JP2014520529A - アルツハイマー病を示すマイクロrnaバイオマーカー - Google Patents
アルツハイマー病を示すマイクロrnaバイオマーカー Download PDFInfo
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Abstract
【選択図】なし
Description
本願は、2011年6月27日に出願された米国特許仮出願第61/501,720号に優先権を主張するものであり、その全体の内容は、参照により本明細書に組み込まれる。
−545、若しくはmiR−301a及びmiR−545から選択され得る。一実施形態では、本方法は、miR−545、let7g、及びmiR−15b;miR−15b及びmiR−545;miR−301a、miR−545、let−7g及びmiR−15b;miR−191及びmiR−15b;Let−7g及びmiR−15b;miR−191、miR−301a、及びmiR−545;miR−301a、let−7g、及びmiR−15b;並びにmiR−191、miR−301a、miR−545、及びmiR−15b、のうちのmiRNAの組み合わせの1つのレベルを決定することを有する。
本発明は、アルツハイマー病を示す新規なmiRNAバイオマーカーを提供し、このmiRNAバイオマーカーは、対象においてアルツハイマー病を正確に診断するために使用され得る。これに加えて、アルツハイマー病の過程のモニタリングのための方法、アルツハイマー病を有する対象を治療する方法、及びアルツハイマー病を診断するためのキットが提供される。一部の実施形態では、方法は、好適なサンプル中の、好ましくは血液、血漿、血清、尿、又は唾液中の細胞外の循環miRNAの検出を必然的に伴う。
2.用語の定義
3.アルツハイマー病に関するmiRNAバイオマーカー
4.生物学的サンプル
5.サンプル中のmiRNAバイオマーカーのレベルの決定
A.増幅に基づく方法
B.ハイブリダイゼーションに基づく方法
C.配列決定に基づく方法
D.追加のmiRNA検出ツール
E.増幅又は非増幅のmiRNAの検出
6.miRNAバイオマーカーを使用するアルツハイマー病状態の検出
7.アルツハイマー病状態を定量化するための分類アルゴリズムの生成
8.追加診断試験
9.治療方法
10.miRNAバイオマーカーを検出するためのキット
本試験の目的は、ヒト血液の血漿分画からmiRNAプロファイルを生成し、アルツハイマー病(AD)と診断された患者と正常対照(NC)との間でmiRNA含量及び発現レベルで有意な差があるかどうかを判定するためのものである。
材料及び方法
全RNA抽出
miRNAの高スループット発現プロファイリング
TaqMan qPCRを使用する候補バイオマーカーmiRNAの妥当性確認
実施例2:シグネチャー生成及び予測モデル構築
read.file <− function(file,inv)
{
data.tmp=read.csv(file,sep=“¥t”,header=T)
mat <− matrix(0, nrow=nrow(data.tmp), ncol=ncol((data.tmp))−1)
rownames(mat)=data.tmp[,1]
colnames(mat)=colnames(data.tmp)[2:ncol(data.tmp)]
for(i in 1:nrow(data.tmp))
{
mat[i,]=as.numeric(data.tmp[i,2:ncol(data.tmp)])
}
if(inv==T) {mat=t(mat) }
mat
}
library(MASS)
library(verification)
train=read.file(“train.txt”,F)
validation=read.file(“validation.txt”,F)
train_an=read.table(“train_an.txt”)
validation_an=read.table(“validation_an.txt”)
validation_an=as.factor(validation_an[,1])
train_an=as.factor(train_an[,1])
obs=NULL
obs[validation_an==“normal”]=0
obs[validation_an==“AD”]=1
set=c(“miR.545”,“let.7g”,“miR.15b”)
train_sp=train[,set]
ldatrain=lda((train_sp),train_an)
validation_sp=validation[,set]
prediction= predict(ldatrain,validation_sp)
tb=table(validation_an,prediction$class)
nr=tb[1,1]+tb[2,2]
accuracy=nr/sum(tb)
sensitivity=tb[1,1]/(tb[1,1]+tb[1,2])
specificity=tb[2,2]/(tb[2,1]+tb[2,2])
auc=roc.area(obs,prediction$posteri[,1])$A
実施例3:対象の状態を正常又はアルツハイマー病を有すると予測するmiRNAバイオマーカー
Claims (46)
- 対象におけるアルツハイマー病を診断する方法であって、
前記対象からの循環miRNAを含有するサンプル中の少なくとも1つのmiRNAのレベルを決定することを含み、ここで、前記少なくとも1つのmiRNAが、miR−191、miR−15b、miR−142−3p、Let−7g、Let−7d、及びこれらの組み合わせからなる群から選択され、
