy Diseases 0.000 description 1
- 102000004598 Small Nuclear Ribonucleoproteins Human genes 0.000 description 1
- 108010003165 Small Nuclear Ribonucleoproteins Proteins 0.000 description 1
- 101150069235 Snrpn gene Proteins 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 208000003954 Spinal Muscular Atrophies of Childhood Diseases 0.000 description 1
- 208000033145 Spinal muscular atrophy with respiratory distress type 1 Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 102100034371 Sulfhydryl oxidase 1 Human genes 0.000 description 1
- 102000043168 TGF-beta family Human genes 0.000 description 1
- 108091085018 TGF-beta family Proteins 0.000 description 1
- 102100026749 TOX high mobility group box family member 4 Human genes 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- 108010046722 Thrombospondin 1 Proteins 0.000 description 1
- 102100028709 Thyroxine-binding globulin Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 101710193115 Tropomyosin alpha-4 chain Proteins 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 108010091628 alpha 1-Antichymotrypsin Proteins 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 210000002226 anterior horn cell Anatomy 0.000 description 1
- 229930193936 anticarin Natural products 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- 201000000527 autosomal recessive distal spinal muscular atrophy 1 Diseases 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 108010023337 axl receptor tyrosine kinase Proteins 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
- 108091008324 binding proteins Proteins 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000008436 biogenesis Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000037118 bone strength Effects 0.000 description 1
- 210000003461 brachial plexus Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 230000004640 cellular pathway Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 231100000045 chemical toxicity Toxicity 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229940105784 coagulation factor xiii Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000002920 convulsive effect Effects 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 208000021347 distal spinal muscular atrophy 1 Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000009547 dual-energy X-ray absorptiometry Methods 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000004821 effect on bone Effects 0.000 description 1
- 230000000081 effect on glucose Effects 0.000 description 1
- 230000000667 effect on insulin Effects 0.000 description 1
- 230000001094 effect on targets Effects 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 238000003372 electrophysiological method Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 238000010362 genome editing Methods 0.000 description 1
- 238000003205 genotyping method Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 230000036252 glycation Effects 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 201000004502 glycogen storage disease II Diseases 0.000 description 1
- 230000002394 glycogenic effect Effects 0.000 description 1
- ZEKANFGSDXODPD-UHFFFAOYSA-N glyphosate-isopropylammonium Chemical compound CC(C)N.OC(=O)CNCP(O)(O)=O ZEKANFGSDXODPD-UHFFFAOYSA-N 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 230000010005 growth-factor like effect Effects 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 102000053564 human SMN2 Human genes 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000002684 laminectomy Methods 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000006372 lipid accumulation Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000005399 mechanical ventilation Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 208000037226 minicore myopathy Diseases 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000002062 molecular scaffold Substances 0.000 description 1
