JP5841234B2 - フケ/脂漏性皮膚炎の治療に有効な皮膚活性剤を特定及び評価するためのシステム、モデル、及び方法 - Google Patents
フケ/脂漏性皮膚炎の治療に有効な皮膚活性剤を特定及び評価するためのシステム、モデル、及び方法 Download PDFInfo
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Description
図2、4、及び5を参照して、撹乱因子と、皮膚組織/フケ状態と、皮膚組織/フケ状態に関連付けられる遺伝子と間の関係を特定に使用するための本発明によるシステム及び装置のいくつかの例をここで説明する。システム10は、計算装置12、14、計算装置12と関連付けられるコンピュータ読み取り可能な媒体16、及び通信網18のうちの1つ以上を備える。
一部の実施形態では、本発明の方法は、複数の遺伝子発現プロファイリング実験から得られたデータを含む複数のインスタンス(例えば、22、24、26)を少なくとも第1のデジタルファイル20に投入する工程を含んでもよく、これらの実験のうちの1つ以上は、例えば、ケラチノサイト細胞(又は他の皮膚細胞、例えばヒト皮膚等価物培養物若しくはエクスビボ培養したヒト皮膚)を少なくとも1つの撹乱因子に暴露することを含む。説明を簡単にするために、下記で説明する遺伝子発現プロファイリングは、マイクロアレイ実験の状況とする。
本発明の一部の方法は、対象皮膚状態、特にフケに関連付けられる上方制御及び下方制御された遺伝子を表す遺伝子発現シグネチャを特定する工程を含む。フケの病因は通常、複雑な過程を含み、これには、多数の既知の及び未知の外因性及び内因性因子、並びに比較的短い期間にわたってはわずかであるが、長い期間にわたってはわずかではない、そのような因子に対する応答を伴う。これは、特定の標的、遺伝子、又は作用機序が興味の対象である、薬物開発及び薬物スクリーニングの方法で通常観察されるものとは対照的である。フケ状態に関連する独特のスクリーニングの困難により、対象状態を表す遺伝子発現シグネチャの質は、撹乱因子への応答に実際に関連付けられる遺伝子発現データと、バックグラウンド発現データとを区別するために重要となり得る。
図6及び図7を参照すると、1つ以上のフケ遺伝子シグネチャを用いて複数のインスタンスに問い合わせるための方法をここで説明する。概して、本方法は、1つ以上のフケ遺伝子シグネチャを用いて複数のインスタンスに問い合わせる工程と、統計的方法を適用して、シグネチャ遺伝子がインスタンス中の制御された遺伝子とどれほど強く一致するかを決定する工程を含む。正の関連は、インスタンス中の上方制御された遺伝子の中で、上方制御されたシグネチャリスト中の遺伝子が濃縮されている場合、及びインスタンス中の下方制御された遺伝子の中で、下方制御されたシグネチャリスト中の遺伝子が濃縮されている場合に存在する。一方、インスタンスの下方制御された遺伝子の中にシグネチャの上方制御された遺伝子が主に認められる場合、及びその逆の場合には、これは負の関連としてスコアされる。図6は、シグネチャ90と、プローブID 102を含むインスタンス104との正の関連の極端な例を概略的に図示しており、このときインスタンスのプローブIDは、最も上方制御されたものから最も下方制御されたものへと順序付けられる。この例では、上方リスト97及び下方リスト99を含む遺伝子シグネチャ90のプローブID 100(例えば、X1、X2、X3、X4、X5、X6、X7、X8)は、インスタンス104の最も上方制御及び下方制御されたプローブID 102とそれぞれ一対一の正の対応を有する。同様に、図7は、シグネチャ94と、プローブID 90を含むインスタンス88との負の関連の極端な例を概略的に図示しており、このときインスタンスのプローブIDは、最も上方制御されたものから最も下方制御されたものへと順序付けられる。この例では、上方リスト93のプローブID(例えば、X1、X2 X3、X4)は、インスタンス88の最も下方制御された遺伝子と正確に一致し、下方リスト95のプローブID(例えば、X5、X6、X7、X8)は、インスタンス88の最も上方制御されたプローブIDと正確に一致する。図8は、中間的関連の極端な例を概略的に図示しており、このとき正であれ負であれ、インスタンスの上方及び下方制御された遺伝子の中に、シグネチャの上方及び下方制御された遺伝子の一致する濃縮は存在しない。したがって、遺伝子シグネチャ108(上方リスト107及び下方リスト109を含む)のプローブID 106(例えば、X1、X2 X3、X4、X5、X6、X7、X8)は、インスタンス112のプローブID 110との序列に関して散在し、このときインスタンスのプローブIDは、最も上方制御されたものから最も下方制御されたものへと順序付けられる。上記の実施形態は、遺伝子シグネチャが皮膚状態の最も顕著に上方及び下方制御された遺伝子を表す上方リスト及び下方リストの双方を含む場合の過程を図示しているが、対象状態に関連付けられる主要なバイオロジーが、主に1つの方向への遺伝子制御を示すときに、遺伝子シグネチャが上方リストのみ又は下方リストのみを含んでもよいことが意図される。
