JP2018515501A - 発毛を促進する方法及び組成物 - Google Patents
発毛を促進する方法及び組成物 Download PDFInfo
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Abstract
Description
本出願は、2015年5月7日に出願された米国仮特許出願第62/157,959号に対する優先権を主張する。上記の出願の全体が引用することにより本明細書の一部をなすものとする。
本発明は、米国立衛生研究所により付与された認可番号R01AR056016及びR21AR061881の下で政府による支援を受けている。米国政府は本発明に対して一定の権利を有する。
本発明で開示される主題は、或る特定の実施の形態では、発毛を誘導するためにJAK−STAT経路を阻害する組成物及び方法に関する。或る特定の実施の形態では、本発明で開示される主題は、発毛を誘導するためのJAK−STAT経路の低分子阻害剤による局所治療に関する。
幾つかの発毛障害は、毛周期の成長相(成長期)に再エントリーすることができないことを特徴とする。これは、アンドロゲン性脱毛症の場合、毛包(HF:hair follicle)の小型化に起因するか、円形脱毛症の場合は免疫機能不全に起因する可能性がある。
或る特定の実施の形態では、本開示は、哺乳動物の被験体において発毛を誘導する方法であって、治療的有効量のJak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、及び/又はOSM−Rβの阻害剤を被験体の毛包に投与することを含む、方法に関する。
限定ではなく明確性のため、本発明の詳細な説明は、以下のサブセクションに分割される。
5.1 定義
5.2 JAK−STAT経路遺伝子
5.3 治療方法
5.4 医薬組成物及び投与
5.5 治療の効力をモニタリングする方法
5.6 キット
本開示によれば、「被験体」又は「患者」はヒト又は非ヒトの動物である。動物被験体はヒトであることが好ましいが、本発明の化合物及び組成物は、獣医学にも同様に適用され、例えば、イヌ、ネコ、ネズミ及び様々な他のペット等の飼い慣らされた種;ウシ、ウマ、ヒツジ、ヤギ、ブタ等の家畜種;並びに例えば野生又は動物園における野生動物、非ヒト霊長動物等の治療に適用される。
JAK−STATシグナル伝達経路は、細胞外の環境から核に生物学的シグナルを伝達し、分化、アポトーシス、免疫、増殖、及び腫瘍形成に関与する遺伝子のDNA転写及び発現をもたらす。該経路の3つの主な構成要素は、細胞表面受容体、ヤーヌスキナーゼ(JAK:Janus kinase)、及びシグナル伝達性転写因子(STAT)タンパク質である。
発毛を誘導又は促進する方法
本開示は、発毛を誘導又は促進するための治療的有効量の1以上のJAK/STATタンパク質(例えばJak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR又はOSM−Rβ)の阻害剤(例えばルキソリチニブ(INCB 018424)、トファシチニブ(CP690550)、AG490、CYT387、SB1518、LY3009104、TG101348、BMS−911543、CEP−701、フルダラビン、エピガロカテキン−3−ガレート(EGCG)、バリシチニブ、モメロチニブ、パクリチニブ、ペフィシチニブ、ABT 494、AT 9283、デセルノチニブ、フィルゴチニブ、ガンドチニブ、INCB 39110、レスタウルチニブ、PF 4965842、R348、AZD 1480、BMS 911543、セルデュラチニブ、INCB 052793、NS 018、C 410、CT 1578、JTE 052、PF 6263276、R 548、TG 02、ルンブリカス・レベルス抽出物、ARN 4079、AR 13154、UR 67767、CS510、VR588、DNX 04042、又はハイパーフォリン)の使用に関する。かかる発毛の誘導又は促進が望まれる非限定的な状況としては、限定されないが、被験体がアンドロゲン性脱毛症、休止期脱毛、円形脱毛症、頭部白癬、完全脱毛症、貧毛症、遺伝性単純型貧毛症、前頭部線維化性脱毛症、瘢痕性脱毛症、扁平毛孔性苔癬、リング型脱毛症、瘢痕化脱毛症、非瘢痕化脱毛症、化学療法による脱毛症、又は全身性脱毛症を有する状況が挙げられる。或る特定の実施形態では、毛包が休止中期相又は休止後期相にある場合に被験体の毛包に上記阻害剤を投与する。特定の実施形態では、阻害剤は局所的に又は経口で投与される。
本開示は、更に、毛乳頭の誘導力の促進ための1以上のJAK/STATタンパク質(例えばJak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR又はOSM−Rβ)の阻害剤(例えばルキソリチニブ(INCB 018424)、トファシチニブ(CP690550)、AG490、モメロチニブ(CYT387)、パートシチニブ(SB1518)、バリシチニブ(LY3009104)、フェドラチニブ(TG101348)、BMS−911543、レスタウルチニブ(CEP−701)、フルダラビン、エピガロカテキン−3−ガレート(EGCG)、バリシチニブ、モメロチニブ、パクリチニブ、ペフィシチニブ、ABT 494、AT 9283、デセルノチニブ、フィルゴチニブ、ガンドチニブ、INCB 39110、PF 4965842、R348、AZD 1480、BMS 911543、セルデュラチニブ、INCB 052793、NS 018、C 410、CT 1578、JTE 052、PF 6263276、R 548、TG 02、ルンブリカス・レベルス抽出物、ARN 4079、AR 13154、UR 67767、CS510、VR588、DNX 04042、若しくはハイパーフォリン、又はそれらの組み合わせ)の使用に関する。