- 238000009126 molecular therapy Methods 0.000 description 1
- 238000011294 monotherapeutic Methods 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 208000010924 multiminicore myopathy Diseases 0.000 description 1
- 238000001964 muscle biopsy Methods 0.000 description 1
- 230000009756 muscle regeneration Effects 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 210000003365 myofibril Anatomy 0.000 description 1
- 108010076969 neogenin Proteins 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000007383 nerve stimulation Effects 0.000 description 1
- 238000010984 neurological examination Methods 0.000 description 1
- 230000007514 neuronal growth Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229940097998 neurotrophin 4 Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QNTASHOAVRSLMD-FCARAQADSA-N olesoxime Chemical compound C1CC2=C\C(=N/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 QNTASHOAVRSLMD-FCARAQADSA-N 0.000 description 1
- 229950001051 olesoxime Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960005244 oxymetholone Drugs 0.000 description 1
- ICMWWNHDUZJFDW-DHODBPELSA-N oxymetholone Chemical compound C([C@@H]1CC2)C(=O)\C(=C/O)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 ICMWWNHDUZJFDW-DHODBPELSA-N 0.000 description 1
- ICMWWNHDUZJFDW-UHFFFAOYSA-N oxymetholone Natural products C1CC2CC(=O)C(=CO)CC2(C)C2C1C1CCC(C)(O)C1(C)CC2 ICMWWNHDUZJFDW-UHFFFAOYSA-N 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 108010029648 pantetheinase Proteins 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 108010049224 perlecan Proteins 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 210000003105 phrenic nerve Anatomy 0.000 description 1
- 208000024335 physical disease Diseases 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229940127126 plasminogen activator Drugs 0.000 description 1
- 108010049148 plastin Proteins 0.000 description 1
- 229930192033 plastin Natural products 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229940124606 potential therapeutic agent Drugs 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 108010066823 proline dipeptidase Proteins 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000003614 protease activity assay Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 239000012474 protein marker Substances 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000025488 response to cold Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000009183 running Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000025185 skeletal muscle atrophy Effects 0.000 description 1
- 210000003875 slow muscle fiber Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 108010060815 thrombospondin 4 Proteins 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 102000014898 transaminase activity proteins Human genes 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000003945 type 2b muscle cell Anatomy 0.000 description 1
- 208000005606 type IV spinal muscular atrophy Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 210000000636 white adipocyte Anatomy 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Description
i)肥大を促進するために治療しようとする筋肉が、十分な同化能力を保持または回復していること、
ii)肥大を促進するためにおよび/または萎縮を予防するために治療しようとする筋肉が、運動ニューロンの少なくとも部分的な機能的神経支配を保持するかまたは取り戻していること、およびさらに一部の場合では、
iii)治療しようとする筋肉が、速筋(例えば、II型)線維に依存する運動機能に必要であること。
定義
脊髄性筋萎縮症(SMA)
SMAの治療手法−SMN修正因子
ミオスタチンを標的とした筋肉機能の改善−ミオスタチン阻害剤
脊髄性筋萎縮症を治療するための併用療法
患者集団
投薬量および投与
ミオスタチン阻害剤およびSMN修正因子の生物学的効果
拡大ハマースミス運動機能評価スケール
運動機能尺度(MFM)
上肢モジュール(ULM)
改訂版上肢モジュール
CHOP INTENDスコア
CMAP試験
MUNE試験
ヒト対象における筋肉の質量および/または機能に対する効果
筋肉内脂肪沈着のレベルに対する効果
ヒト対象の生活の質に対する効果
筋肉喪失または萎縮の予防に対する効果
骨恒常性に対する効果
代謝制御に対する効果
i)ヒト対象のインスリン感受性に対する効果
ii)ヒト対象の脂肪組織のレベルに対する効果
iii)ヒト対象の脂肪対筋組織の比に対する効果
iv)ヒト対象のグルコース取込みに対する効果
v)ヒト対象の筋肉内脂肪浸潤に対する効果