本研究者らは、皮膚疾患状態のインビトロモデルを得るため、及び病態のインビトロ又はインビボシミュレーションの十分性を評価するためのCマップの新規の用途を発見した。
一般に、フケ又はフケ関連皮膚状態の治療用に特定された皮膚活性剤は、当該技術分野において周知の化粧品組成物及び製剤パラメーターに従って適用することができる。治療、適用、制御、又は改善の様々な方法は、本発明の方法によって特定される皮膚活性剤を含むスキンケア組成物を利用してもよい。組成物は、毛髪及び頭皮に関する日常的衛生法の一部として適用してもよく、シャンプー、コンディショナー、ヘアスプレー、クリーム、軟膏等として製剤化されてもよい。組成物は、フケ、又は他の皮膚疾患に存在するフケの症状を治療するために頭皮に適用することができる。
インスタンスの生成
個々の実験(バッチと称する)は、概して、ビヒクルコントロール(例えば、DMSO)の6個の複製、使用する細胞型に強い再現可能効果を与える陽性コントロールの2個の複製サンプル、及び試験材料/撹乱因子のサンプルを含む、Affymetrix GeneChip(登録商標)技術プラットフォームを用いて解析される30〜96個のサンプルを含む。試験材料の複製は、バッチ影響のため、別のバッチで実施する。GeneChip(登録商標)解析に十分なRNA(2〜4μgの全RNA収量/ウェル)を提供するために、インビトロ試験を6ウェルプレートで実施した。
フケ発現シグネチャの取得
20,000個を上回る遺伝子の転写産物に相補的な54,613個のプローブセットを含むAffymetrix HG−U133 Plus 2.0 GeneChipで、サンプルを解析した。しかしながら、使用した提供されるデータベース中のインスタンスは、Plus 2.0 GeneChip上に存在するものサブセットである、22,214個のプローブセットを含むAffymetrix HG−U133A 2.0 GeneChipを用いた遺伝子発現プロファイリング実験から得られた。したがって、臨床データから遺伝子発現シグネチャを生成する際には、HG−U133A 2.0遺伝子チップに含まれるものについてプローブセットをフィルターにかけた。
a.統計的尺度によるフィルタリング。例えば、好適な統計的尺度は、t検定からのp値、ANOVA、相関関数、又は他のモデルに基づく解析であってよい。一例として、p値を統計的尺度として選択し、カットオフ値p=0.05を選択することができる。適切なコントロールと比較して、ある合理的な統計的有意性のカットオフを満たす遺伝子にシグネチャリストを限定することは、対象となる生物学的状態の特徴を示す遺伝子の選択を可能にするために重要である。これは、測定値周囲のノイズを考慮しない倍率変化値を使用するよりも好ましい。符号が付されて、遺伝子発現変化の方向性(つまり、上方又は下方制御)を提供し、また統計的有意性を提供することから、t統計量を用いてシグネチャ中のプローブセットを選択した。
b.プローブセットの並べ替え。すべてのプローブセットは、統計的尺度を用いて、上方制御されたセットと下方制御されたセットとに並べ替えられる。例えば、p値を計算するためにt検定を使用した場合、p値が常に正であることから、t統計量の値(正及び負)を用いてリストを並べ替える。並べ替えられたt統計量は、最も有意なp値を有するセットをリストの最上部及び最下部に、最も有意でないものを中央付近に配置する。
c.遺伝子発現シグネチャの作成。作成されたフィルタリング及び並べ替えされたリストを使用して、上部及び下部から好適な数のプローブセットを選択して、好ましくは上部から選択されたセットが下部から選択されたセットとほぼ同じ数を有する遺伝子発現シグネチャを作成する。例えば、作成される遺伝子発現シグネチャは、少なくとも約10個、50個、70個、100個、200個、又は300個、及び/又は約800個、600個、400個、又は約100個未満の、チップ上のプローブセットに対応する遺伝子を有してもよい。プローブセットの数は、遺伝子の数とほぼ一致するが、ほとんどの遺伝子は、1つを超えるプローブセットによって表される。本明細書で使用する「遺伝子の数」という表現が「プローブセットの数」という表現と概ね一致することは理解される。