或る特定の実施形態では、本開示は毛乳頭の誘導力を促進する方法であって、被験体の毛包に由来する毛乳頭3Dスフェアに治療的有効量のJak/STAT阻害剤を投与することを含む、方法に関する。毛包では、毛包由来の真皮細胞は局所上皮と相互作用して、様々な無毛のレシピエント皮膚部位において毛包を新たに誘導することができることが当該技術で知られている(Higgins, et, al., Proc Natl Acad Sci U S A 110, 19679 (Dec 3, 2013)、引用することにより本明細書の一部をなす)。ヒト毛乳頭細胞は、3Dスフェロイドとして生育した場合に、ヒト皮膚において新たに毛包を誘導することができることも当該技術において知られている(Higgins, et, al.; Y. Zheng et al., J Invest Dermatol 124, 867 (May, 2005)、引用することにより本明細書の一部をなす)。或る特定の実施形態では、その後、毛乳頭3Dスフェアを被験体に投与することで、アンドロゲン性脱毛症、休止期脱毛、円形脱毛症、頭部白癬、完全脱毛症、貧毛症、遺伝性単純型貧毛症、前頭部線維化性脱毛症、瘢痕性脱毛症、扁平毛孔性苔癬、リング型脱毛症、瘢痕化脱毛症、非瘢痕化脱毛症、化学療法による脱毛症、又は全身性脱毛症を治療する。
或る特定の実施形態では、本開示のJAK−STAT阻害剤組成物を、薬学的に許容可能な担体又は賦形剤との混合によって医薬組成物又は医薬製剤として製剤化することができる。或る特定の実施形態では、医薬製剤は、治療的有効量のJAK−STAT阻害剤と、生理学的に許容可能な希釈剤又は担体とを含んでもよい。或る特定の実施形態では、医薬組成物は、1以上の追加の治療成分及び/又はアジュバントを更に含んでもよい。
本開示は、更に哺乳動物の被験体の発毛を誘導又は促進する治療の効力を評価する方法に関する。或る特定の実施形態では、上記方法は、(a)被験体から得られた毛包試料中の1以上の発毛バイオマーカーのレベルを判定すること、及び(b)治療法の間に1以上の時間点において被験体から得られた毛包試料中の1以上のバイオマーカーのレベルを判定することを含み、ここで、第1の試料と比較して、第2の試料又はその後の試料中の1以上のバイオマーカーの変化が存在する場合、該治療法が被験体の発毛の誘導又は促進に効果的である。或る特定の実施形態では、バイオマーカーは、Wnt経路、Shh経路、毛発生経路、メラニン形成経路、又はそれらの任意の組み合わせから選択される。或る特定の実施形態では、バイオマーカーは、CD34、Lhx2、NFATc1、Axin2、FoxC1、OSMR、OSM、Jak3、FAS、Irf1、Ifnar1、Nr3c1、Stat5A、Il6st、Ptprc、Ghr、IL10ra、Il2rg、Pdgfra、Spfi1、Socs2、Stat5b、Crp、Il4、Prlr、Insr、IL2ra、Cebpd、Stat3、Jak1、Acvr2a、Sfrp4、Sox5、Cdh2、Fzd5、Wif1、Wnt2、Fzd8、Apc、Sox9、Ilk、Shh、Krt25、Dlx2、Prom1、S100a9、Vegfc、Ptgfr、Pdgfrl、Igfbp4、Gli2、Tyrp1、Syt4、Mlana、Pmel、Dct、Tyr、Sos1、Dbf4、Pax3、PIK3ca、Rps6kb1、Mlph、及びStx17からなる群から選択される。
本開示は、更に、哺乳動物の被験体の発毛を誘導又は促進するキットに関する。或る特定の実施形態では、該キットは(a)Jak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、及び/又はOSM−Rβの阻害剤と、(b)薬学的に許容可能な担体とを備える。或る特定の実施形態では、Jak/STAT阻害剤は、Jak/STATタンパク質又はそのフラグメントに特異的に結合する抗体;Jak/STATタンパク質をコードする遺伝子の発現を減少させるアンチセンスRNA、アンチセンスDNA、siRNA、shRNA、microRNA、若しくはそれらの変異体若しくは修飾体;Jak/STATタンパク質の発現を減少させるアンチセンスRNA、アンチセンスDNA、siRNA、shRNA、microRNA、若しくはそれらの変異体若しくは修飾体;低分子;又はそれらの組み合わせである。或る特定の実施形態では、阻害剤はルキソリチニブ(INCB 018424)である。或る特定の実施形態では、阻害剤はトファシチニブ(CP690550)である。或る特定の実施形態では、阻害剤は、ルキソリチニブ(INCB 018424)、トファシチニブ(CP690550)、AG490、モメロチニブ(CYT387)、パートシチニブ(SB1518)、バリシチニブ(LY3009104)、フェドラチニブ(TG101348)、BMS−911543、レスタウルチニブ(CEP−701)、フルダラビン、エピガロカテキン−3−ガレート(EGCG)、バリシチニブ、モメロチニブ、パクリチニブ、ペフィシチニブ、ABT 494、AT 9283、デセルノチニブ、フィルゴチニブ、ガンドチニブ、INCB 39110、PF 4965842、R348、AZD 1480、BMS 911543、セルデュラチニブ、INCB 052793、NS 018、C 410、CT 1578、JTE 052、PF 6263276、R 548、TG 02、ルンブリカス・レベルス抽出物、ARN 4079、AR 13154、UR 67767、CS510、VR588、DNX 04042、若しくはハイパーフォリン、又はそれらの組み合わせである。
以下の実施例は、限定されないが、JAK−STAT経路の阻害剤の投与による発毛を誘導する組成物及び方法を含む、本発明で開示される主題を如何にして作製し使用するかの十分な開示及び説明を当業者に提供するように述べる。以下の実施例は、本発明で開示される主題の範囲を限定することは意図されない。上に提供される全般的な記載を考慮して、様々な他の実施形態が実行され得ることが理解される。
結果
JAK−STAT阻害はマウスにおける発毛の迅速な開始をもたらす。はじめに、休止期のC57/B6マウスの背後部の半分を、ビヒクル対照(陰性対照、左側)、以前に成長期開始を促進することが示された(2)ソニックヘッジホッグ(Shh)アゴニスト(陽性対照)、又はトファシチニブ(JAK1/3>JAK2>TYK2)(3)及びルキソリチニブ(JAK1/2>Tyk2>JAK3)(4〜7)(右側)を含むいくつかのJAK−STAT経路の低分子阻害剤のいずれかで3週間治療した(図1(A))。予想されたように、Shhアゴニストによる治療の7日以内に成長期へのエントリーがはっきりと表れたのに対し、ビヒクル治療マウスは実験期間に亘って休止期のままであった。興味深いことに、JAK阻害剤による治療はShhアゴニストに類似する動態で毛周期への迅速な再エントリーをもたらした(図1(A))。幹細胞活性化に対する直接効果を調べるため、休止期のマウスを4日の短期間に亘りトファシチニブ又はルキソリチニブで治療した。著しい増殖が薬物治療HFの毛芽コンパートメント(P−cad+)内に認められ(図5(A))、前駆細胞集団の活性化を示した。皮膚ホメオスタシスに対する薬物治療効果の定量は、薬物誘発性発毛が正常な発毛を再現することを実証した(図5(B))。まとめると、これらのデータは、JAK−STAT経路の局所阻害が発毛の迅速な開始をもたらすことを示唆する。
本明細書に提示される知見は、JAK−STATシグナル伝達の阻害が発毛を促進することを実証する。これらの所見は、JAK−STATと抗発毛パターンとの関連(29)、成体マウスの正常な毛周期の進行におけるSTAT3の役割を立証する証拠(21、22)と一致する。さらに、最近の研究は、老齢マウスにおけるJAK−STATシグナル伝達の増加が、in vitroでのHF幹細胞機能を阻害すること(50)、及びSTAT5シグナル伝達が妊娠及び乳汁分泌中のHF幹細胞静止状態を制御すること(51)を示した。
実験計画. JAK−STATシグナル伝達の阻害が、マウスにおける毛周期へのエントリーを促進することが仮定された。成長期の開始を判定するため、背部皮膚の毛を電気カミソリにより刈り込み、成長期へのHFのエントリーを皮膚の黒化、及び毛の再成長の出現によって観察した。図1(A)に記載される毛周期実験のため、生検材料を1時点当たり2匹のマウスから採取し、3セットの同腹仔に対して実験を繰り返した。図1(B)においてグラフに提示されるデータは、図5(E)に示されるように、治療後の経時的な皮膚の黒化を観察することによって生成された。補足の図1(C)及び図1(D)に記載される実験について、1つの群(7週対8.5週)当たり3匹〜4匹のマウスを使用し、実験を3回繰り返した。図1(B)及び図5(E)に記載される実験に対し、4匹のマウスを対照(背部皮膚の半分)及びルキソリチニブ(背部皮膚の半分)で治療し、4匹のマウスを対照(背部皮膚の半分)及びトファシチニブ(背部皮膚の半分)で治療した。図1(E)に提示される実験を、1条件当たり3匹のマウスで独立して一回行った。図2(A)に記載される実験では、1遺伝子型当たり3匹のマウスを利用し、2セットの同腹仔に対して実験を繰り返した。
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緒言
JAK−STATシグナル伝達はネズミ科の毛周期の休止期(静止相)中に毛包幹細胞(HFSC)の静止状態の維持に関与する。JAK阻害が野生型マウス休止期皮膚において成長期を開始することができることが実証されている(1)。遺伝子発現及び細胞動態分析を使用することにより、増殖の最初の徴候が毛乳頭に隣接する二次毛芽(secondary hair germ)で観察され、このプロセスが本来の毛周期の初期の現象を再現したことを示した。JAK−STATシグナル伝達は複雑にサイトカインシグナル伝達と関連することが示唆される。特に、サイトカインのIL−6ファミリーは成長期に拮抗し、マウス皮膚の退行期/休止期を促進することが示されている。サイトカインのIL−6ファミリーのうち、オンコスタチンM(OSM)は、他の系の幹細胞、主に筋幹細胞での静止状態の維持と密接に結び付けられている。免疫蛍光研究を使用して、本発明者らは、ネズミ科の毛包の二次毛芽において、このコンパートメントの静止状態の維持においてOSMに対する自己分泌の役割を示唆する、活性化(リン酸化)STAT3及びSTAT5のシグナル伝達分子に相補的なパターンのOSM及びその受容体(OSM−Rβ)の共発現を見出した。これらの観察は、培養マウス角化細胞に対するin vitro実験で確認された。OSM及びOSM−Rβと共にJAK−STATシグナル伝達の構成要素の時間的及び空間的なコンディショナルノックアウトを使用することにより、本発明者らは、OSM及びその受容体が二次毛芽、及びおそらくHFの他の幹細胞におけるHFSCの静止状態に必要十分であるかどうかを試験した。HFSCの静止状態の促進における活性なJAK−STATシグナル伝達の驚くべき役割は、休止期の維持におけるBMPシグナル伝達及びWnt阻害等の経路と並ぶものである。
リン酸化されたSTAT3及びSTAT5タンパク質が休止初期及び休止中期(P46、P60)の間HFSCコンパートメントに検出され、これは休止後期(P80)に減少した(図9(A))。OSM免疫蛍光は、この間にHFSCに共局在化された。OSM受容体(OSM−Rβ)もまた、免疫組織化学によりHFSC毛隆起コンパートメントへ共局在化することがわかった(図9(B))。いずれの画像も倍率20倍で撮影した。in vitro培養角化細胞では、OSMは、OSM治療の10分以内にSTAT1、STAT3、及びSTAT5の転写因子を活性化し、これはトファシチニブ(TOFA)によって効率的に停止された(図9(C))。TOFAで治療したin vivoでの全皮膚もまた、STAT3及びSTAT5の活性化の有効な阻害を実証する(図9(D))。P60の休止期皮膚に毎日皮下注射したOSM−Rβに対する中和抗体は局所の成長期を誘導し、HFSCコンパートメントのOSM−Rβ活性化が休止期中に静止状態を維持するのに必要であったことを示唆した(図9(E))。PBS対照、及びIL−6とその受容体に対する中和抗体には効果がなかった(図9(E))。図9(F)は、gp130も毛隆起において増幅されたことを示す。
1. Harel S, Higgins CA, Cerise JE, et al. Science Adv 1(9), October 2015
2. Xing L, Dai Z, Jabbari A et al., Nat Med 20, September 2014
3. Blau HM, Cosgrove BD, Ho AT. Nat Med 21(8), August 2015
4. Doles J, Storer M, Cozzuto L, et al. Genes Development 26(19), October 2012
5. Woo SH, Stumpfova M, Jensen UB, et al. Development 137(23), December 2010
Claims (61)
- 哺乳動物の被験体において毛の発毛を誘導する方法であって、治療的有効量のJak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、及び/又はOSM−Rβの阻害剤を前記被験体の毛包に投与することを含む、方法。
- 前記毛包が休止中期相又は休止後期相にある場合に前記投与を行う、請求項1に記載の方法。
- 前記被験体が、アンドロゲン性脱毛症、休止期脱毛、円形脱毛症、頭部白癬、完全脱毛症、貧毛症、遺伝性単純型貧毛症、前頭部線維化性脱毛症、瘢痕性脱毛症、扁平毛孔性苔癬、リング型脱毛症、瘢痕化脱毛症、非瘢痕化脱毛症、化学療法による脱毛症、又は全身性脱毛症を有する、請求項1に記載の方法。
- 前記阻害剤が、Jak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、若しくはOSM−Rβをコードする遺伝子の発現を特異的に阻害するアンチセンスRNA、siRNA、shRNA、microRNA、若しくはそれらの変異体若しくは修飾体、又は低分子である、請求項1に記載の方法。
- 前記阻害剤がルキソリチニブ(INCB 018424)である、請求項4に記載の方法。
- 前記阻害剤がトファシチニブ(CP690550)である、請求項4に記載の方法。
- 前記低分子が、ルキソリチニブ(INCB 018424)、トファシチニブ(CP690550)、AG490、モメロチニブ(CYT387)、パートシチニブ(SB1518)、バリシチニブ(LY3009104)、フェドラチニブ(TG101348)、BMS−911543、レスタウルチニブ(CEP−701)、フルダラビン、エピガロカテキン−3−ガレート(EGCG)、バリシチニブ、モメロチニブ、パクリチニブ、ペフィシチニブ、ABT 494、AT 9283、デセルノチニブ、フィルゴチニブ、ガンドチニブ、INCB 39110、PF 4965842、R348、AZD 1480、BMS 911543、セルデュラチニブ、INCB 052793、NS 018、C 410、CT 1578、JTE 052、PF 6263276、R 548、TG 02、ルンブリカス・レベルス抽出物、ARN 4079、AR 13154、UR 67767、CS510、VR588、DNX 04042、若しくはハイパーフォリン、又はそれらの組み合わせである、請求項4に記載の方法。
- 前記阻害剤がOSM−Rβ抗体である、請求項4に記載の方法。
- 前記被験体がヒトである、請求項1に記載の方法。
- 前記毛が頭皮若しくは顔にあるか、又は前記被験体の眉毛若しくは睫毛を構成するものである、請求項1に記載の方法。
- 前記毛が鼻毛である、請求項1に記載の方法。
- 前記阻害剤が局所投与される、請求項1に記載の方法。
- 前記阻害剤が経口投与される、請求項1に記載の方法。
- 1以上の発毛バイオマーカーの発現レベルが、前記阻害剤を投与した後に変化する、請求項1に記載の方法。
- 前記1以上の発毛バイオマーカーが、CD34、Lhx2、NFATc1、Axin2、FoxC1、OSMR、OSM、Jak3、FAS、Irf1、Ifnar1、Nr3c1、Stat5A、Il6st、Ptprc、Ghr、IL10ra、Il2rg、Pdgfra、Spfi1、Socs2、Stat5b、Crp、Il4、Prlr、Insr、IL2ra、Cebpd、Stat3、Jak1、Acvr2a、Sfrp4、Sox5、Cdh2、Fzd5、Wif1、Wnt2、Fzd8、Apc、Sox9、Ilk、Shh、Krt25、Dlx2、Prom1、S100a9、Vegfc、Ptgfr、Pdgfrl、Igfbp4、Gli2、Tyrp1、Syt4、Mlana、Pmel、Dct、Tyr、Sos1、Dbf4、Pax3、PIK3ca、Rps6kb1、Mlph、及びStx17からなる群から選択される、請求項14に記載の方法。
