JP2020508444A - 無症候性脳虚血に関する血清学的アッセイ - Google Patents
無症候性脳虚血に関する血清学的アッセイ Download PDFInfo
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Abstract
Description
(a)被験体から得た試料を、表1または表2より選択される少なくとも1つのマーカーに特異的に結合する試薬と接触させる工程;
(b)マーカーへの結合のレベルを測定する工程;
(c)正常対照に比較したマーカーの測定量を反映する状態スコアを割り当てる工程;
(d)状態スコアが1より有意に大きい場合、メタボリックシンドロームおよび/または脳卒中の治療に、被験体を差し向ける工程
を含む。
(a)被験体から得た試料を、表1または表2より選択される少なくとも1つのマーカーに特異的に結合する試薬と接触させる工程;
(b)マーカーへの結合のレベルを測定する工程;
(c)正常対照に比較したマーカーの測定量を反映する状態スコアを割り当てる工程;
(d)状態スコアが1より有意に大きい場合、メタボリックシンドロームおよび/または脳卒中に関して被験体を治療する工程;
(e)工程(a)〜(c)を繰り返す工程;ならびに
(f)状態スコアが1に向かう傾向がない場合、治療を調整する工程
を含む。
(a)表1より選択される少なくとも1つのマーカーのレベルを測定する工程;
(b)マーカーのレベルが上昇している場合、アスピリン療法、血圧療法、体重管理、ならびに/または食餌および運動のプログラムを被験体に施す工程
を含む。
本出願で用いるすべての科学的および技術的用語は、別に明記しない限り、当該技術分野で一般的に用いる意味を有する。本出願で用いた際、以下の単語または句は明記する意味を有する。
本明細書に記載するのは、肥満、高脂血症、高血圧、およびグルコース不耐性を含む慢性血管リスク要因に曝露された脳内皮細胞によって産生される分子である。これらのストレス分子は、脳内皮細胞によって産生され、血清中で検出可能である。これらの分子は、脳特異的内皮細胞損傷の診断指標として働き、無症候性脳卒中および損なわれた認知機能のMRI指標と相関する。
本明細書に記載するのは、無症候性脳虚血および/またはメタボリックシンドロームを有する被験体を治療する方法である。該方法は、2つ以上のSBIマーカーのレベルが上昇した際に、被験体にアスピリン療法、血圧療法、血糖管理、コレステロール管理、体重管理、ならびに/または食餌および運動のプログラムを施す工程を含む。
(a)被験体から得た試料を、表1または表2より選択される少なくとも1つのマーカーに特異的に結合する試薬と接触させる工程;
(b)マーカーへの結合のレベルを測定する工程;
(c)正常対照に比較したマーカーの測定量を反映する状態スコアを割り当てる工程;
(d)状態スコアが1より有意に大きい場合、メタボリックシンドロームおよび/または脳卒中の治療に、被験体を差し向ける工程
を含む。
(a)被験体から得た試料を、表1または表2より選択される少なくとも1つのマーカーに特異的に結合する試薬と接触させる工程;
(b)マーカーへの結合のレベルを測定する工程;
(c)正常対照に比較したマーカーの測定量を反映する状態スコアを割り当てる工程;
(d)状態スコアが1より有意に大きい場合、メタボリックシンドロームおよび/または脳卒中に関して被験体を治療する工程;
(e)工程(a)〜(c)を繰り返す工程;ならびに
(f)状態スコアが1に向かう傾向がない場合、治療を調整する工程
を含む。
(a)表1より選択される少なくとも1つのマーカーのレベルを測定する工程;
(b)マーカーのレベルが上昇している場合、アスピリン療法、血圧療法、体重管理、ならびに/または食餌および運動のプログラムを被験体に施す工程
を含む。
本発明は、本明細書に記載するような試薬、例えば本発明の1つまたはそれより多いマーカーに特異的に結合する抗体、および場合によって、本発明の試薬を含有する1つまたはそれより多い適切な容器のセットを含む、キットを提供する。試薬には、本発明の1つまたはそれより多いマーカーに特異的に結合する分子が含まれる。試薬の1つの例は、マーカーに特異的な抗体である。試薬には、場合によって、検出可能標識が含まれることも可能である。標識は、蛍光、発光、酵素、発色性または放射性であることも可能である。
以下の例は、本発明を例示し、かつ本発明を実行しかつ用いる際に、一般の当業者を補助するために提示される。例は、いかなる意味でも、本発明の範囲を別に制限するために意図されない。
本実施例は、脳微小血管系に対するメタボリックシンドロームの影響を記載し、これらの変化を制御する分子機構を明らかにする。マウスにおけるこのシンドロームは、肥満、コレステロール上昇、および損なわれたグルコース耐性によって特徴付けられる、ヒト状態を強く模倣する。症状のこの集まりは、脳卒中(6倍)、特に無症候性脳卒中のリスクを非常に増加させる。無症候性脳卒中は、脳白質を損傷し、かつ身体障害、認知症および死を導く。
トランスジェニックマウス(Tie2−Cre:flox−stop tdtomatoプラスflox−RiboTAG)に、脂肪食餌から60%kCalを給餌して、メタボリックシンドロームを誘導した。被験体に高脂肪食餌を2ヶ月齢で12週間給餌し、そして脂肪食餌から10%kCalを対照として用いた。Tie2−Cre:flox−stop tdtomatoマウスの内皮細胞におけるレポーター遺伝子発現によって、白質中の脳血管系の体積を評価した。Ribotagリボソーム免疫沈降技術(Tie2−Cre:flox−RiboTAG)を用いて、脳内皮細胞からトランスクリプトームを単離した。リボソーム会合トランスクリプトーム単離後、RNA−seqを行った。
本実施例は、実施例1で記載する「メタボリックシンドローム」を生成する肥満のマウスモデルを用いる。この肥満のマウスモデルとともに、新規トランスジェニックマウス技術を用いて、本発明者らは肥満およびこれらの一般的な代謝障害のセッティングで起こる初期脳血管損傷の一連の分子指標を同定している。これらの遺伝子のいくつかは、血中に分泌されるタンパク質をコードし、したがって、初期脳血管損傷を示すために用いられうる。
患者血漿の試料を連続希釈して、マイクロタイタープレートの個々のウェル内にピペッティングした。5〜10の本発明者らのユニークな肥満誘導性脳内皮遺伝子に対して生成した新規抗体を、第一に、蛍光指標で標識する。重複しない蛍光指標を含む最大4つの異なる抗体を、各患者試料ウェルとインキュベーションする。プレートを繰り返し洗浄して、非特異的結合を取り除き、次いで、マルチチャネル蛍光分光光度計でスキャンし、各ウェルに関する各チャネルの蛍光強度を記録する。プロファイル中のすべての分子が測定されるまで、このアプローチを繰り返す。累積蛍光強度をすべてのターゲットに渡って平均して、規範的値に比較する。
本実施例は、小血管脳血管疾患(SVD)の新規脳内皮バイオマーカーの同定につながる研究を記載する。肥満、高血圧、高脂血症、および糖尿病は、すべて、白質損傷の有病率を増加させ、相乗的に、脳微小血管系内のシグナル伝達の改変に寄与する。しかし、これらの慢性状態によって、脳微小血管系において活性化される正確な分子経路は未知のままである。この知識のギャップに取り組むため、新規翻訳アプローチを利用して、肥満/メタボリックシンドロームのマウスモデルにおいて、白質内の脳内皮の細胞特異的転写プロファイルを同定した。主要リボソームタンパク質が赤血球凝集素抗原で遺伝子修飾されている、RiboTAGトランスジェニック技術を用いて、細胞特異的Cre−loxPトランスジェニックモデリングと組み合わせると、脳内皮の転写プロファイルを単離することが可能である。この非バイアスアプローチは、慢性血管状態、例えばすべてSVDと直接関連する、肥満、グルコース不耐性、および高脂血症の最初の直接のおよび単離された脳血管シグネチャーを同定する。新規SVDバイオマーカーを合理的に同定するため、このモデリングアプローチを用いて、本実施例は、細胞表面、および血清中で検出されうる分泌分子を含む、肥満誘導性脳血管シグネチャーを同定する。
この脳内皮分子シグネチャーの適切性を確認するため、本発明者らは、Freesurferを用いて、白質低信号(hypointensity)の体積によって指標化されるような、多様な度合いの白質疾患を有するUCSF MAC(記憶および加齢センター)の15人の認知的に正常な被験体におけるCXCL5およびCXCL6(マウスCXCL5に対するヒトオルソログ)のレベルを決定した。少なくとも軽度のSVDを持つ被験体において、白質低信号体積および本発明者らのシグナル伝達因子の間の相関は、本発明者らの少ない試料においてさえ、有意性に近付いた(CXCL5に関するスピアマン・ロー=0.56;CXCL6=0.57;p<0.10)。CXCL5およびCXCL6データを示すスキャッタープロットを図2に示す。これらのデータは、内皮細胞レベルで、脳微小血管疾患を反映するヒト・バイオマーカーとして、マウスにおいて最近発見されたこれらの脳内皮分子を用いることの、変換の妥当性を立証する。
本実施例は、表1に列挙したマーカーと認知障害の関連を裏付け、かつまた、無症候性脳卒中の画像証拠と、マーカーIGFBP2の関連を裏付ける。これらの初期傷害血清指標は、小血管虚血性疾患(SVID)とも称される、脳小血管疾患(CSVD)の画像指標と相関する。
Claims (20)
- 被験体において脳血管状態を監視する方法であって:
(a)被験体から得た試料を、表1または表2より選択される少なくとも1つのマーカーに特異的に結合する試薬と接触させる工程;
(b)マーカーへの結合のレベルを測定する工程;
(c)正常対照に比較したマーカーの測定量を反映する状態スコアを割り当てる工程;
(d)状態スコアが1より有意に大きい場合、メタボリックシンドロームおよび/または脳卒中の治療に、被験体を差し向ける工程
を含む、方法。 - マーカーが、C−X−Cモチーフケモカイン5(CXCL5)またはC−X−Cモチーフケモカイン6(CXCL6)である、請求項1の方法。
- マーカーが表1のマーカーである、請求項1の方法。
- 工程(b)の測定が、表1および/または表2のマーカーの少なくとも3つに関して行われる、請求項1の方法。
- 表3のマーカーを測定する工程をさらに含む、請求項1〜4のいずれか一項の方法。
- 試料がCSF試料、尿試料、血液試料、または他の体液である、請求項1〜5のいずれか一項の方法。
- 被験体において無症候性脳卒中を診断する方法であって:
(a)被験体から得た試料を、表1または表2より選択される少なくとも1つのマーカーに特異的に結合する試薬と接触させる工程;
(b)マーカーへの結合のレベルを測定する工程;
(c)正常対照に比較したマーカーの測定量を反映する状態スコアを割り当てる工程;
(d)状態スコアが1より有意に大きい場合、メタボリックシンドロームおよび/または脳卒中の治療に、被験体を差し向ける工程
を含む、方法。 - 被験体を、メタボリックシンドロームおよび/または脳卒中に関して治療する工程をさらに含む、請求項1〜7のいずれか一項の方法。
- 治療が、アスピリン療法、血圧療法、体重管理、ならびに/または食餌および運動のプログラムである、請求項1〜8のいずれか一項の方法。
- 被験体において無症候性脳卒中を監視する方法であって:
(a)被験体から得た試料を、表1または表2より選択される少なくとも1つのマーカーに特異的に結合する試薬と接触させる工程;
(b)マーカーへの結合のレベルを測定する工程;
(c)正常対照に比較したマーカーの測定量を反映する状態スコアを割り当てる工程;
(d)状態スコアが1より有意に大きい場合、メタボリックシンドロームおよび/または脳卒中に関して被験体を治療する工程;
(e)工程(a)〜(c)を繰り返す工程;ならびに
(f)状態スコアが1に向かう傾向がない場合、治療を調整する工程
を含む、方法。 - 治療が必要な被験体において無症候性脳卒中ならびに/またはメタボリックシンドロームを治療する方法であって:
(a)表1より選択される少なくとも1つのマーカーのレベルを測定する工程;
(b)マーカーのレベルが上昇している場合、アスピリン療法、血圧療法、血糖管理、コレステロール管理、体重管理、ならびに/または食餌および運動のプログラムを被験体に施す工程
を含む、方法。 - 少なくとも1つのマーカーが、C−X−Cモチーフケモカイン5(CXCL5)および/またはC−X−Cモチーフケモカイン6(CXCL6)を含む、請求項11の方法。
- 少なくとも1つのマーカーがIGFBP2を含む、請求項11の方法。
- 工程(a)の測定が、表1のマーカーの少なくとも2つに関して行われる、請求項11の方法。
- 工程(a)の測定が、表1および/または表2のマーカーの少なくとも3つに関して行われる、請求項11の方法。
- 表3のマーカーを測定する工程をさらに含む、請求項11〜15のいずれか一項の方法。
- 試料がCSF試料、尿試料、血液試料、または他の体液である、請求項11〜16のいずれか一項の方法。
- 試薬が抗体または核酸プローブである、請求項1〜10のいずれかの方法。
- 測定がイムノアッセイを含む、先行する請求項のいずれかの方法。
- CXCL5、CXCL6、IGFBP2、および場合によってITGB3の各々に特異的に結合する試薬を含むキット。
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US20230296630A1 (en) * | 2020-08-14 | 2023-09-21 | Roche Diagnostics Operations, Inc. | Multimarker panel for the assessment of silent brain infarcts and cognitive decline |
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