JP2021521241A - オートファジーを活性化することによる発毛のための方法及び組成物 - Google Patents
オートファジーを活性化することによる発毛のための方法及び組成物 Download PDFInfo
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Abstract
Description
[0002] 本願は、2018年4月16日に出願された米国特許出願第62/658,113号(その全体が参照により本明細書中に援用される)の利益を主張する。
[0004] サイズが1.13kbである、「20190415_034044_183WO1_seq_ST25」という名称のASCIIテキストファイルの配列表の内容が2019年4月15日に作成され、EFS-Webを介して本願ととともに電子的に提出され、その全体が参照により本明細書中に援用される。
[0006] 本発明は、政府の支援を得て、アメリカ国立衛生研究所によって付与された認可番号HL090553及びAG049753の下で作成された。政府は、本発明における特定の権利を有する。
[0008] 毛髪の生物学的及び心理学的重要性は、十分に理解されている。哺乳類の発毛は、毛包の休止期(静止)相、成長期(再生)相及び退行期(退化)相の環状的反復からなる。この毛包サイクルは、毛包幹細胞(HFSC)の静止及び活性化を制御する内因性及び外因性シグナルの両方により調節される。不適切なHFSCの活性化及び増殖が、老化を含む極めて多数の生物学的及び病理学的状態下での脱毛症の根底にある。HFSCの活性化及び成長期の開始を促進し得る分子は、毛髪再生がどのように調節されるかを明らかにすることと、治療的及び美容的介入をもたらすこととの両方に役立つことがあることから、集中的に探索されている。
[0012] いくつかの実施形態では、本発明は、毛髪再生の刺激を、それを必要とする対象において行う方法であって、1又は複数のオートファジー誘導剤を対象に投与することを含む方法を対象とする。いくつかの実施形態では、本発明は、新たな発毛の刺激を、それを必要とする対象において行う方法であって、1又は複数のオートファジー誘導剤を対象に投与することを含む方法を対象とする。いくつかの実施形態では、本発明は、対象において脱毛を治療、阻害又は低減するための方法であって、1又は複数のオートファジー誘導剤を対象に投与することを含む方法を対象とする。いくつかの実施形態では、本発明は、対象において発毛を改善又は刺激するための方法であって、1又は複数のオートファジー誘導剤を対象に投与することを含む方法を対象とする。いくつかの実施形態では、本発明は、対象において色素沈着欠損を治療、阻害又は低減するための方法であって、1又は複数のオートファジー誘導剤を対象に投与することを含む方法を対象とする。いくつかの実施形態では、本発明は、対象において色素沈着生成を改善又は刺激するための方法であって、1又は複数のオートファジー誘導剤を対象に投与することを含む方法を対象とする。いくつかの実施形態では、脱毛は、老化している対象の結果である。いくつかの実施形態では、色素沈着欠損は、老化している対象の結果である。いくつかの実施形態では、対象は、老化しつつあり、及び/又は対象は、老化した対象である。いくつかの実施形態では、1又は複数のオートファジー誘導剤は、治療有効量で投与される。いくつかの実施形態では、治療有効量は、所与の期間にわたる数用量、例えば1週間又はそれを超えて一日量として投与される。
[0020] 本発明は、以下の図面を参照することによってさらに理解される。
[0031] オートファジーを誘導し、それにより他に休止期皮膚における毛髪再生(例えば、発毛及び毛包再生)を刺激する化合物が本明細書に開示される。それは、α−ケトグルタル酸(α−KG)、α−ケト酪酸(α−KB)であり、TOR及びAMPKシグナル伝達を侵害するラパマイシン及びメトホルミンなどの薬剤は、オートファジーを誘導し、それにより毛髪再生を刺激する。これらの薬剤による毛髪再生の刺激は、特定のオートファジー阻害剤により遮断され、オートファジーと毛髪再生との間の機構的結合が示唆される。この考えに合致して、増強されたオートファジーは、天然毛包サイクル中の成長期移行時に検出される。本明細書における実験では、オートファジーの誘導を強いることにより、休止期毛包の休止が活性化され得ることが示される。
[0053] 1又は複数のオートファジー誘導剤を含む医薬組成物を含む組成物が本明細書で検討される。用語「医薬組成物」は、対象における薬学的使用に適した組成物を指す。医薬組成物は、一般に有効量の活性薬剤、例えば1又は複数のオートファジー誘導剤及び薬学的に許容できる担体を含む。用語「有効量」は、所望の結果をもたらすのに十分な用量又は量を指す。所望の結果は、その用量又は量のレシピエントにおける客観的又は主観的改善、例えば長期生存、病態の有効な予防などを含み得る。医薬組成物は、1又は複数のオートファジー誘導剤に加えて、1又は複数の補足剤を含み得る。好適な補足剤の例として、国際公開第2018064468号に記載のようなα−ケト酪酸化合物及びグルタル酸化合物、成長因子(例えば、TGF−β2、IGF−1、KGF、HGF)などが挙げられる。
[0064] いくつかの実施形態では、本発明は、1又は複数のオートファジー誘導剤を任意選択的に組成物中において又は1又は複数の補足剤と組み合わせて含み、対象における脱毛を予防、阻害、低減又は治療するための1又は複数の試薬又は薬剤送達装置と一緒にパッケージングされたキットを提供する。いくつかの実施形態では、キットは、1又は複数のオートファジー誘導剤を、任意選択的に1又は複数の単位剤形でパックとして及び/又は薬剤送達デバイス、例えば予備充填シリンジにおいて一緒にパッケージングされて含む。
[0068] マウスにおける毛髪再生についてのアッセイ
[0069] 雄及び雌マウスの両方において、すべての化合物を試験した。あらゆる実験は、独立しており、少なくとも2回反復した。異なる薬剤によるいくつかの処置は、共有対照群と同時に実施した。C57BL/6J雄マウスは、6又は8週齢時にJackson Laboratories(Bar Harbor, ME)から得た。C57BL/6J雌マウスは、8週齢時にJackson Laboratories(Bar Harbor, ME)から得た。マウスに標準の固形飼料食餌を与え、試験全体を通して食物及び水への自由なアクセスを提供した。休止期におけるマウスを、雄において出生後の約43〜45日目(別段の指示がない限り)及び雌において58日目にそれぞれ背側を剪毛した。媒体対照(別段の指示がない限り、25μLのDMSO)又は試験化合物(別段の指示がない限り、25μLのDMSO中)を実験の持続期間(3〜6週)にわたり(別段の指示がない限り)一日おきに剪毛皮膚に局所適用した。皮膚色素沈着及び発毛の外観を監視し、写真及び映像により記録した。進行についても色素沈着レベル及び毛幹密度に基づいて0〜100の値に割り当て、0は、発毛なし(及び色素沈着なし)を示し、より大きい数は、高密な発毛のより暗い皮膚及びより大きい領域に対応する。異なるスコアを表す画像を図9に提示する。各マウスに対して、約250μLのPremium Lecithin Organogel(PLO)基剤(Transderma Pharmaceuticals Inc.)中のα−KG(Sigma, 75890)、オリゴマイシン(Cell Signaling, 9996L)、ラパマイシン(Selleckchem, S1039)、AICAR(Selleckchem, S1802)、メトホルミン(Sigma, PHR1084)、α−KB(Sigma, K401)、SMER28(Selleckchem, S8240)、オートフィニブ(Selleckchem, S8596)、バフィロマイシンA1(Selleckchem, S1413)又は指定の組み合わせを用いた。溶媒DMSOは、局所適用のため、PLO基剤とも混合した。毛髪サイクルのタイミングは、PLO基剤+DMSO対PLO基剤単独を用いて改変されなかった。
[0071] 経口α−KB処置では、高齢雄及び雌C57BL/6Jマウスを87週齢時に得た(NIAの高齢齧歯類コロニー)。マウスは、UCLAの制御されたSPF施設(22±2℃、6:00〜18:00、12時間/12時間の明/暗サイクル)に収容した。マウスに標準の固形飼料食餌を与え、試験全体を通して食物及び水への自由なアクセスを提供した。水(媒体対照)又は飲料水中のα−KB(90mg/kg体重)のいずれかによる処置は、マウスが101週齢に達したときに開始した。局所的α−KB処置では、高齢雄C57BL/6Jマウスを21月齢時に得て(NIAの高齢齧歯類コロニー)、翌週に剪毛し、α−KB(32mM)で1か月間、一日おきに局所的に処置した。すべての実験は、UCLA Chancellor’s Animal Research Committeeによって認可された。
[0073] マウス背側皮膚を、組織学的及び分子的分析のために収集する前に剪毛した。次に、全厚皮膚組織を10%ホルマリン溶液(Sigma,HT501128)で一晩固定し、脱水し、パラフィンで包埋した。5μmのパラフィン切片に対して、ヘマトキシリン/エオシン染色及び免疫組織化学をKi−67(Cell Signaling, 12202)、IL−6(Abcam, ab6672)又はF4/80(Bio-Rad, MCA497G)について実施した。X20の倍率でのLeica Aperio ScanScope AT明視野システムにより、画像を取得した。
[0075] 雄マウスを剪毛し、出生後43日目から一日おきに処置した。5日後、休止期皮膚サンプルを収集し、ステージを確認した。マウス皮膚組織ライセートを、FastPrep 24(MP Biomedicals)による、プロテアーゼ阻害剤(Roche, 11836153001)及びホスファターゼ阻害剤(Sigma, P5726)を有するT-PER Tissue Protein Extraction Buffer(Thermo Scientific, 78510)中での均質化により調製した。遠心分離により組織及び細胞片を除去し、5%β−メルカプトエタノールを含有する1×SDS負荷緩衝液中でライセートを5分間煮沸した。次に、サンプルに対して、NuPAGE Novexの12%ビス−トリスゲル(Invitrogen, NP0343BOX)上でSDS−PAGEを施し、LC3(Novus, NB100 2220)、p62(Sigma, P0068)、Phospho-Beclin-1(Ser15)(マウスにおけるSer14に対応する)(Cell Signaling, 84966)、Phospho-Beclin-1(Ser93)(マウスにおけるSer91に対応する)(Cell Signaling, 14717)、Beclin-1(Abcam, ab207612)又はGAPDH(Ambion, AM4300)に対する抗体を用いて、ウエスタンブロッティングを実施した。
[0077] 処置後24時間後、休止期皮膚サンプルを収集し、TRIzol試薬(Invitrogen)を用いて全厚マウス皮膚組織から全RNAを単離した。iScript Reverse Transcription Supermix(Bio-Rad)を用いて、cDNAを合成した。定量的RT−PCRのためにiTaq Universal SYBR Green Supermix(Bio-Rad)及びBio-Rad CFX Connect機器を用いた。RT−qPCRに用いたプライマー配列は、以下の通りである。
p62フォワード:
配列番号1:GAAGAATGTGGGGGAGAGTGTGG
p62リバース:
配列番号2:TGCCTGTGCTGGAACTTTCTGG
B2mフォワード:
配列番号3:CAGCATGGCTCGCTCGGTGAC
B2mリバース:
配列番号4:CGTAGCAGTTCAGTATGTTCG
[0079] すべての処置を少なくとも2回反復した。データは、生物学的複製を表す。あらゆる図面において、適切な統計学的検定を用いた。データは、各図面において記載の統計学的検定の前提を満たす。すべての図面において、平均±標準偏差をプロットする。
[0081] 必要に応じて、以下の参考文献は、参照により本明細書中に援用される。
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Claims (10)
- 対象において毛髪再生を改善若しくは刺激し;脱毛を治療、阻害若しくは低減し;発毛を改善若しくは刺激し;色素沈着欠損を治療、阻害若しくは低減し;及び/又は色素沈着生成を改善若しくは刺激するための方法であって、1又は複数のオートファジー誘導剤を前記対象に投与することを含む方法。
- 前記1又は複数のオートファジー誘導剤は、ATPシンターゼ阻害剤、TOR阻害剤、AMPKアクチベーター及び/又はTOR非依存性のオートファジーエンハンサーである、請求項1に記載の方法。
- 前記1又は複数のオートファジー誘導剤は、マクロライド、例えばオリゴマイシンである、請求項1に記載の方法。
- 前記1又は複数のオートファジー誘導剤は、ラパマイシン又はラパマイシン誘導体である、請求項1に記載の方法。
- 前記1又は複数のオートファジー誘導剤は、ビグアナイド、例えばメトホルミンである、請求項1に記載の方法。
- 前記1又は複数のオートファジー誘導剤は、5−アミノイミダゾール−4−カルボキサミドリボヌクレオチド(AICAR)である、請求項1に記載の方法。
- 前記1又は複数のオートファジー誘導剤は、SMER28である、請求項1に記載の方法。
- 前記1又は複数のオートファジー誘導剤は、マクロライド、例えばオリゴマイシン、ラパマイシン又はラパマイシン誘導体、ビグアナイド、例えばメトホルミン、5−アミノイミダゾール−4−カルボキサミドリボヌクレオチド(AICAR)、SMER28及びそれらの任意の組み合わせからなる群から選択される、請求項1に記載の方法。
- 前記1又は複数のオートファジー誘導剤は、経口、非経口又は局所投与のために製剤化される、請求項1〜8のいずれか一項に記載の方法。
- 前記1又は複数のオートファジー誘導剤は、ゲル剤、クリーム剤、軟膏剤、ペースト剤又はローション剤として製剤化される、請求項1〜8のいずれか一項に記載の方法。
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US20210145833A1 (en) | 2021-05-20 |
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KR20210008481A (ko) | 2021-01-22 |
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