CN117257958A - Trps1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物 - Google Patents
Trps1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物 Download PDFInfo
- Publication number
- CN117257958A CN117257958A CN202311557165.4A CN202311557165A CN117257958A CN 117257958 A CN117257958 A CN 117257958A CN 202311557165 A CN202311557165 A CN 202311557165A CN 117257958 A CN117257958 A CN 117257958A
- Authority
- CN
- China
- Prior art keywords
- trps1
- drug
- gene
- protein
- inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 101000772560 Homo sapiens Zinc finger transcription factor Trps1 Proteins 0.000 title claims abstract description 56
- 239000003814 drug Substances 0.000 title claims abstract description 48
- 102100030619 Zinc finger transcription factor Trps1 Human genes 0.000 title claims abstract description 44
- 239000003112 inhibitor Substances 0.000 title claims abstract description 25
- 201000004384 Alopecia Diseases 0.000 title claims abstract description 23
- 201000002996 androgenic alopecia Diseases 0.000 title claims abstract description 17
- 206010068168 androgenetic alopecia Diseases 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 32
- 108090000623 proteins and genes Proteins 0.000 claims description 21
- 238000010354 CRISPR gene editing Methods 0.000 claims description 11
- 102000004169 proteins and genes Human genes 0.000 claims description 11
- 108020005004 Guide RNA Proteins 0.000 claims description 8
- 108091034117 Oligonucleotide Proteins 0.000 claims description 8
- 239000002773 nucleotide Substances 0.000 claims description 8
- 125000003729 nucleotide group Chemical group 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 108091027967 Small hairpin RNA Proteins 0.000 claims description 5
- 108020004459 Small interfering RNA Proteins 0.000 claims description 5
- 239000004055 small Interfering RNA Substances 0.000 claims description 5
- 102100021820 E3 ubiquitin-protein ligase RNF4 Human genes 0.000 claims description 4
- 101710202028 E3 ubiquitin-protein ligase RNF4 Proteins 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002860 competitive effect Effects 0.000 claims description 4
- 230000030279 gene silencing Effects 0.000 claims description 4
- 230000036963 noncompetitive effect Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 2
- 239000003098 androgen Substances 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 229940030486 androgens Drugs 0.000 abstract description 3
- 230000002452 interceptive effect Effects 0.000 abstract description 3
- 230000002195 synergetic effect Effects 0.000 abstract description 2
- 208000024963 hair loss Diseases 0.000 abstract 2
- 230000003676 hair loss Effects 0.000 abstract 2
- 101710132471 Zinc finger transcription factor Trps1 Proteins 0.000 abstract 1
- 230000001548 androgenic effect Effects 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 15
