JP2021523365A - 腎線維症を検出するための組成物および方法 - Google Patents
腎線維症を検出するための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2018年5月11日に出願された米国特許仮出願第62/670,344号に基づく優先権を主張する。米国特許仮出願第62/670,344号の開示は、その内容全体が参照により本明細書に組み込まれる。
本開示は、腎線維症を診断するための方法および組成物に関する。
腎線維症の背景にある生物学的メカニズムは大部分未知であり、この状態の信頼できる指標を提供するバイオマーカーは、たとえあったとしてもわずかである。自身のライフスタイルを調整し、その結果、症状の発症が生じることおよび/または疾患が更に進行することが促進されるのを回避するのは腎線維症に対して感受性を有する個体にとって有益であろう。したがって、腎線維症に関するバイオマーカーを開発し、評価することが必要である。
本開示は、さまざまな方法で具体化してもよい。
用語および定義
本開示をより容易に理解するために、ある特定の用語を最初に定義する。以下の用語および他の用語に関する追加の定義は、本明細書全体にわたって明記する。
概要
腎線維症を診断するための方法および組成物
ペプチド、ポリペプチドおよびタンパク質アッセイ
抗体検出
LC−MS/MSアッセイ
核酸アッセイ
対立遺伝子特異的増幅
対立遺伝子特異的プライマー伸長
単一ヌクレオチドプライマー伸長
オリゴヌクレオチドライゲーションアッセイ
ハイブリダイゼーションアプローチ
定量的およびリアルタイムPCR
アレイ
DNAシークエンシング
画像を、「リード」と通常称される、各断片の3’末端の25から60塩基を繰り返す塩基の文字列に変換する。次いでリードを、分析されたDNAに関する参照配列と比較する。25塩基の任意の所与の文字列は、ヒトゲノムにおいて典型的には1回だけ発生するため、大部分のリードはヒトゲノムにおいて1つの特定の場所に「整列させる」ことができる。最後に、各ゲノム領域のコンセンサス配列を、利用可能なリードから構築し、その位置における参照の正確な配列と比較してもよい。コンセンサス配列と参照との間の任意の差を配列バリアントと称する。
検出可能な部分
蛍光染料
酵素
放射性同位体
システム
キット
腎線維症バイオマーカーを識別するための方法
データマイニング
疾患適応モデルの構築
モデル検証
候補バイオマーカーのランキング
分子
腎線維症に関するバイオマーカー
本明細書において開示するバイオマーカーは、上記で検討した技術のいずれかを使用するか、または一部の場合では、以下に開示する非限定的なアッセイのうちの1つによって測定してもよい。
トランスフォーミング増殖因子ベータ1(TGFβ1)
ウロモデュリン(UMOD)
結合組織増殖因子(CTGF)
EGFR
カドヘリン(CDH1)、SMADファミリーメンバー(例えば、SMAD4)
カドヘリン−1は、CAM120/80または上皮カドヘリン(E−カドヘリン)としても公知であり、CDH1遺伝子によってコードされるタンパク質である。CDH1は、CD324(分化クラスター324)としても表されており、腫瘍サプレッサーである。
ガレクチン−1およびガレクチン−3
セルピンファミリーEメンバー1(SERPINE1)
メタロペプチダーゼ(MMP2、MMP7、およびMMP9)
ネフリン(NPHS1)およびポドシン(NPHS2)
シグナル伝達転写活性化因子3(STAT3)
細胞間接着分子1(ICAM1)
インターロイキン6(IL6)
血管内皮増殖因子A(VEGFA)
インターロイキン1ベータ(IL1B)
C−Cモチーフケモカインリガンド2(CCL2)
肝細胞増殖因子(HGF)
コルチコステロンおよびアルドステロン
ADAMメタロプロテイナーゼドメイン17(ADAM17)
フィブロネクチン1(FN1)
クルッペル様因子15(KLF15)
核因子カッパーBサブユニット1(NFKB1)
核受容体サブファミリー3グループCメンバー2(NR3C2)
(実施例2)
実施形態