好適な対照に対して決定される、正常な対象におけるmiRNAのレベルと前記少なくとも1つのmiRNAのレベルとの差が、前記対象におけるアルツハイマー病を示す、方法。 - 前記サンプル中の少なくとも1つのmiRNAのレベルに基づいて、前記対象におけるアルツハイマー病の有無の診断を提供することを更に含む、請求項1に記載の方法。
- 好適な対照に対する少なくとも1つのmiRNAのレベルの差を、前記対象におけるアルツハイマー病の診断に相関させることを更に含む、請求項1に記載の方法。
- 前記サンプル中のmiR−191、miR−15b、miR−142−3p、Let−7g、Let−7dからなる群から選択される1つのmiRNAのレベルを決定することを含み、正常な対象におけるmiRNAのレベルと前記miRNAのレベルとの差が減少である、請求項1〜3のいずれか一項に記載の方法。
- miR−301a;miR−545;並びにmiR−301a及びmiR−545からなる群から選択される、前記サンプル中の少なくとも1つの追加のmiRNAのレベルを決定することを更に含む、請求項1〜3のいずれか一項に記載の方法。
- 前記サンプル中の少なくとも2つのmiRNAのレベルを決定することを含み、前記miRNAが、miR−191、miR−15b、miR−142−3p、Let−7g、Let−7d、及びこれらの組み合わせからなる群から選択される、請求項1〜3のいずれか一項に記載の方法。
- 前記サンプル中の少なくとも2つのmiRNAのレベルを決定することを含む、請求項5に記載の方法。
- 前記miRNAが、miR−545、let7g、及びmiR−15bである、請求項5に記載の方法。
- 前記miRNAが、miR−15b及びmiR−545である、請求項5に記載の方法。
- 前記miRNAが、miR−301a、miR−545、let−7g及びmiR−15bである、請求項5に記載の方法。
- 前記miRNAが、miR−191及びmiR−15bである、請求項1〜3のいずれか一項に記載の方法。
- 前記miRNAが、Let−7g及びmiR−15bである、請求項1〜3のいずれか一項に記載の方法。
- 前記miRNAが、miR−191、miR−301a、及びmiR−545である、請求項5に記載の方法。
- 前記miRNAが、miR−301a、let−7g、及びmiR−15bである、請求項5に記載の方法。
- 前記miRNAが、miR−191、miR−301a、miR−545、及びmiR−15bである、請求項5に記載の方法。
- (i)前記対象からの循環miRNAを含有するサンプル中の2つ以上のmiRNAのレベルを決定することであって、前記miRNAが、
(a)miR−545、let7g、及びmiR−15b、
(b)miR−15b及びmiR−545、
(c)miR−301a、miR−545、let−7g及びmiR−15b、
(d)miR−191及びmiR−15b、
(e)Let−7g及びmiR−15b、
(f)miR−191、miR−301a、及びmiR−545、
(g)miR−301a、let−7g、及びmiR−15b、及び
(h)miR−191、miR−301a、miR−545、及びmiR−15bからなる群から選択される、ことと、
(ii)前記サンプル中の前記2つ以上のmiRNAのレベルを、正常な対象及びアルツハイマー病を有する対象において存在する同一のmiRNAのレベルを表すデータのセットと比較することと、
(iii)ステップ(ii)で行われた前記比較に基づいて、アルツハイマー病の有無について前記対象を診断することと
を含む、請求項5に記載の方法。 - 好適な対照に対する少なくとも1つのmiRNAの前記レベルの差が、ソフトウェア分類アルゴリズムを実行することにより決定される、請求項1〜16のいずれか一項に記載の方法。
- 前記サンプルが、血液、リンパ液、尿、及び唾液からなる群から選択される、請求項1〜17のいずれか一項に記載の方法。
- 前記サンプルが、無細胞サンプルである、請求項1〜17のいずれか一項に記載の方法。
- 前記サンプルが、無微細小胞サンプルである、請求項1〜17及び19のいずれか一項に記載の方法。
- 前記サンプルが、血漿である、請求項1〜17のいずれか一項に記載の方法。
- 前記サンプルが、血清である、請求項1〜17のいずれか一項に記載の方法。
- アルツハイマー病の診断を容易にするための少なくとも1つの追加試験を実行することを更に含む、請求項1〜22のいずれか一項に記載の方法。
- 前記追加試験が、簡易精神状態検査(MMSE)、mini−cog試験、ADAS−cog試験及び時計描画試験からなる群から選択される、請求項23に記載の方法。
- 前記追加試験が、アルツハイマー病に関する少なくとも1つの追加バイオマーカーを検出することを含む、請求項23に記載の方法。
- アルツハイマー病治療薬、或いはその薬学的に許容可能な塩又はエステルを含む医薬組成物の治療的有効量を前記対象に投与することを更に含む、請求項1〜25のいずれか一項に記載の方法。
- 前記アルツハイマー病治療薬が、ガランタミン、リバスチグミン及びドネペジルからなる群から選択される、請求項26に記載の方法。
- miRNAのレベルが、前記miRNAに特異的にハイブリダイズする薬剤を使用して検出される、請求項1〜27のいずれか一項に記載の方法。
- miRNAのレベルが、増幅、ハイブリダイゼーション、及び/又は配列決定法(例えば、定量的PCR)を使用して検出される、請求項1〜27のいずれか一項に記載の方法。
- 対象におけるアルツハイマー病の経過を監視する方法であって、