この実施例は、複雑なフケ状態をケラチノサイトに基づくモデル及びスクリーニング方法によって表すことができること、並びにケラチノサイトからの遺伝子発現プロファイル及びフケ遺伝子発現シグネチャを使用して、フケ用の化粧剤候補を確実にスクリーニングできることを説明している。本実施例は、潜在的な新しい皮膚活性剤を生成するためにCマップに問い合わせるのに有用な、またフケ防止有効性について皮膚活性剤をスクリーニングするのに有用な、生理学的主題シグネチャを決定するための遺伝子発現プロファイルの使用を更に説明している。
本実施例は、本発明の一実施形態によるフケ状態のインビトロモデルの検証、及び皮膚活性剤出力候補を得るためにCマップ問い合わせを導く主題シグネチャの使用を説明している。
本実施例は、フケの病因を調査するため、及びベンチマークフケ防止活性剤の作用機序を判定するための転写プロファイリングの用途を説明している。
2つの別個の研究を実施した。
1)18〜75歳の健康な男性被験者31名を、公表されている剥離スコアリング手順である接着式頭皮剥離スコア(ASFS)で定義されているように、「非フケ」の16名と「フケ」の15名との2つの群に分割した。1つは現在剥離中の部位「発症」で、もう1つは非剥離部位「非発症」で、2つの全層4ミリメートルパンチ生検をフケ被験者から採取した。非罹患者からは、解剖学的に一致する部位で単一の生検を採取した。
2)二重盲検治療試験において、健康な男性被験者45名(ASFS基準で定義されるフケ30名及び非フケ15名、18〜50歳)が登録され、臨床施設において週3回3週間、1% ZPTを含む市販のフケ防止シャンプー(フケ被験者15名)又はZPTを含まない同じ配合物(フケ被験者15名及び非フケ被験者15名)のいずれかで洗髪した。ベースライン時及び試験終了時に、3群すべてから全層2mm生検を採取した。生検から全RNAを抽出し、Affymetrix GeneChip(登録商標)解析のために標識した。合成された標的cRNAを、Affymetrix HG U133Aマイクロアレイにハイブリダイズさせた。統計的に分析したデータを有意性でフィルタリングして(p<.05、フケ対非フケ;ZPT治療対ビヒクル治療)、標準的バイオインフォマティクスアプローチで、発現レベルの増加又は減少を示す遺伝子を特定した。
図10は、すべての個人について、フケ対非フケで観察された差次的遺伝子発現を示している。
ZPTのトランスクリプトミクス試験計画を図18に記載する。注目すべきことに、この試験は、頭皮の遺伝子発現に対するZPTの効果の二重盲検ビヒクル対照評価である。臨床施設において試験担当者が被験者の毛髪/頭皮を週3回3週間洗浄した。ベースライン時及び試験終了時に全層2mmパンチ生検を採取した。剥離スコア、表皮厚、痒み、及びヒスタミンを確実に低下させ、また角質層(SC)バイオマーカープロファイルを実質的に回復することが知られている条件下で、製品暴露を行った。
Claims (12)
- フケに関連付けられる撹乱因子と遺伝子との間の関連性の特定に使用するためのデータアーキテクチャを構築し実行するための方法であって、
(a)コントロールヒト表皮ケラチノサイト細胞の遺伝子発現プロファイルを提供する工程と、
(b)少なくとも1つの撹乱因子に暴露されたヒト表皮ケラチノサイト細胞の遺伝子発現プロファイルを生成する工程と、
(c)(a)及び(b)の前記遺伝子発現プロファイルを比較することにより、前記少なくとも1つの撹乱因子に応答して差次的に発現された遺伝子を特定する工程と、
(d)前記差次的に発現された遺伝子を表す識別子であって、前記遺伝子の前記差次的発現に従って順序付けられた、識別子を含む順序付きリストを作成する工程と、
(e)前記順序付きリストをケラチノサイトインスタンスとして、少なくとも1つのコンピュータ読み取り可能な媒体上に格納する工程と、
(f)(a)〜(e)を繰り返して、格納したケラチノサイトインスタンスのデータアーキテクチャを構築する工程であって、工程(b)の前記少なくとも1つの撹乱因子が、各ケラチノサイトインスタンスで定性的又は定量的に異なる、格納したケラチノサイトインスタンスのデータアーキテクチャを構築する工程と、