- 前記1以上のバイオマーカーの遺伝子発現の変化が定量的PCR又はその変法によって検出される、請求項14に記載の方法。
- 前記1以上のバイオマーカーの遺伝子発現の変化が酵素結合免疫吸着測定法又はその変法によって検出される、請求項14に記載の方法。
- 哺乳動物の被験体において毛の発毛を促進する方法であって、前記被験体の毛包に治療的有効量のJak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、及び/又はOSM−Rβの阻害剤を投与することを含む、方法。
- 前記毛包が休止初期相以外の相にある場合に前記投与を行う、請求項18に記載の方法。
- 前記毛包が成長期相にある、請求項19に記載の方法。
- 前記被験体がアンドロゲン性脱毛症、休止期脱毛、円形脱毛症、頭部白癬、完全脱毛症、貧毛症、遺伝性単純型貧毛症、前頭部線維化性脱毛症、瘢痕性脱毛症、扁平毛孔性苔癬、リング型脱毛症、瘢痕化脱毛症、非瘢痕化脱毛症、化学療法による脱毛症、又は全身性脱毛症を有する、請求項18に記載の方法。
- 前記阻害剤がJak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、若しくはOSM−Rβをコードする遺伝子の発現を特異的に阻害するアンチセンスRNA、siRNA、shRNA、microRNA、若しくはそれらの変異体若しくは修飾体、又は低分子である、請求項18に記載の方法。
- 前記阻害剤がルキソリチニブ(INCB 018424)である、請求項22に記載の方法。
- 前記阻害剤がトファシチニブ(CP690550)である、請求項22に記載の方法。
- 前記低分子が、ルキソリチニブ(INCB 018424)、トファシチニブ(CP690550)、AG490、モメロチニブ(CYT387)、パートシチニブ(SB1518)、バリシチニブ(LY3009104)、フェドラチニブ(TG101348)、BMS−911543、レスタウルチニブ(CEP−701)、フルダラビン、エピガロカテキン−3−ガレート(EGCG)、バリシチニブ、モメロチニブ、パクリチニブ、ペフィシチニブ、ABT494、AT9283、デセルノチニブ、フィルゴチニブ、ガンドチニブ、INCB 39110、PF 4965842、R348、AZD 1480、BMS 911543、セルデュラチニブ、INCB 052793、NS 018、C 410、CT 1578、JTE 052、PF 6263276、R 548、TG 02、ルンブリカス・レベルス抽出物、ARN 4079、AR 13154、UR 67767、CS510、VR588、DNX 04042、若しくはハイパーフォリン、又はそれらの組み合わせである、請求項22に記載の方法。
- 前記阻害剤がOSM−Rβ抗体である、請求項22に記載の方法。
- 前記被験体がヒトである、請求項18に記載の方法。
- 前記毛が頭皮若しくは顔にあるか、又は前記被験体の眉毛若しくは睫毛を構成するものである、請求項18に記載の方法。
- 前記毛が鼻毛である、請求項18に記載の方法。
- 前記阻害剤が局所投与される、請求項18に記載の方法。
- 前記阻害剤が経口投与される、請求項18に記載の方法。
- 1以上の発毛バイオマーカーの発現レベルが、前記阻害剤を投与した後に変化する、請求項18に記載の方法。
- 前記1以上のバイオマーカーが、CD34、Lhx2、NFATc1、Axin2、FoxC1、OSMR、OSM、Jak3、FAS、Irf1、Ifnar1、Nr3c1、Stat5A、Il6st、Ptprc、Ghr、IL10ra、Il2rg、Pdgfra、Spfi1、Socs2、Stat5b、Crp、Il4、Prlr、Insr、IL2ra、Cebpd、Stat3、Jak1、Acvr2a、Sfrp4、Sox5、Cdh2、Fzd5、Wif1、Wnt2、Fzd8、Apc、Sox9、Ilk、Shh、Krt25、Dlx2、Prom1、S100a9、Vegfc、Ptgfr、Pdgfrl、Igfbp4、Gli2、Tyrp1、Syt4、Mlana、Pmel、Dct、Tyr、Sos1、Dbf4、Pax3、PIK3ca、Rps6kb1、Mlph、及びStx17からなる群から選択される、請求項32に記載の方法。
- 前記1以上のバイオマーカーの遺伝子発現の変化が定量PCR又はその変法によって検出される、請求項32に記載の方法。
- 前記1以上のバイオマーカーの遺伝子発現の変化が酵素結合免疫吸着測定法又はその変法によって検出される、請求項32に記載の方法。
- 毛乳頭の誘導力を促進する方法であって、被験体の毛包に由来する毛乳頭3Dスフェアに治療的有効量のJak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、及び/又はOSM−Rβの阻害剤を投与することを含み、前記投与が被験体への前記毛乳頭スフェアの投与の前に行われる、方法。
- 前記毛乳頭3Dスフェアを続いて前記被験体に投与することで、アンドロゲン性脱毛症、休止期脱毛、円形脱毛症、頭部白癬、完全脱毛症、貧毛症、遺伝性単純型貧毛症、前頭部線維化性脱毛症、瘢痕性脱毛症、扁平毛孔性苔癬、リング型脱毛症、瘢痕化脱毛症、非瘢痕化脱毛症、化学療法による脱毛症、又は全身性脱毛症を治療する、請求項36に記載の方法。
- 前記阻害剤が、Jak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、若しくはOSM−Rβをコードする遺伝子の発現を特異的に阻害するアンチセンスRNA、siRNA、shRNA、microRNA、若しくはそれらの変異体若しくは修飾体、又は低分子である、請求項36に記載の方法。
- 前記阻害剤がルキソリチニブ(INCB 018424)である、請求項38に記載の方法。
- 前記阻害剤がトファシチニブ(CP690550)である、請求項38に記載の方法。
- 前記低分子が、ルキソリチニブ(INCB 018424)、トファシチニブ(CP690550)、AG490、モメロチニブ(CYT387)、パートシチニブ(SB1518)、バリシチニブ(LY3009104)、フェドラチニブ(TG101348)、BMS−911543、レスタウルチニブ(CEP−701)、フルダラビン、エピガロカテキン−3−ガレート(EGCG)、バリシチニブ、モメロチニブ、パクリチニブ、ペフィシチニブ、ABT 494、AT 9283、デセルノチニブ、フィルゴチニブ、ガンドチニブ、INCB 39110、PF 4965842、R348、AZD 1480、BMS 911543、セルデュラチニブ、INCB 052793、NS 018、C 410、CT 1578、JTE 052、PF 6263276、R 548、TG 02、ルンブリカス・レベルス抽出物、ARN 4079、AR 13154、UR 67767、CS510、VR588、DNX 04042、若しくはハイパーフォリン、又はそれらの組み合わせである、請求項38に記載の方法。
- 前記阻害剤がOSM−Rβ抗体である、請求項38に記載の方法。
- 前記被験体がヒトである、請求項36に記載の方法。
- 前記毛が頭皮若しくは顔にあるか、又は前記被験体の眉毛若しくは睫毛を構成するものである、請求項36に記載の方法。
- 前記毛が鼻毛である、請求項36に記載の方法。
- 前記阻害剤が局所投与される、請求項36に記載の方法。
- 前記阻害剤が経口投与される、請求項36に記載の方法。
- 1以上の発毛バイオマーカーの発現レベルが、前記阻害剤を投与した後に変化する、請求項36に記載の方法。
- 前記1以上のバイオマーカーが、CD34、Lhx2、NFATc1、Axin2、FoxC1、OSMR、OSM、Jak3、FAS、Irf1、Ifnar1、Nr3c1、Stat5A、Il6st、Ptprc、Ghr、IL10ra、Il2rg、Pdgfra、Spfi1、Socs2、Stat5b、Crp、Il4、Prlr、Insr、IL2ra、Cebpd、Stat3、Jak1、Acvr2a、Sfrp4、Sox5、Cdh2、Fzd5、Wif1、Wnt2、Fzd8、Apc、Sox9、Ilk、Shh、Krt25、Dlx2、Prom1、S100a9、Vegfc、Ptgfr、Pdgfrl、Igfbp4、Gli2、Tyrp1、Syt4、Mlana、Pmel、Dct、Tyr、Sos1、Dbf4、Pax3、PIK3ca、Rps6kb1、Mlph、及びStx17からなる群から選択される、請求項48に記載の方法。
- 前記1以上のバイオマーカーの遺伝子発現の変化が定量的PCR又はその変法によって検出される、請求項48に記載の方法。
- 前記1以上のバイオマーカーの遺伝子発現の変化が酵素結合免疫吸着測定法又はその変法によって検出される、請求項48に記載の方法。
- 哺乳動物の被験体において毛の発毛を誘導又は促進する治療法の効力を評価する方法であって、
(a)前記被験体から得られた毛包試料中の1以上の発毛バイオマーカーのレベルを判定することと、
(b)前記治療法の間の1以上の時間点において前記被験体から得られた毛包試料中の1以上の発毛バイオマーカーのレベルを判定することと、
を含み、
第1の試料と比較して、第2の又はその後の試料中の前記1以上のバイオマーカーに変化がある場合に前記治療法が前記被験体において発毛を誘導又は促進するのに効果的であると評価する、方法。 - 前記1以上のバイオマーカーが、CD34、Lhx2、NFATc1、Axin2、FoxC1、OSMR、OSM、Jak3、FAS、Irf1、Ifnar1、Nr3c1、Stat5A、Il6st、Ptprc、Ghr、IL10ra、Il2rg、Pdgfra、Spfi1、Socs2、Stat5b、Crp、Il4、Prlr、Insr、IL2ra、Cebpd、Stat3、Jak1、Acvr2a、Sfrp4、Sox5、Cdh2、Fzd5、Wif1、Wnt2、Fzd8、Apc、Sox9、Ilk、Shh、Krt25、Dlx2、Prom1、S100a9、Vegfc、Ptgfr、Pdgfrl、Igfbp4、Gli2、Tyrp1、Syt4、Mlana、Pmel、Dct、Tyr、Sos1、Dbf4、Pax3、PIK3ca、Rps6kb1、Mlph、及びStx17からなる群から選択される、請求項52に記載の方法。
- 前記1以上のバイオマーカーの遺伝子発現の変化が定量的PCR又はその変法によって検出される、請求項52に記載の方法。
- 前記1以上のバイオマーカーの遺伝子発現の変化が酵素結合免疫吸着測定法又はその変法によって検出される、請求項52に記載の方法。
- 哺乳動物の被験体において毛の発毛を誘導又は促進するキットであって、
(a)Jak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、及び/又はOSM−Rβの阻害剤と、
(b)薬学的に許容可能な担体と、
を備える、キット。 - 前記阻害剤が、Jak1、Jak2、Jak3、Tyk2、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、OSM、gp130、LIFR、若しくはOSM−Rβをコードする遺伝子の発現を特異的に阻害するアンチセンスRNA、siRNA、shRNA、microRNA、若しくはそれらの変異体若しくは修飾体、又は低分子である、請求項56に記載のキット。
- 前記阻害剤がルキソリチニブ(INCB 018424)である、請求項57に記載のキット。
- 前記阻害剤がトファシチニブ(CP690550)である、請求項57に記載のキット。
- 前記低分子が、ルキソリチニブ(INCB 018424)、トファシチニブ(CP690550)、AG490、モメロチニブ(CYT387)、パートシチニブ(SB1518)、バリシチニブ(LY3009104)、フェドラチニブ(TG101348)、BMS−911543、レスタウルチニブ(CEP−701)、フルダラビン、エピガロカテキン−3−ガレート(EGCG)、バリシチニブ、モメロチニブ、パクリチニブ、ペフィシチニブ、ABT 494、AT 9283、デセルノチニブ、フィルゴチニブ、ガンドチニブ、INCB 39110、PF 4965842、R348、AZD 1480、BMS 911543、セルデュラチニブ、INCB 052793、NS 018、C 410、CT 1578、JTE 052、PF 6263276、R 548、TG 02、ルンブリカス・レベルス抽出物、ARN 4079、AR 13154、UR 67767、CS510、VR588、DNX 04042、若しくはハイパーフォリン、又はそれらの組み合わせである、請求項57に記載のキット。
- 前記阻害剤がOSM−Rβ抗体である、請求項57に記載の方法。
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US201562157959P | 2015-05-07 | 2015-05-07 | |
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PCT/US2016/031541 WO2016179605A1 (en) | 2015-05-07 | 2016-05-09 | Methods and compositions for promoting hair growth |
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EP (1) | EP3291794A4 (ja) |
JP (1) | JP2018515501A (ja) |
KR (1) | KR20180002838A (ja) |
CN (1) | CN107847428A (ja) |
AU (1) | AU2016259023A1 (ja) |
CA (1) | CA2985185A1 (ja) |
IL (1) | IL255462A (ja) |
MX (1) | MX2017014253A (ja) |
WO (1) | WO2016179605A1 (ja) |
Cited By (2)
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JP2022544701A (ja) * | 2019-08-20 | 2022-10-20 | ケアジェン カンパニー,リミテッド | 発毛促進活性を有するペプチド、及びその用途 |
JP2022545242A (ja) * | 2019-08-20 | 2022-10-26 | ケアジェン カンパニー,リミテッド | 発毛促進活性を有するペプチド、及びその用途 |
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JP2019534304A (ja) * | 2016-11-10 | 2019-11-28 | ガラパゴス・ナムローゼ・フェンノートシャップGalapagos N.V. | 炎症性疾患の治療のための化合物及びその医薬組成物 |
WO2018167283A1 (en) * | 2017-03-17 | 2018-09-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the diagnosis and treatment of pancreatic ductal adenocarcinoma associated neural remodeling |
CN107334784A (zh) * | 2017-06-08 | 2017-11-10 | 深圳培元生物科技有限公司 | 利用巨噬细胞培养液促进毛囊再生的方法 |
CA3069990A1 (en) | 2017-08-01 | 2019-02-07 | Theravance Biopharma R&D Ip, Llc | Pyrazolo and triazolo bicyclic compounds as jak kinase inhibitors |
US20190142722A1 (en) * | 2017-11-10 | 2019-05-16 | The Trustees Of Columbia University In The City Of New York | Methods and compositions for promoting or inducing hair growth |
WO2019103572A1 (ko) * | 2017-11-27 | 2019-05-31 | (주)프로스테믹스 | Mirna를 포함하는 탈모 방지 또는 발모 촉진용 조성물 |
MX2020007062A (es) * | 2018-01-09 | 2021-03-09 | Dermavant Sciences GmbH | Composiciones farmacéuticas para la piel tópicas que contienen cerdulatinib y usos de estas. |
EP3746086A4 (en) * | 2018-01-31 | 2021-10-20 | TWI Biotechnology, Inc. | TOPICAL FORMULATIONS INCLUDING TOFACITINIB |
CN110423719B (zh) * | 2018-05-01 | 2024-02-27 | 云南济慈再生医学研究院有限公司 | 调控Jak-Stat通路使细胞分化、去分化、年轻化的技术及其应用 |
JP2021532066A (ja) * | 2018-06-04 | 2021-11-25 | ケミストリーアールエックス.Chemistryrx. | 発毛を刺激するための局所的組成物 |
CN113498352A (zh) | 2019-01-23 | 2021-10-12 | 施万生物制药研发Ip有限责任公司 | 作为jak抑制剂的咪唑并[1,5-a]吡啶、1,2,4-三唑并[4,3-a]吡啶和咪唑并[1,5-a]吡嗪 |
EP4065578A1 (en) | 2019-11-26 | 2022-10-05 | Theravance Biopharma R&D IP, LLC | Fused pyrimidine pyridinone compounds as jak inhibitors |
US20230241121A1 (en) * | 2020-03-31 | 2023-08-03 | North Carolina State University | Compositions and methods relating to exosomes derived from human dermal papilla cells |
CN112175947B (zh) * | 2020-09-01 | 2022-02-01 | 暨南大学 | 一种靶向抑制SOS1基因表达的siRNA及其应用 |
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US9109204B2 (en) * | 2006-02-28 | 2015-08-18 | The Trustees Of Columbia University In The City Of New York | Methods for compact aggregation of dermal cells |
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- 2016-05-09 AU AU2016259023A patent/AU2016259023A1/en not_active Abandoned
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- 2016-05-09 CA CA2985185A patent/CA2985185A1/en not_active Abandoned
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- 2016-05-09 WO PCT/US2016/031541 patent/WO2016179605A1/en active Application Filing
- 2016-05-09 CN CN201680040071.1A patent/CN107847428A/zh active Pending
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WO2014013014A1 (en) * | 2012-07-18 | 2014-01-23 | Fundació Privada Centre De Regulació Genòmica (Crg) | Jak inhibitors for activation of epidermal stem cell populations |
Cited By (4)
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JP2022544701A (ja) * | 2019-08-20 | 2022-10-20 | ケアジェン カンパニー,リミテッド | 発毛促進活性を有するペプチド、及びその用途 |
JP2022545242A (ja) * | 2019-08-20 | 2022-10-26 | ケアジェン カンパニー,リミテッド | 発毛促進活性を有するペプチド、及びその用途 |
JP7323706B2 (ja) | 2019-08-20 | 2023-08-08 | ケアジェン カンパニー,リミテッド | 発毛促進活性を有するペプチド、及びその用途 |
JP7323705B2 (ja) | 2019-08-20 | 2023-08-08 | ケアジェン カンパニー,リミテッド | 発毛促進活性を有するペプチド、及びその用途 |
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MX2017014253A (es) | 2018-04-20 |
EP3291794A1 (en) | 2018-03-14 |
CN107847428A (zh) | 2018-03-27 |
KR20180002838A (ko) | 2018-01-08 |
EP3291794A4 (en) | 2019-02-13 |
IL255462A (en) | 2018-01-31 |
US20180291378A1 (en) | 2018-10-11 |
AU2016259023A1 (en) | 2017-11-30 |
CA2985185A1 (en) | 2016-11-10 |
WO2016179605A1 (en) | 2016-11-10 |
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