α−運動ニューロン喪失遅延の効果
バイオマーカーの発現
筋肥大を促進するための療法
筋萎縮を予防するための療法
本発明を実施するための非限定的な実施形態としては、以下のものが挙げられる。
上記に記載される本発明のさらなる実施形態では、抗体またはその抗原結合性部分は、プロ型/潜在型ミオスタチンには結合するが、成熟ミオスタチンまたはGDF11とは結合しない。上記に記載される本発明の異なる実施形態では、抗体またはその抗原結合性部分は、成熟ミオスタチンには結合するが、成熟GDF11とは結合しない。上記に記載される本発明の別の実施形態では、抗体またはその抗原結合性部分は、1mg/kg〜30mg/kgの間の範囲の投薬量で対象に投与される。上記に記載される本発明の異なる実施形態では、抗体またはその抗原結合性部分は、週2回、週1回、2週に1回、または月1回で対象に投与される。ミオスタチン阻害剤が記載されている上記の実施形態のいずれかでは、抗体またはその抗原結合性部分は、対象に静脈内投与(つまり、静脈に注射される)または皮下投与される(つまり、皮膚に注射される)。
SRK−015:ミオスタチン活性化の特異的阻害
他のTGFβファミリーメンバーと同様に、ミオスタチンは、プロドメインが存在することにより、その受容体への増殖因子の接近が遮断されている、プロミオスタチンと称される不活性前駆体として分泌される。ミオスタチン活性化は、2つの別個のタンパク質分解的切断ステップに起因する(図1)。プロミオスタチンは、まず、プロドメインと成熟増殖因子との間のRXXR部位を認識する、フューリンなどのプロタンパク質転換酵素により切断される(30、62)。切断後、増殖因子およびプロドメインは、依然として一緒のままであり、その受容体に結合することができない潜在型複合体(潜在型ミオスタチン)を形成する。活性増殖因子は、BMP/トロイドファミリー(TLL−2、トロイド様タンパク質2など)のメンバーによる第2の切断後に放出される(63)。活性化後、ミオスタチンは、I型受容体(Alk4/5)およびII型受容体(ActRIIA/B)からなる受容体複合体に結合し、Smad2/3のリン酸化および活性化をもたらす。最終的に、このシグナル伝達経路の活性化は、タンパク質合成の低減およびタンパク質分解の増強を引き起こす(64)。ミオスタチンは、in vivoでは2つの区画:循環中および筋肉中で検出されている。循環中では潜在型が多く、筋肉中ではプロミオスタチンが多く、これは、パールカンなどの細胞外マトリックスタンパク質と結合している(65〜68)。
(実施例2)
ミオスタチンプロ型のin situ局在化
(実施例3)
SRK−015はデキサメタゾン誘導性筋萎縮を予防する
(実施例4)
SRK−015Pは、健常動物の筋肉重量および機能を増強する
(実施例5)
ミオスタチン阻害は、スプライス修正因子で治療したSMAマウスの筋肉機能を改善する
(実施例6)
ミオスタチン阻害の利益は、十分な筋神経支配を必要とする
(実施例7)
SMNΔ7マウスでの標的結合
(実施例8)
scidマウスにおけるSRK−015の薬物動態および薬力学
(実施例9)
カニクイザルにおけるSRK−015の薬物動態および薬力学
(実施例10)
出生時から十分な治療用量のSMN−C1で治療したSMNΔ7マウスの筋肉性能
参考文献
Claims (22)
- 対象の脊髄性筋萎縮症(SMA)を治療するための方法において使用するためのミオスタチン選択的なミオスタチン阻害剤を含む医薬組成物であって、
前記選択的なミオスタチン阻害剤は、SMAの治療に有効な量で投与されるものであり、
前記対象が、
(i)SMN修正因子療法を受けているか、または前記ミオスタチン阻害剤の6カ月以内にSMN修正因子療法で治療される、および
(ii)成長期にある、および/または、長期療法を受ける必要があり;ここで、場合により前記長期療法はSMAの生涯にわたる管理を含み、
前記選択的ミオスタチン阻害剤は:
(a)プロ型および/または潜在型のミオスタチンと結合することによってミオスタチンの活性化を阻害する抗体またはその抗原結合性部分;または
(b)成熟ミオスタチンと結合する抗体またはその抗原結合性部分、
であり、
前記SMN修正因子療法は:
i)スプライス修飾因子、
ii)SMN遺伝子置換もしくは遺伝子療法、
iii)SMN転写エンハンサー、
iv)SMNタンパク質翻訳エンハンサー、または
v)SMNタンパク質安定化剤
を含む、
医薬組成物。 - 前記対象が、依然として成長中であり、同化作用的に活性な小児対象または若年成人である、請求項1に記載の医薬組成物。
- 前記抗体またはその抗原結合性部分が、前記プロ型および/または潜在型のミオスタチンのプロドメインと結合する、請求項1または2に記載の医薬組成物。
- 前記抗体またはその抗原結合性部分が、前記プロ型および/または潜在型のミオスタチンに関連していない成熟ミオスタチンには結合しない、請求項1〜3のいずれか一項に記載の医薬組成物。
- 前記SMN修正因子が、アンチセンスRNAまたは低分子である、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記対象が、歩行不可能なSMAまたは歩行可能なSMAを有する、請求項1〜5のいずれか一項に記載の医薬組成物。
- 前記対象が、I型SMA、II型SMA、またはIII型SMAと診断されている、請求項1〜6のいずれか一項に記載の医薬組成物。
- 前記対象が、前記ミオスタチン阻害剤の投与前に、≦65のベースラインの拡大ハマースミス運動機能評価スケールスコアを有する、請求項1〜7のいずれか一項に記載の医薬組成物。
- SMAの治療に有効な量が、
a)筋萎縮を遅延または緩和すること、
b)α−運動ニューロンの喪失を遅延させること、
c)未熟筋肉マーカーの発現を予防または遅延させること、
d)筋組織の脂肪置換を特徴とする筋肉内脂肪沈着を予防、緩和、または遅延させること、
e)拡大ハマースミス運動機能評価スケールスコアを、未治療対照群と比較して≧1ポイント、または治療前に測定されたベースラインから≧1ポイント増加させること、
f)12カ月、24カ月、または36カ月間にわたって拡大ハマースミス運動機能評価スケールの漸進的減少を遅延させること、
g)CHOP INTENDスコアを、未治療対照と比較して≧1ポイント増加させること、および/または
h)MFM−32スコアを、未治療対照と比較して少なくとも1ポイント増加させること
に有効な量である、請求項1〜8のいずれか一項に記載の医薬組成物。 - 前記ミオスタチン阻害剤が、静脈内注射または注入によりまたは皮下注射により投与される、請求項1〜9のいずれか一項に記載の医薬組成物。
- 対象の脊髄性筋萎縮症(SMA)を治療するための方法において使用するための、SMN修正因子と組み合わせて使用される、ミオスタチン選択的なミオスタチン阻害剤を含む医薬組成物であって、
前記対象が、成長期にある、および/または、長期療法を受ける必要があり;ここで、場合により前記長期療法はSMAの生涯にわたる管理を含み、
前記選択的ミオスタチン阻害剤は:
(a)プロ型および/または潜在型のミオスタチンと結合することによってミオスタチンの活性化を阻害する抗体またはその抗原結合性部分;または
(b)成熟ミオスタチンと結合する抗体またはその抗原結合性部分、
であり、
前記SMN修正因子は:
i)スプライス修飾因子、
ii)SMN遺伝子置換剤もしくは遺伝子療法剤、
iii)SMN転写エンハンサー、
iv)SMNタンパク質翻訳エンハンサー、または
v)SMNタンパク質安定化剤
を含む、
医薬組成物。 - ミオスタチン阻害剤およびSMN修正因子は、対象に同時にまたは連続的に投与される、請求項11に記載の医薬組成物。
- 前記対象は、SMN修正因子およびミオスタチン阻害剤を互いに6ヶ月以内に受容する、請求項11または12に記載の医薬組成物。
- 前記対象が、依然として成長中であり、同化作用的に活性な小児対象または若年成人である、請求項11〜13のいずれか一項に記載の医薬組成物。
- 前記抗体またはその抗原結合性部分が、前記プロ型および/または潜在型のミオスタチンのプロドメインと結合する、請求項11〜14のいずれか一項に記載の医薬組成物。
- 前記抗体またはその抗原結合性部分が、前記プロ型および/または潜在型のミオスタチンに関連していない成熟ミオスタチンには結合しない、請求項11〜15のいずれか一項に記載の医薬組成物。
- 前記SMN修正因子が、アンチセンスRNAまたは低分子である、請求項11〜16のいずれか一項に記載の医薬組成物。
- 前記対象が、歩行不可能なSMAまたは歩行可能なSMAを有する、請求項11〜17のいずれか一項に記載の医薬組成物。
- 前記対象が、I型SMA、II型SMA、またはIII型SMAと診断されている、請求項11〜18のいずれか一項に記載の医薬組成物。