(g)フケの治療に有効な皮膚活性剤を特定するために有用な関連性を生成するために、データアーキテクチャを実行する工程であって、前記工程は、フケ遺伝子発現シグネチャを用いて前記データアーキテクチャを問い合わせる工程を含み、該問い合わせる工程が、前記フケ遺伝子発現シグネチャをそれぞれの格納されたケラチノサイトインスタンスと比較することを含み、前記フケ発現シグネチャが、状態と関連して差次的に発現される遺伝子を表す、データアーキテクチャを実行する工程と
を含む方法。 - プログラム可能なコンピュータを使用して、工程(c)、(d)、(e)、(f)および(g)のうちの1つ以上を実行することを含むことを特徴とする請求項1に記載の方法。
- 前記生成工程が、処理された細胞から生体サンプルを抽出し、前記生体サンプルをマイクロアレイ解析に供することによって実行されることを特徴とする請求項1又は2に記載の方法。
- 前記マイクロアレイが、網羅的マイクロアレイ又は特異的マイクロアレイであり、
前記特異的マイクロアレイが、細胞表現型の遺伝子発現シグネチャに対応する遺伝子にハイブリダイズするオリゴヌクレオチドを含む、
ことを特徴とする請求項1から3のいずれか一項に記載の方法。 - 少なくとも1つの撹乱因子が、抗真菌剤であることを特徴とする請求項1から4のいずれか一項に記載の方法。
- 抗真菌剤が、ジンクピリチオン(ZPT)、硫化セレン、又はそれら双方を含むことを特徴とする請求項1から5のいずれか一項に記載の方法。
- 前記フケ発現シグネチャが、
(i)コントロールと比較して、フケ状態で上方制御された発現を有する遺伝子を特定する工程と、
(ii)コントロールと比較して、前記フケ状態で下方制御された発現を有する遺伝子を特定する工程と、
(iii)(i)及び(ii)で特定された複数の遺伝子に対応する識別子を含む前記フケ遺伝子発現シグネチャに関連付けられる1つ以上の遺伝子発現シグネチャリストを作成する工程と、
前記1つ以上の遺伝子発現シグネチャリストを前記少なくとも1つのコンピュータ読み取り可能な媒体上に格納する工程と、
を含む方法によって構築される、
ことを特徴とする請求項1から6のいずれか一項に記載の方法。 - 生体サンプルが、前記フケ状態を呈するヒト被験者から採取された少なくとも1つの皮膚サンプルから抽出され、
前記少なくとも1つの皮膚サンプルの遺伝子発現プロファイルが、前記工程(i)及び(ii)のうちの少なくとも1つより前に生成される、
ことを特徴とする請求項7に記載の方法。 - 前記皮膚サンプルが、前記ヒト被験者の頭皮の表皮層に由来する細胞を含むことを特徴とする請求項1から8のいずれか一項に記載の方法。
- 前記比較が、複数のインスタンスそれぞれに関連性スコアを割り当てることを更に含むことを特徴とする請求項1から9のいずれか一項に記載の方法。
- 皮膚科学的に許容可能な担体と少なくとも1つの撹乱因子とを含むフケ防止組成物を製剤化する工程を更に含み、
前記少なくとも1つの撹乱因子に関連付けられる前記インスタンスの前記関連性スコアが、負相関を有する、
ことを特徴とする請求項1から10のいずれか一項に記載の方法。 - ヒト表皮ケラチノサイト細胞を含むサンプルを受容するためのマイクロアレイスキャナを提供する工程と、
遺伝子発現データを、前記スキャナから前記少なくとも1つのコンピュータ読み取り可能な媒体を含む第2のプログラム可能なコンピュータに送信するための第1のプログラム可能なコンピュータを構成する工程を更に含む、
ことを特徴とする請求項1から11のいずれか一項に記載の方法。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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US201161470131P | 2011-03-31 | 2011-03-31 | |
US61/470,131 | 2011-03-31 | ||
US201161488501P | 2011-05-20 | 2011-05-20 | |
US61/488,501 | 2011-05-20 | ||
US201161519504P | 2011-05-24 | 2011-05-24 | |
US61/519,504 | 2011-05-24 | ||
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KR20130058107A (ko) | 2011-11-25 | 2013-06-04 | (주)아모레퍼시픽 | 콩으로부터 저분자 펩타이드 추출물을 분리하는 방법 및 이를 함유하는 화장료 조성물 |