(a)循環miRNAを含有する対象からの第1のサンプル中の、miR−191、miR−15b、miR−142−3p、Let−7g、Let−7d、及びこれらの組み合わせからなる群から選択される少なくとも1つのmiRNAのレベルを決定することと、
(b)循環miRNAを含有する前記対象からの第2のサンプル中の、前記少なくとも1つのmiRNAのレベルを決定することであって、前記第2のサンプルが、前記第1のサンプルの後に取得されることと、
(c)ステップ(a)及び(b)において決定された前記レベルを比較することであって、前記レベルがアルツハイマー病の進行を示すことと
を含む、方法。 - 前記サンプル中の少なくとも1つの追加のmiRNAのレベルを測定することを更に含み、前記追加のmiRNAが、miR−301a;miR−545;並びにmiR−301a及びmiR−545からなる群から選択される、請求項30に記載の方法。
- 対象におけるアルツハイマー病を治療する方法であって、
(a)前記対象からの循環miRNAを含有するサンプル中の少なくとも1つのmiRNAのレベルを決定することであって、ここで、前記少なくとも1つのmiRNAが、miR−191、miR−15b、miR−142−3p、Let−7g、Let−7d、及びこれらの組み合わせからなる群から選択され、好適な対照に対して決定される、正常な対象におけるmiRNAのレベルと前記少なくとも1つのmiRNAのレベルとの差が、前記対象におけるアルツハイマー病を示すことと、
(b)少なくとも1つのmiRNAのレベルの差が検出された場合に、アルツハイマー病治療薬、或いはその薬学的に許容可能な塩又はエステルを含む医薬組成物の治療的有効量を前記対象に投与することと
を含む、方法。 - 前記サンプル中の少なくとも1つの追加のmiRNAのレベルを決定することを更に含み、前記追加のmiRNAが、miR−301a;miR−545;並びにmiR−301a及びmiR−545からなる群から選択される、請求項32に記載の方法。
- アルツハイマー病を有する対象を治療する方法であって、
(a)前記対象からの循環miRNAを含有するサンプル中の少なくとも1つのmiRNAのレベルが、好適な対照に対して異なる、アルツハイマー病を有する対象を特定することであって、前記少なくとも1つのmiRNAが、miR−191、miR−15b、miR−142−3p、Let−7g、Let−7d、及びこれらの組み合わせからなる群から選択されることと、
(b)アルツハイマー病治療薬、或いはその薬学的に許容可能な塩又はエステルを含む組成物の治療的有効量を前記対象に投与することと
を含む、方法。 - 前記サンプル中の少なくとも1つの追加のmiRNAのレベルが、好適な対照に対して異なる対象を特定することを更に含み、前記追加のmiRNAが、miR−301a;miR−545;並びにmiR−301a及びmiR−545からなる群から選択される、請求項34に記載の方法。
- 前記アルツハイマー病治療薬が、ガランタミン、リバスチグミン及びドネペジルからなる群から選択される、請求項32〜35のいずれか一項に記載の方法。
- 対象におけるアルツハイマー病を診断するためのキットであって、
(i)対象からの循環miRNAを含有するサンプル中の少なくとも1つのmiRNAの存在を選択的に検出する薬剤であって、前記少なくとも1つのmiRNAが、miR−191、miR−15b、miR−142−3p、Let−7g、Let−7d、及びこれらの組み合わせからなる群から選択される薬剤と、
(ii)前記少なくとも1つのmiRNAのレベルの決定のための使用説明書と、
を含み、好適な対照に対して決定される、正常な対象におけるmiRNAのレベルと前記少なくとも1つのmiRNAのレベルとの差が、前記対象におけるアルツハイマー病を示す、キット。 - 前記サンプル中の少なくとも1つの追加のmiRNAの存在を選択的に検出する薬剤を更に含み、前記追加のmiRNAが、miR−301a;miR−545;並びにmiR−301a及びmiR−545からなる群から選択される、請求項37に記載のキット。
- 前記薬剤が、前記miRNAに特異的にハイブリダイズする、請求項37又は38に記載のキット。
- 前記サンプルが、血液に由来する、請求項1〜39のいずれか一項に記載の方法又はキット。
- 前記サンプルが無細胞サンプルである、請求項40に記載の方法又はキット。
- 前記サンプルが、無微細小胞サンプルである、請求項41に記載の方法又はキット。
- 好適な対照に対する少なくとも1つのmiRNAのレベルの差が、ソフトウェア分類アルゴリズムを実行することにより決定される、請求項1〜42のいずれか一項に記載の方法又はキット。
- 正常な対象におけるmiRNAのレベルと前記miRNAのレベルとの差が減少である、請求項1〜43のいずれか一項に記載の方法又はキット。
- 前記対象が哺乳動物である、請求項1〜44のいずれか一項に記載の方法又はキット。
- 前記対象がヒトである、請求項45に記載の方法又はキット。
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EP2723894A2 (en) | 2014-04-30 |
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RU2014102357A (ru) | 2015-08-10 |
BR112013033488A2 (pt) | 2017-03-01 |
WO2013003350A2 (en) | 2013-01-03 |
US20140378439A1 (en) | 2014-12-25 |
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