- 210000003780 hair follicle Anatomy 0.000 description 15
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 229960004039 finasteride Drugs 0.000 description 10
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 9
- 229960003473 androstanolone Drugs 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 210000004209 hair Anatomy 0.000 description 7
- 230000003797 telogen phase Effects 0.000 description 7
- 230000003698 anagen phase Effects 0.000 description 6
- 230000003779 hair growth Effects 0.000 description 6
- 108091033409 CRISPR Proteins 0.000 description 5
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 102100032187 Androgen receptor Human genes 0.000 description 4
- 230000004156 Wnt signaling pathway Effects 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 231100000360 alopecia Toxicity 0.000 description 4
- 108010080146 androgen receptors Proteins 0.000 description 4
- 230000002280 anti-androgenic effect Effects 0.000 description 4
- 238000009395 breeding Methods 0.000 description 4
- 230000001488 breeding effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 101000783976 Mus musculus N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase Proteins 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 230000003325 follicular Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011814 C57BL/6N mouse Methods 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 208000030695 Sparse hair Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 2
- 239000003433 contraceptive agent Substances 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960004199 dutasteride Drugs 0.000 description 2
- JWJOTENAMICLJG-QWBYCMEYSA-N dutasteride Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)N[C@@H]4CC3)C)CC[C@@]21C)NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F JWJOTENAMICLJG-QWBYCMEYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003781 hair follicle cycle Effects 0.000 description 2
- 230000009583 hair follicle growth Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 229960003632 minoxidil Drugs 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 2
- 229960002256 spironolactone Drugs 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 201000000541 Ambras type hypertrichosis universalis congenita Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000031999 Congenital generalized hypertrichosis, Ambras type Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000010638 Kinesin Human genes 0.000 description 1
- 108010063296 Kinesin Proteins 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 101100154415 Mus musculus Trps1 gene Proteins 0.000 description 1
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 1
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 206010043345 Testicular pain Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000013814 Wnt Human genes 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000035617 depilation Effects 0.000 description 1