- 前記対象が、前記ミオスタチン阻害剤の投与前に、≦65のベースラインの拡大ハマースミス運動機能評価スケールスコアを有する、請求項11〜19のいずれか一項に記載の医薬組成物。
- 前記ミオスタチン阻害剤が、以下:
a)筋萎縮を遅延または緩和すること、
b)α−運動ニューロンの喪失を遅延させること、
c)未熟筋肉マーカーの発現を予防または遅延させること、
d)筋組織の脂肪置換を特徴とする筋肉内脂肪沈着を予防、緩和、または遅延させること、
e)拡大ハマースミス運動機能評価スケールスコアを、未治療対照群と比較して≧1ポイント、または治療前に測定されたベースラインから≧1ポイント増加させること、
f)12カ月、24カ月、または36カ月間にわたって拡大ハマースミス運動機能評価スケールの漸進的減少を遅延させること、
g)CHOP INTENDスコアを、未治療対照と比較して≧1ポイント増加させること、および/または
h)MFM−32スコアを、未治療対照と比較して少なくとも1ポイント増加させること
に有効な量で投与される、請求項11〜20のいずれか一項に記載の医薬組成物。 - 前記ミオスタチン阻害剤が、静脈内注射または注入によりまたは皮下注射により投与される、請求項11〜21のいずれか一項に記載の医薬組成物。
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662349596P | 2016-06-13 | 2016-06-13 | |
US62/349,596 | 2016-06-13 | ||
US201762470157P | 2017-03-10 | 2017-03-10 | |
US62/470,157 | 2017-03-10 | ||
US201762486934P | 2017-04-18 | 2017-04-18 | |
US62/486,934 | 2017-04-18 | ||
US201762511702P | 2017-05-26 | 2017-05-26 | |
US62/511,702 | 2017-05-26 | ||
US201762512254P | 2017-05-30 | 2017-05-30 | |
US62/512,254 | 2017-05-30 | ||
PCT/US2017/037332 WO2017218592A1 (en) | 2016-06-13 | 2017-06-13 | Use of myostatin inhibitors and combination therapies |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021000367A Division JP7161554B2 (ja) | 2016-06-13 | 2021-01-05 | ミオスタチン阻害剤の使用および併用療法 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2019523295A JP2019523295A (ja) | 2019-08-22 |
JP2019523295A5 JP2019523295A5 (ja) | 2020-07-16 |
JP6823167B2 true JP6823167B2 (ja) | 2021-01-27 |
Family
ID=59093642
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019517209A Active JP6823167B2 (ja) | 2016-06-13 | 2017-06-13 | ミオスタチン阻害剤の使用および併用療法 |
JP2021000367A Active JP7161554B2 (ja) | 2016-06-13 | 2021-01-05 | ミオスタチン阻害剤の使用および併用療法 |
JP2022064360A Active JP7344337B2 (ja) | 2016-06-13 | 2022-04-08 | ミオスタチン阻害剤の使用および併用療法 |
JP2023142275A Pending JP2023164920A (ja) | 2016-06-13 | 2023-09-01 | ミオスタチン阻害剤の使用および併用療法 |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021000367A Active JP7161554B2 (ja) | 2016-06-13 | 2021-01-05 | ミオスタチン阻害剤の使用および併用療法 |
JP2022064360A Active JP7344337B2 (ja) | 2016-06-13 | 2022-04-08 | ミオスタチン阻害剤の使用および併用療法 |
JP2023142275A Pending JP2023164920A (ja) | 2016-06-13 | 2023-09-01 | ミオスタチン阻害剤の使用および併用療法 |
Country Status (19)
Country | Link |
---|---|
US (2) | US10946036B2 (ja) |
EP (3) | EP3368069B1 (ja) |
JP (4) | JP6823167B2 (ja) |
KR (4) | KR20230028813A (ja) |
AU (3) | AU2017283546C1 (ja) |
CL (1) | CL2018003588A1 (ja) |
CY (1) | CY1123678T1 (ja) |
DK (1) | DK3368069T3 (ja) |
ES (1) | ES2830440T3 (ja) |
HR (1) | HRP20201764T1 (ja) |
HU (1) | HUE051480T2 (ja) |
IL (2) | IL301468A (ja) |
LT (1) | LT3368069T (ja) |
MY (1) | MY185614A (ja) |
PE (1) | PE20190205A1 (ja) |
PT (1) | PT3368069T (ja) |
RS (1) | RS61090B1 (ja) |
SI (1) | SI3368069T1 (ja) |
WO (1) | WO2017218592A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11454633B2 (en) | 2014-12-19 | 2022-09-27 | Chugai Seiyaku Kabushiki Kaisha | Anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use |
US11780912B2 (en) | 2016-08-05 | 2023-10-10 | Chugai Seiyaku Kabushiki Kaisha | Composition for prophylaxis or treatment of IL-8 related diseases |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007114319A1 (ja) | 2006-03-31 | 2007-10-11 | Chugai Seiyaku Kabushiki Kaisha | 抗体の血中動態を制御する方法 |
JP5334319B2 (ja) | 2007-09-26 | 2013-11-06 | 中外製薬株式会社 | Cdrのアミノ酸置換により抗体の等電点を改変する方法 |
PL2708558T3 (pl) | 2008-04-11 | 2018-09-28 | Chugai Seiyaku Kabushiki Kaisha | Cząsteczka wiążąca antygen zdolna do wiązania dwóch lub więcej cząsteczek antygenu w sposób powtarzalny |
WO2012073992A1 (ja) | 2010-11-30 | 2012-06-07 | 中外製薬株式会社 | 複数分子の抗原に繰り返し結合する抗原結合分子 |
US11236168B2 (en) | 2012-08-24 | 2022-02-01 | Chugai Seiyaku Kabushiki Kaisha | Mouse FcγammaRII-specific Fc antibody |
SG11201508170TA (en) | 2013-04-02 | 2015-11-27 | Chugai Pharmaceutical Co Ltd | Fc REGION VARIANT |