US20130165470A1 (en) | 2011-12-21 | 2013-06-27 | The Procter & Gamble Company | Methods for Detecting and Treating Rhinovirus Infection |
US20130217589A1 (en) | 2012-02-22 | 2013-08-22 | Jun Xu | Methods for identifying agents with desired biological activity |
EP2831271B1 (en) | 2012-03-30 | 2018-07-25 | The Procter and Gamble Company | System for identifying connections between perturbagens and genes associated with a skin hyperpigmentation condition |
KR101458383B1 (ko) | 2012-05-10 | 2014-11-05 | 한국콜마주식회사 | 도인발효추출물, 호박씨발효추출물 및 강화약쑥 추출물을 포함하는 피부 보습용 화장료 조성물 |
US9920357B2 (en) | 2012-06-06 | 2018-03-20 | The Procter & Gamble Company | Systems and methods for identifying cosmetic agents for hair/scalp care compositions |
US9593363B2 (en) | 2012-06-18 | 2017-03-14 | The Procter & Gamble Company | Methods and models for assessing anti-aging benefits of agents |
WO2014028568A1 (en) | 2012-08-15 | 2014-02-20 | The Procter & Gamble Company | Systems, models and methods for identifying and evaluating skin-active agents effective for treating an array of skin disorders |
WO2015031708A1 (en) | 2013-08-30 | 2015-03-05 | The Procter & Gamble Company | Methods of identifying cosmetic agents for treating periorbital dyschromia and systems therefor |
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2012
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- 2012-03-30 WO PCT/US2012/031509 patent/WO2012135651A1/en active Application Filing
- 2012-03-30 JP JP2014502843A patent/JP5841234B2/ja active Active
- 2012-03-30 EP EP12716832.6A patent/EP2691539B1/en active Active
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EP2691539A1 (en) | 2014-02-05 |
US20120258074A1 (en) | 2012-10-11 |
US10072293B2 (en) | 2018-09-11 |
JP2014515606A (ja) | 2014-07-03 |
MX2013010977A (es) | 2013-10-30 |
WO2012135651A1 (en) | 2012-10-04 |
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