- 230000002951 depilatory effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000000079 gynecomastia Diseases 0.000 description 1
- 230000031774 hair cycle Effects 0.000 description 1
- 230000034756 hair follicle development Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000030760 negative regulation of anagen Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
Classifications
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Abstract
本发明属于医药技术领域，具体涉及TRPS1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物。本发明首次发现锌指转录因子TRPS1的功能与雄激素性脱发的发病有着密切关系；并证实雄激素需要在TRPS1的协同作用下才能引起脱发，而抑制TRPS1可阻断雄激素脱发的发生。由此本发明找到了一个不干扰雄激素信号通路的治疗AGA的新靶点，进而提供了TRPS1抑制剂在制备治疗和/或预防雄激素性秃发的药物中的用途，具有很好的应用前景。
Description
技术领域
本发明属于医药技术领域，具体涉及TRPS1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物。
背景技术
雄激素性秃发（androgenic alopecia，AGA）是男性最常见的脱发疾病，发病率高达20%，AGA多发病于青春期和青春期后，病程可长达几十年，特征为毛囊生长期缩短，进行性的毛发微小化。AGA的毛囊并未消失，而是由终毛转化为毳毛。AGA的发病机制的主流学说是雄激素敏感性学说，认为AGA是由二氢睾酮（DHT）激活毛囊的雄激素受体（AR）诱发的。二氢睾酮与雄激素受体结合后进入细胞核，活化雄激素受体共激活因子，启动靶基因转录和蛋白质的翻译等多步骤的分子通路，从而发挥生物学效应。
AGA虽不影响身体健康，但对外形的不利影响给脱发人群带来严重的心理负担，这促使脱发者积极的寻求治疗。目前对AGA有明确疗效的药物只有米诺地尔和非那雄胺，其他的治疗方法还包括毛发移植术、中胚层疗法和低能量激光治疗等。使用非那雄胺的个别服药者可出现“非那雄胺后综合征（post-finasteride symptoms），包括前列腺特异性抗原减少、男性乳房发育、睾丸疼痛、过敏性反应、性功能受损等不良反应。而其他一线治疗药物，例如米诺地尔，则是从促进毛发生长的角度进行干预，并不能从根本上解决AGA的病因。
非那雄胺潜在的不良反应是导致患者抗拒治疗的主要原因。为了减少非那雄胺系统性的副作用，有厂家尝试开发外用剂型的非那雄胺，但外用非那雄胺仍在一定程度上对血液DHT水平有影响。另一方面，为取得更好的抗雄治疗效果，一些其他类型的抗雄药物也被尝试用于AGA，例如度他雄胺、螺内酯、避孕药等。但是这些药物的安全性更令人担忧。例如度他雄胺的不良反应发生率为非那雄胺的2-3倍，螺内酯长期服用可影响电解质水平、增加乳腺癌风险，避孕药有增加血栓发现率的风险。然而脱离了抗雄治疗，AGA的疗效则显著下降，因此尽管有不良反应，非那雄胺多年来一直是AGA治疗的一线用药。由此可见，寻找一种即针对发病原因又不影响雄激素通路的治疗新靶点具有重要的临床需求和应用前景。
TRPS1基因位于第8号染色体，TRPS1在毛发中的作用较为复杂，基因内突变导致的TRPS1功能丧失可出现毛发稀疏，而位置效应导致的TRPS1表达不足可出现毛发过度生长或异位生长 （Ambras 综合征）。动物研究显示TRPS1在毛囊的发生和生长中均发挥着调控作用，但是具体机制尚不明确。TRPS1与雄激素性秃发的关系目前尚无仍和研究和报道。
发明内容
针对现有技术的问题，本发明提供TRPS1抑制剂在制备雄激素性秃发治疗药物中的用途。
TRPS1抑制剂在制备雄激素性秃发治疗药物中的用途。
优选的，所述TRPS1抑制剂是如下药物中的至少一种：敲除或沉默TRPS1基因的药物、抑制TRPS1蛋白的功能的药物。
优选的，所述敲除或沉默TRPS1基因的药物包括siRNA、shRNA或用于实现CRISPR基因编辑的药物；抑制TRPS1蛋白的功能的药物包括：竞争性抑制剂、非竞争性抑制剂或调节性抑制剂。
优选的，所述用于实现CRISPR基因编辑的药物包括gRNA和供体寡核苷酸，所述gRNA的核苷酸序列如SEQ ID NO.1所示，所述供体寡核苷酸的核苷酸序列如SEQ ID NO.2所示；
所述抑制TRPS1蛋白的功能的药物选自动力蛋白轻链8蛋白（LC8a）或RING finger蛋白4（Rnf4）。
优选的，所述TRPS1基因的Gene Bank编号为7227。
本发明还提供一种用于治疗雄激素性秃发的药物，它是以TRPS1抑制剂作为活性成分，加入药学上可接受的辅料或辅助性成分制成的。
优选的，所述敲除或沉默TRPS1基因的药物包括siRNA、shRNA或用于实现CRISPR基因编辑的药物；抑制TRPS1蛋白的功能的药物包括：竞争性抑制剂、非竞争性抑制剂或调节性抑制剂。
优选的，所述敲除或沉默TRPS1基因的药物包括用于实现如下技术中至少一种的药物：腺病毒转染、慢病毒转染、siRNA/shRNA、CRISPR基因编辑。
优选的，所述用于实现CRISPR基因编辑的药物包括gRNA和供体寡核苷酸，所述gRNA的核苷酸序列如SEQ ID NO.1所示，所述供体寡核苷酸的核苷酸序列如SEQ ID NO.2所示；
所述抑制TRPS1蛋白的功能的药物选自动力蛋白轻链8蛋白或RING finger蛋白4。
优选的，所述TRPS1基因的Gene Bank编号为7227。
本发明通过对比健康毛囊和AGA毛囊的差异蛋白，首次发现了一个关键蛋白——TPRS1；再通过构建基因鼠模型发现TRPS1的功能与毛囊生长、毛囊周期有着密切关系；接着通过构建AGA动物模型证实雄激素需要在TRPS1的协同作用下才能引起脱发，而抑制TRPS1可阻断雄激素脱发的发生，由此找到了一个不干扰雄激素信号通路的治疗AGA的新靶点。
因此，本发明达到了如下有益效果：为AGA治疗药物的开发提供了一种新的、不干扰雄激素信号通路的靶点，从而提供了新的药物开发思路，具有很好的应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为实施例1的实验技术路线图。