EP3215175A4 (en) | 2014-11-06 | 2018-06-27 | Scholar Rock, Inc. | Anti-pro/latent-myostatin antibodies and uses thereof |
CA2974547A1 (en) | 2015-02-05 | 2016-08-11 | Chugai Seiyaku Kabushiki Kaisha | Antibodies comprising an ion concentration dependent antigen-binding domain, fc region variants, il-8-binding antibodies, and uses thereof |
CA3036652A1 (en) | 2015-09-15 | 2017-03-23 | Scholar Rock, Inc. | Anti-pro/latent-myostatin antibodies and uses thereof |
WO2017110981A1 (en) | 2015-12-25 | 2017-06-29 | Chugai Seiyaku Kabushiki Kaisha | Anti-myostatin antibodies and methods of use |
JP6823167B2 (ja) | 2016-06-13 | 2021-01-27 | スカラー ロック インコーポレイテッドScholar Rock,Inc. | ミオスタチン阻害剤の使用および併用療法 |
AU2017285764B2 (en) * | 2016-06-17 | 2024-05-02 | Chugai Pharmaceutical Co Ltd | Anti-myostatin antibodies and methods of use |
WO2018187209A1 (en) * | 2017-04-03 | 2018-10-11 | Acceleron Pharma Inc. | Compositions and methods for treating spinal muscular atrophy |
KR102636384B1 (ko) | 2017-08-04 | 2024-02-14 | 스카이호크 테라퓨틱스, 인코포레이티드 | 스플라이싱을 조절하는 방법 및 조성물 |
WO2019170930A1 (es) * | 2018-03-09 | 2019-09-12 | Universitat De Lleida | Tratamiento para la atrofia muscular espinal |
EP3781214A4 (en) * | 2018-04-17 | 2022-04-13 | Applied StemCell, Inc. | COMPOSITIONS AND METHODS FOR THE TREATMENT OF SPINAL MUSCLE ATROPHY |
CR20210416A (es) | 2019-01-30 | 2021-09-14 | Scholar Rock Inc | INHIBIDORES ESPECIFICOS DEL COMPLEJO DE LTBP DE TGFß Y USOS DE LOS MISMOS |
KR20210135241A (ko) | 2019-02-05 | 2021-11-12 | 스카이호크 테라퓨틱스, 인코포레이티드 | 스플라이싱을 조절하는 방법 및 조성물 |
KR20210135507A (ko) | 2019-02-06 | 2021-11-15 | 스카이호크 테라퓨틱스, 인코포레이티드 | 스플라이싱을 조절하는 방법 및 조성물 |
US11918570B2 (en) | 2020-04-13 | 2024-03-05 | The Research Foundation For The State University Of New York | Method of treatment for prevention of glucocorticoid toxicity and/or enhancement of muscle regeneration via neutrophil elastase inhibition |
AU2021369471A1 (en) | 2020-10-26 | 2023-06-15 | Scholar Rock, Inc. | Use of anti-pro/latent myostatin antibody for treating spinal muscular atrophy |
AU2022299185A1 (en) | 2021-06-23 | 2024-01-25 | Scholar Rock, Inc. | A myostatin pathway inhibitor in combination with a glp-1 pathway activator for use in treating metabolic disorders |
WO2023288277A1 (en) | 2021-07-14 | 2023-01-19 | Scholar Rock, Inc. | Ltbp complex-specific inhibitors of tgfb1 and uses thereof |
WO2023057404A1 (en) * | 2021-10-06 | 2023-04-13 | F. Hoffmann-La Roche Ag | Novel combined administration |
WO2023215384A2 (en) * | 2022-05-04 | 2023-11-09 | Scholar Rock, Inc. | Use of myostatin inhibitor for treating spinal muscular atrophy |
Family Cites Families (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6291158B1 (en) | 1989-05-16 | 2001-09-18 | Scripps Research Institute | Method for tapping the immunological repertoire |
US6172197B1 (en) | 1991-07-10 | 2001-01-09 | Medical Research Council | Methods for producing members of specific binding pairs |
WO1993011236A1 (en) | 1991-12-02 | 1993-06-10 | Medical Research Council | Production of anti-self antibodies from antibody segment repertoires and displayed on phage |
US7566768B1 (en) | 1995-10-26 | 2009-07-28 | The Johns Hopkins University School Of Medicine | Promyostatin peptides and methods of using same |
DK0690873T3 (da) | 1993-03-19 | 2003-09-29 | Univ Johns Hopkins Med | Vækstdifferentieringsfaktor-8 |
US7393682B1 (en) | 1993-03-19 | 2008-07-01 | The Johns Hopkins University School Of Medicine | Polynucleotides encoding promyostatin polypeptides |
US5994618A (en) | 1997-02-05 | 1999-11-30 | Johns Hopkins University School Of Medicine | Growth differentiation factor-8 transgenic mice |
ATE305036T1 (de) | 1994-07-08 | 2005-10-15 | Univ Johns Hopkins Med | Wachstums-differenzierungsfaktor-11 |