個体から生物学的試料を得るステップと;
生物学的試料中の、バイオマーカーの量、および/またはバイオマーカーをコードするかもしくはその発現を調節する核酸(例えばゲノムDNAまたはmRNA)の量もしくはそこにおける突然変異を測定することと
を含む方法。
個体から生物学的試料を得るステップと;
バイオマーカーの量、および/またはバイオマーカーをコードするかもしくはその発現を調節する核酸(例えばゲノムDNAまたはmRNA)の量もしくはそこにおける突然変異を測定するステップと;
生物学的試料中の、バイオマーカーの量、および/またはバイオマーカーをコードするかもしくはその発現を調節する核酸の量もしくはそこにおける突然変異を、バイオマーカーに関する対照値と比較することと
を含む方法。
個体から試料を得ることと;
試料中の、バイオマーカーの量、および/またはバイオマーカーをコードするかもしくはその発現を調節する核酸(例えばゲノムDNAまたはmRNA)の量もしくはそこにおける突然変異を測定することと;
試料中の、バイオマーカーの量、および/またはバイオマーカーをコードするかもしくはその発現のうちの少なくとも1つの発現を調節する核酸の量もしくはそこにおける突然変異を、バイオマーカーに関する対照値と比較することと;
個体における遺伝子発現と対照値との間の差が、個体が、腎線維症を発症している場合があるか(すなわち、その存在を診断されるか)、または発症することに対する感受性が強い(すなわち、そのリスクが高い)ことを示す場合に、腎線維症に関して個体を処置するかまたは腎線維症が発症する速度を減少させることと
を含む方法。
Claims (24)
- 個体において腎線維症と関連するバイオマーカーを検出するための方法であって、
前記個体から試料を得ることと;
生物学的試料中の、前記バイオマーカーの量、および/または前記バイオマーカーをコードするかもしくはその発現を調節する核酸(例えばゲノムDNAまたはmRNA)の量もしくはそこにおける突然変異を測定することであって、前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)またはメタロペプチダーゼ2(MMP2)のうちの少なくとも1つを含むことと
を含む方法。 - 前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)、メタロペプチダーゼ2(MMP2)、ウロモデュリン(UMOD)、SMADファミリーメンバー2(SMAD2)、またはSMADファミリーメンバー7(SMAD7)のうちの少なくとも1つを含む、請求項1に記載の方法。
- 前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)、メタロペプチダーゼ2(MMP2)、ウロモデュリン(UMOD)、SMADファミリーメンバー2(SMAD2)、SMADファミリーメンバー7(SMAD7)、結合組織増殖因子(CTGF)、またはC−Cモチーフケモカインリガンド2(CCL2)のうちの少なくとも1つを含む、請求項1または2に記載の方法。
- 前記バイオマーカーが、コルチコステロン、アルドステロン、ADAMメタロペプチダーゼドメイン17(ADAM17)、C−Cモチーフケモカインリガンド2(CCL2)、カドヘリン1(CDH1)、結合組織増殖因子(CTGF)、表皮増殖因子受容体(EGFR)、フィブロネクチン1(FN1)、ガレクチン−1(LGALS1)、ガレクチン−3(LGAS3)、肝細胞増殖因子(HGF)、細胞間接着分子1(ICAM1)、インターロイキン1ベータ(IL1B)、インターロイキン6(IL6)、クルッペル様因子15(KLF15)、マトリックスメタロペプチダーゼ2(MMP2)、マトリックスメタロペプチダーゼ7(MMP7)、マトリックスメタロペプチダーゼ9(MMP9)、核因子カッパーBサブユニット1(NFKB1)、ネフリン(NPHS1)、ポディシン(NPHS2)、核受容体サブファミリー3グループCメンバー2(NR3C2)、セルピンファミリーEメンバー1(SERPINE1)、SMADファミリーメンバー2(SMAD2)、SMADファミリーメンバー3(SMAD3)、SMADファミリーメンバー4(SMAD4)、SMADファミリーメンバー7(SMAD7)、シグナル伝達転写活性化因子3(STAT3)、トランスフォーミング増殖因子ベータ1(TGFB1)、ウロモデュリン(UMOD)、または血管内皮増殖因子A(VEGFA)のうちの少なくとも1つを含む、請求項1から3のいずれか一項に記載の方法。
- 前記測定するステップが、タンパク質測定、イムノアッセイ、フローサイトメトリー、質量分析、または核酸配列もしくは発現の分析を含む、請求項1から4のいずれか一項に記載の方法。
- 前記生物学的試料が、体液または組織生検、無細胞核酸、血液、尿、血清または血漿を含む、請求項1から5のいずれか一項に記載の方法。
- 個体において腎線維症と関連するバイオマーカーを識別する方法であって、正常対照と比較して、腎線維症において発現が増加したまたは低下したバイオマーカーを識別することを含む方法。
- 個体における腎線維症の存在またはそれに対する感受性を検出するための方法であって、
前記個体から生物学的試料を得ることと;
前記生物学的試料中の、バイオマーカーの量、および/または前記バイオマーカーをコードするかもしくはその発現を調節する核酸(例えばゲノムDNAまたはmRNA)の量もしくはそこにおける突然変異を測定することと;
前記生物学的試料中の、前記バイオマーカーの量、および/または前記バイオマーカーをコードするかもしくはその発現を調節する核酸の量もしくはそこにおける突然変異を、前記バイオマーカーに関する対照値と比較することと
を含む方法。 - 前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)またはメタロペプチダーゼ2(MMP2)のうちの少なくとも1つを含む、請求項8に記載の方法。
- 前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)、メタロペプチダーゼ2(MMP2)、ウロモデュリン(UMOD)、SMADファミリーメンバー2(SMAD2)、またはSMADファミリーメンバー7(SMAD7)のうちの少なくとも1つを含む、請求項8または9に記載の方法。
- 前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)、メタロペプチダーゼ2(MMP2)、ウロモデュリン(UMOD)、SMADファミリーメンバー2(SMAD2)、SMADファミリーメンバー7(SMAD7)、結合組織増殖因子(CTGF)、またはC−Cモチーフケモカインリガンド2(CCL2)のうちの少なくとも1つを含む、請求項8から10のいずれか一項に記載の方法。
- 前記バイオマーカーが、コルチコステロン、アルドステロン、ADAMメタロペプチダーゼドメイン17(ADAM17)、C−Cモチーフケモカインリガンド2(CCL2)、カドヘリン1(CDH1)、結合組織増殖因子(CTGF)、表皮増殖因子受容体(EGFR)、フィブロネクチン1(FN1)、ガレクチン−1(LGALS1)、ガレクチン−3(LGAS3)、肝細胞増殖因子(HGF)、細胞間接着分子1(ICAM1)、インターロイキン1ベータ(IL1B)、インターロイキン6(IL6)、クルッペル様因子15(KLF15)、マトリックスメタロペプチダーゼ2(MMP2)、マトリックスメタロペプチダーゼ7(MMP7)、マトリックスメタロペプチダーゼ9(MMP9)、核因子カッパーBサブユニット1(NFKB1)、ネフリン(NPHS1)、ポディシン(NPHS2)、核受容体サブファミリー3グループCメンバー2(NR3C2)、セルピンファミリーEメンバー1(SERPINE1)、SMADファミリーメンバー2(SMAD2)、SMADファミリーメンバー3(SMAD3)、SMADファミリーメンバー4(SMAD4)、SMADファミリーメンバー7(SMAD7)、シグナル伝達転写活性化因子3(STAT3)、トランスフォーミング増殖因子ベータ1(TGFB1)、ウロモデュリン(UMOD)、または血管内皮増殖因子A(VEGFA)のうちの少なくとも1つを含む、請求項8から11のいずれか一項に記載の方法。
- 前記測定することが、タンパク質測定、イムノアッセイ、フローサイトメトリー、質量分析、または核酸配列もしくは発現の分析を含む、請求項8から12のいずれか一項に記載の方法。
- 前記試料が、体液または組織生検、無細胞核酸、血液、尿、血清または血漿を含む、請求項8から13のいずれか一項に記載の方法。
- 個体において腎線維症と関連するバイオマーカーを検出するための組成物であって、前記バイオマーカーの量、および/または前記バイオマーカーをコードするかもしくはその発現を調節する核酸(例えばゲノムDNAまたはmRNA)の量もしくはそこにおける突然変異を測定する試薬を含む、組成物。
- 前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)またはメタロペプチダーゼ2(MMP2)のうちの少なくとも1つを含む、請求項15に記載の組成物。
- 前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)、メタロペプチダーゼ2(MMP2)、ウロモデュリン(UMOD)、SMADファミリーメンバー2(SMAD2)、またはSMADファミリーメンバー7(SMAD7)のうちの少なくとも1つを含む、請求項15または16に記載の組成物。
- 前記バイオマーカーが、トランスフォーミング増殖因子ベータ1(TGFB1)、メタロペプチダーゼ2(MMP2)、ウロモデュリン(UMOD)、SMADファミリーメンバー2(SMAD2)、SMADファミリーメンバー7(SMAD7)、結合組織増殖因子(CTGF)、またはC−Cモチーフケモカインリガンド2(CCL2)のうちの少なくとも1つを含む、請求項15から17のいずれか一項に記載の組成物。
- 前記バイオマーカーが、コルチコステロン、アルドステロン、ADAMメタロペプチダーゼドメイン17(ADAM17)、C−Cモチーフケモカインリガンド2(CCL2)、カドヘリン1(CDH1)、結合組織増殖因子(CTGF)、表皮増殖因子受容体(EGFR)、フィブロネクチン1(FN1)、ガレクチン−1(LGALS1)、ガレクチン−3(LGAS3)、肝細胞増殖因子(HGF)、細胞間接着分子1(ICAM1)、インターロイキン1ベータ(IL1B)、インターロイキン6(IL6)、クルッペル様因子15(KLF15)、マトリックスメタロペプチダーゼ2(MMP2)、マトリックスメタロペプチダーゼ7(MMP7)、マトリックスメタロペプチダーゼ9(MMP9)、核因子カッパーBサブユニット1(NFKB1)、ネフリン(NPHS1)、ポディシン(NPHS2)、核受容体サブファミリー3グループCメンバー2(NR3C2)、セルピンファミリーEメンバー1(SERPINE1)、SMADファミリーメンバー2(SMAD2)、SMADファミリーメンバー3(SMAD3)、SMADファミリーメンバー4(SMAD4)、SMADファミリーメンバー7(SMAD7)、シグナル伝達転写活性化因子3(STAT3)、トランスフォーミング増殖因子ベータ1(TGFB1)、ウロモデュリン(UMOD)、または血管内皮増殖因子A(VEGFA)のうちの少なくとも1つを含む、請求項15から18のいずれか一項に記載の組成物。
- 前記測定することが、タンパク質測定、イムノアッセイ、フローサイトメトリー、質量分析、または核酸配列もしくは発現の分析を含む、請求項15から19のいずれか一項に記載の組成物。
- 前記試料が、体液または組織生検、無細胞核酸、血液、尿、血清または血漿を含む、請求項15から20のいずれか一項に記載の組成物。
- 前記試薬のうちの少なくとも1つが標識されている、請求項15から21のいずれか一項に記載の組成物。
- 請求項15から22のいずれかに記載の組成物を含む、キット。
- 請求項1から23に記載の方法のいずれかを行うための、または請求項1から23に記載の組成物もしくはキットのいずれかを使用するための、システム。
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