图2为实施例1中利用CRISPR /Cas9技术首次构建新型TPRS1mu基因小鼠的表征结果图。其中，a. qPCR显示转录水平实验结果图。b.免疫印迹实验结果图。c.毛囊休止期结果图。d.毛囊生长期结果图。
图3为实施例1中TPRS1mu基因小鼠AGA模型的毛发生长及毛囊周期结果图。其中，a.TPRS1muAGA小鼠毛发生长结果图。b. TPRS1muAGA小鼠组织切片HE染色结果图。c. TPRS1mu小WNT信号通路结果图。
具体实施方式
以下实施例和实验例中，未具体说明的试剂和原料均为市售品。
实施例1 TRPS1在雄激素脱发中的作用
1实验方法及技术路线
1.1构建TPRS1mu基因小鼠
将小鼠TRPS1基因的gRNA、含有p.W1110*(TGG to TAG)突变和同义突变p.S1106=(AGT to TCG)的供体寡核苷酸和Cas9共同注射到小鼠受精卵中，产生靶向敲入子代。
其中，gRNA的序列（SEQ ID NO.1）为：
AGAGTGAAGCTGATTGGCTACGG；
供体寡核苷酸的序列（SEQ ID NO.2）为：
CCCATCGAAAAGTACCAATACCCGCTTTTTGGAGTTCCTTTTGTACATAATGACTTCCAGTCGGAAGCTGATTAGCTACGGTTCTGGAGTAAATATAAGCTCTCCGTTCCTGGGAATCCGCACTACTTGAGTCA。
用PCR方法鉴定F0代始祖动物，并进行序列分析，结果如下：
野生型（SEQ ID NO.3）:
TTTGGAGTTCCTTTTGTACATAATGACTTCCAGAGTGAAGCTGATTGGCTACGGTTCTGGAGTAAATATAAGCTCTCCGT；
突变型（SEQ ID NO.4）:
TTTGGAGTTCCTTTTGTACATAATGACTTCCAGTCGGAAGCTGATTAGCTACGGTTCTGGAGTAAATATAAGCTCTCCGT。
用自然繁育的方式进行纯合子繁育，先后共合6笼，得到24雄13雌杂合子，未能得到纯合子。对早产死亡小鼠进行测序鉴定，结果显示均为纯合子。基于繁育结果及参考文献确定该基因敲除纯合子无法存活。进而对杂合子TPRS1mu基因小鼠TRPS1转录水平和蛋白水平进行检测，基于检查结果繁育杂合子TPRS1mu基因小鼠用于后续研究。
1.2构建AGA模型
选取8-9周龄C57BL/6N小鼠，背部皮下注射2.5mg/ml DHT玉米油溶液，每次注射200ul，隔日一次，共25天
1.3诱导毛囊休止期
在AGA造模第5天采用剃毛+脱毛膏脱毛法诱导毛囊休止期，以背部出现粉红色皮肤提示诱导成功。
1.4实验分组及技术路线
分别对野生型C57BL/6N小鼠和TPRS1mu基因鼠构建AGA模型，实验分为4组：野生型组（WT）、野生型AGA组（WT+DHT）、TPRS1mu组(MU)、TPRS1muAGA组（MU+DHT）。通过剃毛+脱毛法诱导毛囊休止期，在脱毛后15天内对小鼠毛发生长情况进行观察和评估，隔日在吸入麻醉诱导下进行背部大体照相评估毛发生长情况。脱毛后25天进行皮肤取材评估AGA相关指标，包括HE切片比较两组毛囊休止期、生长期、毛囊数量、毛囊直径，通过WB检测比较WNT信号通路（技术路线如图1所示）。
2 实验结果
如图2所示，通过CRISPR/Cas9技术繁育TPRS1mu小鼠，qPCR显示转录水平TPRS1mu小鼠（MU）皮肤组织TRPS1较野生型小鼠（WT）降低,WB检测显示蛋白水平TPRS1mu小鼠皮肤组织TRPS1降低，而WNT通路的下游因子β-catenine升高。上述结果提示新构建的TPRS1mu小鼠为TRPS1抑制型动物模型。通过观察TPRS1mu小鼠的毛囊周期发现，TPRS1mu小鼠毛囊生长期较野生型延长。
如图3所示，给予TPRS1mu小鼠经典的AGA模型干预（MU+DHT），野生型小鼠AGA模型作为阳性对照（WT+DHT），未干预的TPRS1mu小鼠作为阴性对照（MU），未干预的野生型小鼠作为空白对照（WT）。结果显示WT+DHT组出现毛发稀疏、休止期延长的表型，组织切片也显示毛囊数量、直径均下降，休止期比例明显上升；而MU+DHT组的毛发生长和生长期均不受影响，组织切片下毛囊数量、直径、休止期比例较MU组均显著性差异。此外WNT信号通路是毛囊周期最重要的信号通路之一，WB检测结果显示WT+DHT组WNT信号通路下调，而MU+DHT组信号通路未见明显变化。上述研究结果提示，雄激素对生长期的抑制作用与TRPS1的功能密切相关，下调TRPS1可对抗雄激素对毛囊生长期的干扰。
上述实验结果证实抑制TRPS1可消除雄激素对生长期的抑制作用、促进毛发生长，具有治疗AGA的潜力。
通过上述实施例可以看到，本发明首次发现了TRPS1在AGA中的重要作用，证明了抑制TRPS1可阻断雄激素脱发的发生，由此找到了一个不干扰雄激素信号通路的治疗AGA的新靶点，为AGA治疗药物的开发提供了一种新的思路，具有很好的应用前景。
Claims (10)
1.TRPS1抑制剂在制备治疗和/或预防雄激素性秃发的药物中的用途。
2.按照权利要求1所述的用途，其特征在于，所述TRPS1抑制剂是如下药物中的至少一种：敲除或沉默TRPS1基因的药物、抑制TRPS1蛋白的功能的药物。
3.按照权利要求2所述的用途，其特征在于，所述敲除或沉默TRPS1基因的药物包括siRNA、shRNA或用于实现CRISPR基因编辑的药物；抑制TRPS1蛋白的功能的药物包括：竞争性抑制剂、非竞争性抑制剂或调节性抑制剂。
4.按照权利要求3所述的用途，其特征在于，所述用于实现CRISPR基因编辑的药物包括gRNA和供体寡核苷酸，所述gRNA的核苷酸序列如SEQ ID NO.1所示，所述供体寡核苷酸的核苷酸序列如SEQ ID NO.2所示；
所述抑制TRPS1蛋白的功能的药物选自动力蛋白轻链8蛋白或RING finger蛋白4。
5.按照权利要求2所述的用途，其特征在于：所述TRPS1基因的Gene Bank编号为7227。
6.一种用于治疗和/或预防雄激素性秃发的药物，其特征在于：它是以TRPS1抑制剂作为活性成分，加入药学上可接受的辅料或辅助性成分制成的。
7.按照权利要求6所述的药物，其特征在于，所述TRPS1抑制剂是如下药物中的至少一种：敲除或沉默TRPS1基因的药物、抑制TRPS1蛋白的功能的药物。
8.按照权利要求7所述的药物，其特征在于，所述敲除或沉默TRPS1基因的药物包括siRNA、shRNA或用于实现CRISPR基因编辑的药物；抑制TRPS1蛋白的功能的药物包括：竞争性抑制剂、非竞争性抑制剂或调节性抑制剂。