US20030167492A1 (en) | 1994-07-08 | 2003-09-04 | Johns Hopkins University School Of Medicine | Transgenic non-human animals expressing a gdf-11 dominant negative polypeptide, and methods of making and using same |
US6656475B1 (en) | 1997-08-01 | 2003-12-02 | The Johns Hopkins University School Of Medicine | Growth differentiation factor receptors, agonists and antagonists thereof, and methods of using same |
GB9722131D0 (en) | 1997-10-20 | 1997-12-17 | Medical Res Council | Method |
WO2002002641A1 (en) | 2000-06-16 | 2002-01-10 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to blys |
AU2011244851A1 (en) | 2000-07-27 | 2011-11-24 | The John Hopkins University School Of Medicine | Promyostatin peptides and methods of using same |
US7320789B2 (en) | 2001-09-26 | 2008-01-22 | Wyeth | Antibody inhibitors of GDF-8 and uses thereof |
DE60128914T2 (de) | 2001-10-05 | 2008-05-08 | Affimed Therapeutics Ag | Antikörper menschlichen Ursprungs zur Hemmung der Thrombozytenaggregation |
US8455627B2 (en) | 2001-10-05 | 2013-06-04 | Affimed Therapeutics, Ag | Human antibody specific for activated state of platelet integrin receptor GPIIb/IIIa |
US20040044063A1 (en) | 2002-05-31 | 2004-03-04 | Brent Stockwell | SMA therapy and cell based assay for identifying therapies |
CN102755646A (zh) | 2002-07-19 | 2012-10-31 | 艾博特生物技术有限公司 | TNF α相关疾病的治疗 |
JP4547561B2 (ja) | 2002-09-16 | 2010-09-22 | ザ ジョンズ ホプキンス ユニバーシティー | メタロプロテアーゼによるミオスタチンの活性化、およびミオスタチン活性の調節法 |
US7261893B2 (en) | 2002-10-22 | 2007-08-28 | Wyeth | Neutralizing antibodies against GDF-8 and uses therefor |
CN100434440C (zh) | 2002-12-02 | 2008-11-19 | 阿布格尼克斯公司 | 针对肿瘤坏死因子的抗体及其用途 |
SG153874A1 (en) | 2003-12-31 | 2009-07-29 | Schering Plough Ltd | Neutralizing epitope-based growth enhancing vaccine |
US7456149B2 (en) | 2004-03-02 | 2008-11-25 | Acceleron Pharma, Inc. | ALK7 and myostatin inhibitors and uses thereof |
EP1740946B1 (en) | 2004-04-20 | 2013-11-06 | Genmab A/S | Human monoclonal antibodies against cd20 |
AU2005247508A1 (en) | 2004-05-27 | 2005-12-08 | Acceleron Pharma Inc. | Cerberus/coco derivatives and uses thereof |
JP2008515774A (ja) | 2004-08-03 | 2008-05-15 | ダイアックス コーポレイション | hK1結合タンパク質 |
WO2006081139A2 (en) | 2005-01-26 | 2006-08-03 | Abgenix, Inc. | Antibodies against interleukin-1 beta |
US20060216279A1 (en) * | 2005-03-22 | 2006-09-28 | Glass David J | Myostatin inhibiting fusion polypeptides and therapeutic methods thereof |
PE20061395A1 (es) | 2005-04-25 | 2007-01-15 | Amgen Fremont Inc | Anticuerpos contra miostatina |
AU2006283725B2 (en) | 2005-08-19 | 2012-02-16 | The Trustees Of The University Of Pennsylvania | Antagonist antibodies against GDF-8 and uses in treatment of ALS and other GDF-8-associated disorders |
UA92504C2 (en) | 2005-10-12 | 2010-11-10 | Эли Лилли Энд Компани | Anti-myostatin monoclonal antibody |
WO2007061995A2 (en) | 2005-11-21 | 2007-05-31 | Novartis Ag | Biomarkers for statin-induced myopathy or rhabdomyolysis |
US8097596B2 (en) | 2006-06-30 | 2012-01-17 | Lakewood-Amedex, Inc. | Compositions and methods for the treatment of muscle wasting |
WO2008030367A2 (en) * | 2006-09-01 | 2008-03-13 | The General Hospital Corporation | Selective myostatin inhibitors |
EP2097095B1 (en) | 2006-11-29 | 2016-01-27 | Nationwide Children's Hospital | Myostatin inhibition for enhancing muscle and/or improving muscle function |
EP2769731A1 (en) | 2007-02-23 | 2014-08-27 | The Trustees of Columbia University in the City of New York | Methods to activate or block the HLA-E/QA-1 restricted CD8+ T cell regulatory pathway to treat immunological disease |
US8119026B2 (en) | 2007-03-30 | 2012-02-21 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Birefringent layer with negative optical dispersion |
US7935687B2 (en) | 2007-04-12 | 2011-05-03 | Paratek Pharmaceuticals, Inc. | Methods for treating spinal muscular atrophy using tetracycline compounds |
WO2008150530A2 (en) | 2007-06-01 | 2008-12-11 | Biogen Idec Ma Inc. | Cripto binding molecules |
TW200918553A (en) | 2007-09-18 | 2009-05-01 | Amgen Inc | Human GM-CSF antigen binding proteins |
PE20091163A1 (es) | 2007-11-01 | 2009-08-09 | Wyeth Corp | Anticuerpos para gdf8 |
AR074777A1 (es) | 2008-12-19 | 2011-02-09 | Glaxo Group Ltd | Proteinas de union a antigeno |
WO2010099219A2 (en) | 2009-02-24 | 2010-09-02 | The Salk Institute For Biological Studies | Designer ligands of tgf-beta superfamily |
CN104725512A (zh) | 2009-04-27 | 2015-06-24 | 诺华股份有限公司 | 增加肌肉生长的组合物和方法 |
CN104840944A (zh) | 2009-06-08 | 2015-08-19 | 阿塞勒隆制药公司 | 用于增加产热脂肪细胞的方法 |
MX340295B (es) | 2010-03-10 | 2016-07-05 | Genmab As | Anticuerpos monoclonales anti-c-met. |
JO3340B1 (ar) | 2010-05-26 | 2019-03-13 | Regeneron Pharma | مضادات حيوية لـعامل تمايز النمو 8 البشري |
CN105440134A (zh) | 2010-08-16 | 2016-03-30 | 安姆根公司 | 结合肌肉生长抑制素的抗体、组合物和方法 |
JP6268097B2 (ja) | 2011-11-11 | 2018-01-24 | デューク・ユニヴァーシティ | 固形腫瘍治療のための併用薬物療法 |
US20130178454A1 (en) | 2011-11-17 | 2013-07-11 | Shalender Bhasin | Combination of testosterone and ornithine decarboxylase (odc) inhibitors |
WO2013148284A1 (en) | 2012-03-29 | 2013-10-03 | Genentech, Inc. | Antibodies that bind to a pcsk9 cleavage site and methods of use |
WO2013165972A2 (en) | 2012-04-30 | 2013-11-07 | Cell Signaling Technology, Inc. | Anti-hepatitis b virus antibodies and use thereof |
EP2861617A1 (en) | 2012-06-15 | 2015-04-22 | Pfizer Inc. | Improved antagonist antibodies against gdf-8 and uses therefor |
AU2013341353B2 (en) | 2012-11-06 | 2017-03-16 | Children's Medical Center Corporation | Compositions and methods for modulating cell signaling |
WO2014178863A1 (en) * | 2013-05-01 | 2014-11-06 | Genzyme Corporation | Compositions and methods for treating spinal muscular atrophy |
AU2014262843B2 (en) | 2013-05-06 | 2017-06-22 | Scholar Rock, Inc. | Compositions and methods for growth factor modulation |
EP2853898B1 (en) | 2013-09-27 | 2017-01-04 | Medizinische Hochschule Hannover | Analysis of myostatin in serum |
US10004814B2 (en) | 2013-11-11 | 2018-06-26 | Sirna Therapeutics, Inc. | Systemic delivery of myostatin short interfering nucleic acids (siNA) conjugated to a lipophilic moiety |
WO2015195094A1 (en) * | 2014-06-17 | 2015-12-23 | Ember Therapeutics, Inc. | Anti-activin and nati-myostatin antibodies and methods of using the same |
EP3215175A4 (en) * | 2014-11-06 | 2018-06-27 | Scholar Rock, Inc. | Anti-pro/latent-myostatin antibodies and uses thereof |
WO2016073879A2 (en) | 2014-11-06 | 2016-05-12 | Scholar Rock, Inc. | Transforming growth factor-related antibodies and uses thereof |
PE20221834A1 (es) | 2014-12-19 | 2022-11-29 | Chugai Pharmaceutical Co Ltd | Anticuerpos antimiostatina |
EA201792298A1 (ru) * | 2015-04-15 | 2018-04-30 | Регенерон Фармасьютикалз, Инк. | Способы увеличения силы и функциональности с помощью ингибиторов gdf8 |
CA3036652A1 (en) | 2015-09-15 | 2017-03-23 | Scholar Rock, Inc. | Anti-pro/latent-myostatin antibodies and uses thereof |
KR20180094110A (ko) | 2016-01-08 | 2018-08-22 | 스칼러 락, 인크. | 항-프로/잠재성 미오스타틴 항체 및 그의 사용 방법 |
JP6823167B2 (ja) | 2016-06-13 | 2021-01-27 | スカラー ロック インコーポレイテッドScholar Rock,Inc. | ミオスタチン阻害剤の使用および併用療法 |
JOP20190152A1 (ar) | 2016-12-21 | 2019-06-20 | Novartis Ag | مضادات الميوستاتين، الآكتيفين أو مستقبلات الآكتيفين للاستخدام في علاج السمنة والحالات ذات الصلة |
-
2017
- 2017-06-13 JP JP2019517209A patent/JP6823167B2/ja active Active
- 2017-06-13 WO PCT/US2017/037332 patent/WO2017218592A1/en active Application Filing
- 2017-06-13 AU AU2017283546A patent/AU2017283546C1/en active Active
- 2017-06-13 ES ES17732001T patent/ES2830440T3/es active Active
- 2017-06-13 LT LTEP17732001.7T patent/LT3368069T/lt unknown
- 2017-06-13 IL IL301468A patent/IL301468A/en unknown
- 2017-06-13 KR KR1020237005734A patent/KR20230028813A/ko active Application Filing
- 2017-06-13 DK DK17732001.7T patent/DK3368069T3/da active
- 2017-06-13 KR KR1020197000822A patent/KR102271635B1/ko active IP Right Grant
- 2017-06-13 EP EP17732001.7A patent/EP3368069B1/en active Active
- 2017-06-13 EP EP20179533.3A patent/EP3785728A3/en active Pending
- 2017-06-13 HU HUE17732001A patent/HUE051480T2/hu unknown
- 2017-06-13 SI SI201730485T patent/SI3368069T1/sl unknown
- 2017-06-13 EP EP23157280.1A patent/EP4218804A3/en active Pending
- 2017-06-13 MY MYPI2018002494A patent/MY185614A/en unknown
- 2017-06-13 US US16/308,007 patent/US10946036B2/en active Active
- 2017-06-13 PE PE2018003207A patent/PE20190205A1/es unknown
- 2017-06-13 PT PT177320017T patent/PT3368069T/pt unknown
- 2017-06-13 RS RS20201327A patent/RS61090B1/sr unknown
- 2017-06-13 KR KR1020217019817A patent/KR20210082548A/ko not_active IP Right Cessation
- 2017-06-13 KR KR1020237042111A patent/KR20230169484A/ko active Application Filing
-
2018
- 2018-12-05 IL IL263510A patent/IL263510A/en unknown
- 2018-12-13 CL CL2018003588A patent/CL2018003588A1/es unknown
-
2020
- 2020-07-27 AU AU2020210134A patent/AU2020210134B2/en active Active
- 2020-10-30 HR HRP20201764TT patent/HRP20201764T1/hr unknown
- 2020-11-03 CY CY20201101038T patent/CY1123678T1/el unknown
-
2021
- 2021-01-05 JP JP2021000367A patent/JP7161554B2/ja active Active
- 2021-02-03 US US17/248,700 patent/US20210283166A1/en active Pending
- 2021-11-04 AU AU2021261907A patent/AU2021261907A1/en active Pending
-
2022
- 2022-04-08 JP JP2022064360A patent/JP7344337B2/ja active Active
-
2023
- 2023-09-01 JP JP2023142275A patent/JP2023164920A/ja active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11454633B2 (en) | 2014-12-19 | 2022-09-27 | Chugai Seiyaku Kabushiki Kaisha | Anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use |
US11780912B2 (en) | 2016-08-05 | 2023-10-10 | Chugai Seiyaku Kabushiki Kaisha | Composition for prophylaxis or treatment of IL-8 related diseases |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6823167B2 (ja) | ミオスタチン阻害剤の使用および併用療法 | |
US11351161B2 (en) | Use of CDK9 inhibitors to reduce cartilage degradation | |
US20240002490A1 (en) | Use of anti-pro/latent myostatin antibody for treating spinal muscular atrophy | |
NZ789269A (en) | Use of myostatin inhibitors and combination therapies | |
NZ789250A (en) | Use of myostatin inhibitors and combination therapies | |
NZ789268A (en) | Use of myostatin inhibitors and combination therapies | |
US11851490B2 (en) | Methods and compositions for treating, inhibiting, and/or preventing heterotopic ossification | |
Hauck | Mineralocorticoid Receptor Signaling in Acute and Chronic Muscle Injury | |
JP2024020797A (ja) | 筋萎縮の治療剤 | |
WO2023048878A1 (en) | Depletion of fndc5 reduces cancer induced muscle loss/cachexia | |
WO2023023189A2 (en) | Clusterin overexpression in alzheimer's disease | |
KR20240043778A (ko) | 장시간-작용하는 glp1/글루카곤 수용체 작용제를 위한 용량 용법 | |
Sahenk et al. | Dystrophinopathies | |
Younger | 20 CHAPTER Childhood Muscular Dystrophies |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20190613 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20190905 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200601 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200601 |
|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20200601 |
|
A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20200617 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200706 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200928 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20201208 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210107 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6823167 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
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 |