9.按照权利要求8所述的药物，其特征在于，所述用于实现CRISPR基因编辑的药物包括gRNA和供体寡核苷酸，所述gRNA的核苷酸序列如SEQ ID NO.1所示，所述供体寡核苷酸的核苷酸序列如SEQ ID NO.2所示；
所述抑制TRPS1蛋白的功能的药物选自动力蛋白轻链8蛋白或RING finger蛋白4。
10.按照权利要求7所述的药物，其特征在于：所述TRPS1基因的Gene Bank编号为7227。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311557165.4A CN117257958B (zh) | 2023-11-21 | 2023-11-21 | Trps1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311557165.4A CN117257958B (zh) | 2023-11-21 | 2023-11-21 | Trps1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117257958A true CN117257958A (zh) | 2023-12-22 |
| CN117257958B CN117257958B (zh) | 2024-02-09 |
Family
ID=89201223
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311557165.4A Active CN117257958B (zh) | 2023-11-21 | 2023-11-21 | Trps1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117257958B (zh) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006128084A2 (en) * | 2005-05-27 | 2006-11-30 | The Trustees Of Columbia University In The City Of New York | Trps1-mediated modulation of hair growth |
| CN103184234A (zh) * | 2003-04-15 | 2013-07-03 | 圣诺菲·帕斯图尔有限公司 | 用于预防和/或治疗癌症的肿瘤抗原bfa5 |
| WO2014018423A2 (en) * | 2012-07-25 | 2014-01-30 | The Broad Institute, Inc. | Inducible dna binding proteins and genome perturbation tools and applications thereof |
| US20150071934A1 (en) * | 2012-03-29 | 2015-03-12 | The Trustees Of Columbia University In The City Of New York | Methods For Regulating Hair Growth Disorders |
| CN104862312A (zh) * | 2015-05-08 | 2015-08-26 | 华南理工大学 | 哺乳类实验动物snp标记筛查的引物对及其应用 |
| CN111494384A (zh) * | 2020-05-07 | 2020-08-07 | 中国医学科学院医药生物技术研究所 | Imb-znu-g8在治疗雄激素受体活性相关疾病中的应用 |
| CN113195719A (zh) * | 2018-09-26 | 2021-07-30 | 卡斯西部储备大学 | 用于增加蛋白质表达和/或治疗单倍剂量不足症的方法及组合物 |
| WO2023128862A1 (en) * | 2021-12-29 | 2023-07-06 | Livius Pte. Ltd. | Method for repairing hair cycle-related genes and method for treating hair cycle-related diseases using mir-520d-5p |
-
2023
- 2023-11-21 CN CN202311557165.4A patent/CN117257958B/zh active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103184234A (zh) * | 2003-04-15 | 2013-07-03 | 圣诺菲·帕斯图尔有限公司 | 用于预防和/或治疗癌症的肿瘤抗原bfa5 |
| WO2006128084A2 (en) * | 2005-05-27 | 2006-11-30 | The Trustees Of Columbia University In The City Of New York | Trps1-mediated modulation of hair growth |
| US20080051342A1 (en) * | 2005-05-27 | 2008-02-28 | Christiano Angela M | TRPS1-mediated modulation of hair growth |
| US20150071934A1 (en) * | 2012-03-29 | 2015-03-12 | The Trustees Of Columbia University In The City Of New York | Methods For Regulating Hair Growth Disorders |
| WO2014018423A2 (en) * | 2012-07-25 | 2014-01-30 | The Broad Institute, Inc. | Inducible dna binding proteins and genome perturbation tools and applications thereof |
| CN104862312A (zh) * | 2015-05-08 | 2015-08-26 | 华南理工大学 | 哺乳类实验动物snp标记筛查的引物对及其应用 |
| CN113195719A (zh) * | 2018-09-26 | 2021-07-30 | 卡斯西部储备大学 | 用于增加蛋白质表达和/或治疗单倍剂量不足症的方法及组合物 |
| CN111494384A (zh) * | 2020-05-07 | 2020-08-07 | 中国医学科学院医药生物技术研究所 | Imb-znu-g8在治疗雄激素受体活性相关疾病中的应用 |
| WO2023128862A1 (en) * | 2021-12-29 | 2023-07-06 | Livius Pte. Ltd. | Method for repairing hair cycle-related genes and method for treating hair cycle-related diseases using mir-520d-5p |
Non-Patent Citations (2)
| Title |
|---|
| 张舒;蒋献;: "毛发移植中的毛囊保存液的应用和研究进展", 中国医疗美容, no. 03 * |
| 章星琪;: "第七届世界毛发研究大会会议内容简介", 皮肤性病诊疗学杂志, no. 04 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117257958B (zh) | 2024-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Stine et al. | EBF2 promotes the recruitment of beige adipocytes in white adipose tissue | |
| Boulan et al. | Inter-organ growth coordination is mediated by the Xrp1-Dilp8 axis in Drosophila | |
| US9701675B2 (en) | Activation of TRPV4 ion channel by physical stimuli and critical role for TRPV4 in organ-specific inflammation and itch | |
| Baldino Jr et al. | Coordinate hormonal and synaptic regulation of vasopressin messenger RNA | |
| Manils et al. | CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation | |
| US11938135B2 (en) | Compositions and methods for treating vascular Ehlers Danlos syndrome and associated disorders | |
| Zhang et al. | S100a16 deficiency prevents hepatic stellate cells activation and liver fibrosis via inhibiting CXCR4 expression | |
| Hael et al. | The transcriptional regulator PRDM12 is critical for Pomc expression in the mouse hypothalamus and controlling food intake, adiposity, and body weight | |
| Wang et al. | Indirubin protects chondrocytes and alleviates OA by inhibiting the MAPK and NF-κB pathways | |
| US11077110B2 (en) | Compositions and methods for treating and preventing metabolic disorders | |
| CN117257958B (zh) | Trps1抑制剂的新用途及用于治疗和/或预防雄激素性秃发的药物 | |
| WO2023208013A1 (zh) | HIF-1α抑制剂在雄激素性脱发治疗中的应用 | |
| CN115721716A (zh) | Mdh2抑制剂在雄激素性脱发治疗中的应用 | |
| CN112089723B (zh) | 靶向FGF5的siRNA在治疗脱发中的应用 | |
| US20130039930A1 (en) | Biomarker for sensitivity to therapy with a notch inhibitor | |
| Wang et al. | LncRNA CCRR Attenuates Post-Myocardial Infarction Inflammatory Response by Inhibiting the TLR Signaling Pathway | |
| BR112013029331B1 (pt) | Proteína agonista de eda, composição farmacêutica e seus usos | |
| CN114377130B (zh) | 一种调控皮肤及其毛发再生的内源性小rna分子靶标及其应用 | |
| Bolt et al. | A distant downstream enhancer directs essential expression of Tbx18 in urogenital tissues | |
| WO2021104208A1 (zh) | 预防皮肤衰老与早衰的内源性小rna分子标靶及其应用 | |
| CN108434137A (zh) | 一种治疗前列腺癌的组合物 | |
| WO2021147740A1 (zh) | Mapk/erk通路抑制剂在拮抗皮肤老化与辐射性皮肤早衰中的应用 | |
| Wang et al. | Suppression of miR-199a-5p alleviates ulcerative colitis by upregulating endoplasmic reticulum stress component XBP1 | |
| CN117482238A (zh) | TRPMLs通道激动剂在制备促进毛发生长的药物中的用途 | |
| Copping | Effect of the E3 Ubiquitin-Protein Ligase on Translational Neurophysiology Phenotypes in Preclinical Models of Neurodevelopmental Disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |