JP2022512664A - 骨髄幹細胞治療に対する応答の予測方法 - Google Patents
骨髄幹細胞治療に対する応答の予測方法 Download PDFInfo
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Abstract
Description
(i)被験体の試料において、遺伝子および/または遺伝子発現をバイオマーカーとして測定することであって、遺伝子および/または遺伝子発現が突然変異体を含み、
(ii)測定された遺伝子および/または遺伝子発現突然変異体を基準値および/または参照と、好ましくは基準値および/または体細胞変異遺伝子および/または遺伝子発現をもたない無病型もしくは個体の参照細胞の参照と比較すること、
(iii)比較結果に基づき、被験体において、疾患治療、特に組織修復、好ましくは心修復に対する応答が、期待されるか、期待されないか、または両価であるかどうかを予測すること
を含む方法に関する。
(i)被験体の試料において、SH2B3-遺伝子および/またはSH2B3-遺伝子発現をバイオマーカーとして測定することであって、SH2B3-遺伝子および/またはSH2B3-遺伝子発現が突然変異体を含み、
(ii)測定されたSH2B3-遺伝子および/またはSH2B3-遺伝子発現突然変異体を基準値および/または参照と、好ましくは基準値および/または体細胞変異遺伝子および/または遺伝子発現をもたないSH2B3無病型もしくは個体の参照細胞の参照と比較すること、
(iii)比較結果に基づき、被験体において、疾患治療、特に組織修復、好ましくは心修復に対する応答が、期待されるか、期待されないか、または両価であるかどうかを予測すること
を含む方法に関する。
(i)測定されたバイオマーカーを基準値および/または参照と、好ましくは基準値および/または突然変異体のないSH2B3-遺伝子および/またはSH2B3-遺伝子発現の参照と比較すること、
(ii)比較の結果に基づいて、被験体における疾患治療、特に組織再生、好ましくは心臓血管再生への応答が期待されるか、期待されないか、または両価であるかどうかを予測すること
を含む。
(i)被験体のサンプル中の本発明に係るバイオマーカーの各々の量を測定するための分析ユニット、および
(ii)本発明に係るコンピュータ装置(上述されたような)
を含む。
(i)被験体のサンプルにおいてバイオマーカーの各々の量を測定し、
(ii)測定された量をベースライン値および/または参照と比較し、
(iii)比較の結果に基づいて、被験体において心臓血管修復への応答が期待されるか、期待されないか、または両価であるかどうかを予測する
ことを含む。
(SF)を意味し、パラクリン細胞の増殖、運動、および形態因子である。それは間葉系細胞により分泌され、主に上皮細胞および内皮細胞を標的として作用するが、造血前駆細胞およびT細胞にも作用する。
末梢血骨髄応答は、完全に利用可能なバイオバンク、臨床(プロトコルごと)、およびバイオマーカーデータ(n=23)を用いてロストック臨床サイトの無作為フェーズ3PERFECT試験バイオマーカーサブグループにおいて全ゲノムおよび循環EPC分析により研究した(Steinhoff G, Nesteruk J, Wolfien M, et al. EBioMedicine 2017 Aug; 22:208-224. doi: 10.1016/j.ebiom.2017.07.022. Epub 2017 Jul 29.)。CD133+BMSC治療(n=13)およびプラセボ対照(n=14)を平等に分配した。PERFECT試験のバイオマーカー患者コホート(n=23;プラセボ/CD133+ 9/14)において、両方の処置群(心筋内プラセボ vs. CD133+)中の、180日後ΔLVEF≧5%により分類されるレスポンダー(R)(n=14;プラセボ/CD133+ 7/7)および180日後ΔLVEF<5%により分類されるノンレスポンダー(NR)(n=9;プラセボ/CD133+ 5/4)における末梢血での全身性骨髄幹細胞応答を調査した。
PERFECT試験は、虚血性心筋梗塞後の冠動脈バイパス移植(CABG)血行再建術と組み合わせた心筋内CD133+BMSC治療の心筋再生効果を調べる、無作為、多施設、プラセボ-対照、二重盲検のフェーズ3試験であった(Steinhoff G, Nesteruk J, Wolfien M, et al. EBioMedicine 2017 Aug; 22:208-224. doi: 10.1016/j.ebiom.2017.07.022. Epub 2017 Jul 29., Baughn LB, Meredith MM, Oseth L, Smolarek TA, Hirsch B. Cancer Genet. 2018 Oct; 226-227:30-35. doi: 10.1016/j.cancergen.2018.05.004. Epub 2018 Jun 8.)。事前に特定された事後バイオマーカー結果解析が公開された(Steinhoff G, Nesteruk J, Wolfien M, et al. EBioMedicine 2017; Aug;22:208-224. doi: 10.1016/j.ebiom.2017.07.022. Epub 2017 Jul 29.)。PERFECT試験の試験対象患者基準は、(a)CABGの適応を有するMI後の冠動脈疾患、(b)減少したLVEF(25~50%)、および(c)SC標的領域を規定する左心室(LV)心筋の局在化した運動/運動低下性/過潅流領域の存在であった。評価は、術前および術後1日、3日、10日、90日、180日および730日で行った。
PBにおけるRNAseq分析およびmRNA RT-PCR:分析および実験は、試験の割り付けを明らかにする前に、データプライバシーの保護を注意深く順守(偽名)したもとで行った。
凍結EDTA血液試料のRNAは三段階法において単離した。第一に、GeneJET Stabilized and Fresh Whole Blood Kit(サーモサイエンティフィック社)を製造者の取扱説明書にしたがって使用した。第二に、単離されたRNAを、高い塩条件下(3M酢酸ナトリウムの10%、pH5.2)、2.5容量エタノールで沈殿させた。DNase消化(サーモサイエンティフィック社)の後、RNAを最終的にAgencourt RNAClean XP beads(ベックマンコールター社)を用いて精製した。単離されたRNAは、RNA 600 Nano Chips(アジレント社)を用いてバイオアナライザー(アジレント社)で分析した。品質管理RNAを使用し、製造者の取扱説明書にしたがってUniversal Plus mRNA-Seq Technology(ヌゲン(Nugen)社)を用いてシーケンシングライブラリを構築した。概略:mRNAはオリゴd(T)ビーズにより選択され、逆転写され、Globin誘導cDNAはGlobin枯渇モジュール(ヌゲン社)により開裂された。品質が制御され量化されたライブラリが、HiSeq1500システム(イルミナ社)のシングルエンドモード(100nt読み取り長)で配列決定された。RNAデータ分析については、我々は、データ前処理のためにアダプタークリッピングおよびクォリティートリミングを行い、Kallistoを活用して読み取りをhg19ゲノムに整列(align)させた。スルースパッケージ(sleuth package)の尤度比検定を用いて差次的発現分析を行った(二倍超の変化とq値<0.05を有する遺伝子が有意に差次的に発現されたとみなされる)。機能的注釈クラスタリングおよび機能的分類などの遺伝子注釈がEnrichrで行われた(Kuleshov, M. V. et al., Nucleic Acids Res. 2016, vol 44(W1), doi: 10.1093/nar/gkw377, Epub 2016 May 3)。
先に前処理されたRNAseqデータセット(術前および術後)を、Star(2-パスモード)によりhg19参照に整列された。変異体呼び出しが、特異的フィルター(例えば、それらが五つの独立した読み取りで確認された場合にのみ変異体とみなされる)を備えたGatk toolkit(McKenna, A. et al., Genome Res. 2010, vol. 20(9): 1297-1303, doi: 10.1101/gr.107524.110)により適用された。変異体注釈はReftoolで行った。
Lnk/SH2B3-/-マウス系統は、先に説明されている(Takaki S. et al., J. Exp. Med. 2002; 195:151-160)ように作出した。C57BL/6マウス(日本クレア(株)、東京、日本)をWT対照マウスとして用いた。GFPトランスジェニックマウス(GFP-Tgマウス;C57BL/6TgN[act EGFP] Osb Y01)をWTマウスまたはLnk/SH2B3-/-マウスと交配させ、WT/GFPマウスまたはLnk/SH2B3-/-/GFPマウスをBM移植(BMT)研究のためにそれぞれ作出した。すべての実験手法は、実験動物のケアおよび使用のための日本生理学会のガイドラインおよび発生生物学のための理研の倫理委員会により承認された研究プロトコルにしたがい行われた。
8週齢から12週齢のマウスを、400mg/kgの2,2,2-トリブロモエタノール(アバルチン;シグマ社、セントルイス、ミズーリ州)の腹腔内注射により麻酔した。先に説明されている(Fabregat A, Sidiropoulos K, Garapati P, et al. Nucleic Acids Res 2016, Jan 4; 44 (D1):D481-7. doi: 10.1093/nar/gkv1351. Epub 2015 Dec 9.)ように左冠動脈前下行枝(LAD)を結紮することによりMIを誘導した。
部検時、心臓をO.C.T(商標)コンパウンド(Tissue-Tek(登録商標))に埋め込み、液体窒素で即時に凍結し、クライオスタット(ライカマイクロシステムズ社、ウェッツラー、ドイツ)により6μmの薄片とした。LV心筋における線維化および梗塞周囲領域の選択的切開によりRT-PCR分析のためのトータルRNAを単離した。BrdU組み込み試験のために、犠牲死させる16時間前に、腹腔内に100μLの10mg/mL BrdU溶液(BDファーミンゲン)をマウスに注射した。
TRlzl(インビトロジェン社)を用い、製造業者の取扱説明書にしたがい、MI前およびMIの3日後にマウス心臓組織からトータルRNAを得た。ファーストストランドcDNAをPrimeScript RT試薬キット(タカラバイオ社、大津、日本)を用いて合成し、AmpliTaq Gold DNAポリメラーゼ(アプライドバイオシステムズ社、フォスターシティー、カリフォルニア州)により増幅した。マウスLnk/SH2B3およびβ-アクチンを次の条件で増幅した。Lnk/SH2B3、94℃、30秒、57℃、30秒および72℃、30秒を42サイクル、その後72℃、5分の最終ホールド;β-アクチン、94℃、30秒、57℃、30秒および72℃、30秒を35サイクル、その後72℃、5分の最終ホールド。その後、100-bpDNAラダー(インビトロジェン社)を用い1.5%エチジウムブロミド染色したアガロースゲルにおいて、PCR産物を可視化した。プライマー配列を補足の表1Sに示す。
RNeasy Miniキット(キアゲン社、ハイデン、ドイツ)を用い、製造業者の取扱説明書にしたがい、KSL細胞からトータルRNAを得た。ファーストストランドcDNAを合成した後、リアルタイム定量RT-PCRを、SYBR Green Master Mix Reagent(アプライドバイオシステムズ社)を用いてABI Prism 7700(アプライドバイオシステムズ社)で行った。プライマー配列を補足の表1Sに示す。
ソフトウェアパッケージ(Statview 5.0、アバカスコンセプト社(Abacus concepts Inc)、バークレー、カリフォルニア州)を使用して結果を統計学的に分析した。すべての値は、平均±標準偏差(平均±SD)として表した。3群より多くの間の比較は、Prism4(グラフパッドソフトウェア社、サンディエゴ、カリフォルニア州)において一次元配置分散分析(ANOVA)を用いてなされた。事後分析は、チューキー多重比較検定により行った。P<0.05の差を、統計的有意性を示すものとみなした。
カギとなる特徴と包括的な患者データの分類の特定は、教師付きおよび教師なしMLアルゴリズムを用いて得られた(Steinhoff G, Nesteruk J, Wolfien M, et al. EBioMedicine 2017 Aug; 22:208-224. doi: 10.1016/j.ebiom.2017.07.022. Epub 2017 Jul 29.)。我々は、ベストプラクティスレコメンデーションを受け、次元削減のため、低い分散と高い相関を有する特徴を取り除きながらデータを前処理した。我々は、次の教師付きアルゴリズム:AdaBoost、Gradient Boosting(GB)、Support Vector Machines(SVM)およびRandom Forest(RF)を比較した(Steinhoff G, Nesteruk J, Wolfien M, et al. EBioMedicine 2017 Aug; 22:208-224. doi: 10.1016/j.ebiom.2017.07.022. Epub 2017 Jul 29.)。我々は、小さなデータセットを用いたトレーニングに好適な分類子を用いた。ほとんど訓練を与えられていない特徴の比較のための小さなデータセットにおける訓練に適している分類器を用い、過学習に向けた精度およびロバスト性にしたがい最も適切なアルゴリズムを選択した(Al-Naqeb D. Scientifica (Cairo). 2016; 2016:2079704. doi: 10.1155/2016/2079704. Epub 2016 May 30.)。教師付きMLモデルは、10倍クロス検証され、100回繰り返された。その後、我々は、特徴の数をさらに20未満に減らすためにAdaBoost、GBおよびRF分類器のために特徴選択を適用した。我々は、教師なし機械学習分類および非線形次元削減のためにt分布型確率的近傍埋め込み法(t-SNE)を採用した(Steinhoff G, Nesteruk J, Wolfien M, et al. EBioMedicine 2017 Aug; 22:208-224. doi: 10.1016/j.ebiom.2017.07.022. Epub 2017 Jul 29.)。
システム生物学のアプローチにより、我々は、調査患者データセットの中で経時的発現応答パターンを明らかにすることを目的とした。富化されたシグナル伝達経路の同定は、キュレートされかつ実験的に検証されたデータベース内で、増強された経路およびネットワークパターンを見つけるために設計されたReactome Functional Interaction(RFI) and the BisoGenenet Cytoscapeを用いてなされた(Fabregat A, Sidiropoulos K, Garapati P, et al. Nucleic Acids Res 2016; Jan 4; 44 D1:D481-7. doi: 10.1093/nar/gkv1351. Epub 2015 Dec 9.)。さらに、我々はその後、患者特異的発現データの経時ネットワーク富化分析のためにTiCoNE(Time Course Network Enricher)を使用した。このツールは、特別なk-medoidクラスタリングアプローチである、medoidsによる分割(partitioning around medoid)(PAM)およびClustering for Large Applications(CLARA)アルゴリズムを使用して、特定の相互作用ネットワークの発現データに現れる時間パターンを識別するためにさまざまな数学的アルゴリズムを採用する。エラー率(FDR)とp値は、1000回の反復でグローバル置換を使用して計算された。Pearson Product Moment Correlation(PPMC)は、さまざまなクラスターを比較するために使用された。 モチーフ内の遺伝子発現パターンは、p値<0.05に共通であると見なされた。
末梢血(PB)全ゲノム発現および循環内皮前駆細胞(EPC)分析は、レスポンダー(R、n=14;ΔLVEF+16% 180/0日)およびノンレスポンダー(NR、n=9;ΔLVEF-1.1% 180/0日)のフェーズ3PERFECT(CABGおよびCD133+BMSCまたはプラセボ)トライアルバイオマーカーサブグループ(n=23)において、および独立したセンターのバイオマーカー患者コホート(n=14)において、0、1、3、10日目に調べた。
ACE=アンジオテンシン変換酵素
AE=有害事象
AESI=特別に関心のある有害事象
AFAP1=アクチンフィラメント関連タンパク質
AHA=アメリカ心臓協会
ANCOVA=共分散分析
ANOVA=分散分析
Ang-1=アンジオポイエチン1
AP1B1=アダプター関連タンパク質複合体1サブユニットベータ1
ASS=アセチルサリチル酸
ATII=アンジオテンシンII
AUC=曲線の下の領域
BAZ1A=ジンクフィンガードメインに隣接したブロモドメイン・タンパク質1A
BCIP=5-ブロモ-4-クロロ-3-インドリル-ホスフェート
BEX3=脳発現X連鎖3
BM=骨髄
BMSC=骨髄幹細胞
CABG=冠動脈バイパス移植
CAP-EPC=濃縮周囲分子-内皮前駆細胞
CBA=サイトメトリービーズアレイ
CCS=カナダ心臓血管学会
CCTRN=心臓血管細胞療法研究ネットワーク
CD=分化抗原群
CEC=循環内皮細胞、CECパネル、PB中で測定されるCD
CFU=コロニー形成単位
CI=信頼区間
CMV=サイトメガロウイルス
CXCL12=C-X-Cモチーフケモカイン12
DAB=ジアミノベンジジン
DELFIA=解離促進ランタニド蛍光イムノアッセイ
Delta_CT_SH2B3(ΔCT SH2B3)=SH2B3遺伝子発現の正規化された値(正規化 対 ハウスキーピング遺伝子グリセリンアルデヒド-3-ホスフェート-デヒドロゲナーゼ(GAPDH))
EA=早期抗原
EC=内皮細胞
ECG=心エコー
ECLIA=電気化学発光免疫測定法
EDTA=エチレンジアミン四酢酸
ELISA=酵素結合免疫吸着アッセイ
EMG1=EMG1 N1-特異的プソイドウリジンメチルトランスフェラーゼ
EPC=内皮前駆細胞、EPCパネル、PB中で測定されるCD
EPO=エリスロポエチン
FGF=線維芽細胞増殖因子
GFP=緑色蛍光タンパク質
GRB2=成長因子受容体結合タンパク質2
GMP=適性製造基準
HA=血球凝集素
HGF=肝細胞増殖因子
HR=ハザード比
HIF=低酸素誘導因子、転写因子
ICH GCP=三者ガイドライン 良い臨床慣行のためのガイドライン
IGF-1=インスリン様成長因子1
IHG=ISHAGEガイドラインに従って行われる分析
IL=インターロイキン
KLF8=クルッペル様因子
LMCA=左主冠状動脈
LPCAT2=リソホスファチジルコリンアセチルトランスフェラーゼ2
LTB=リンホトキシン-ベータ
LVEDV=左室拡張終末期容積
LVEF=左室駆動率
LVESD=左室収縮終末期径
MACE=主要な有害な心臓血管事象
MARK3=微小管親和性調節キナーゼ3
MIBI SPECT=メトキシイソブチルイソニトリルSPECT
ML=機械学習
MNC=単核細胞
MRI=核磁気共鳴画像法
MS=質量分析法
6MWT=6分歩行テスト
NBT=4ニトロブルーテトラゾリウム
NGS=次世代シークエンシング
NMR=核磁気共鳴
NYHA=ニューヨーク心臓協会
PB=末梢血
PBMNC=末梢血から単離された単核細胞
PCI=経皮的冠動脈介入
PDGFRB=血小板由来増殖因子受容体ベータ
PEI=ポール・エーリッヒ研究所
PLCG1=ホスホリパーゼCガンマ1
PPS=パー・プロトコル・セットの患者群
REX1BD=切除に要求される1-Bドメイン(Required For Excision 1-B Domain)
ROC=受信者動作特性
RT-RCR=逆転写ポリメラーゼ連鎖反応
SACM1L=黄色ブドウ球菌Cowan1ホスファチジルイノシチドホスファターゼ
SAE=重大有害事象
SAS=安全性解析対象集団の患者群
SDF-1=間質細胞由来因子1
SDS=ドデシル硫酸ナトリウム
SF=散乱係数
SH2B3=重要なアダプター機能を有するSH2含有タンパク質に属する
SCF=幹細胞因子
SPA=シンチレーション近接アッセイ
STEMI=STセグメント上昇心筋梗塞
SUM=サポートベクターマシン
SUSAR=予期せぬ重篤な副作用の疑い
TNF=腫瘍壊死因子
t-SNE=t分布型確率的近傍埋め込み法
VAD=心室補助装置
VCA=ビールス-カプシド-抗原
VEGF=血管内皮増殖因子
VEGF rec=血管内皮増殖因子受容体
ZNF205=ジンクフィンガータンパク質205
Claims (30)
- 疾患治療、特に心臓血管再生に対する応答の予測方法であって、
(i)被験体の試料において、遺伝子および/または遺伝子発現をバイオマーカーとして測定することであって、遺伝子および/または遺伝子発現が突然変異体を含み、
(ii)測定された遺伝子および/または遺伝子発現突然変異体を基準値および/または参照と、好ましくは基準値および/または体細胞変異遺伝子および/または遺伝子発現をもたない無病型もしくは個体の参照細胞と比較すること、
(iii)比較結果に基づき、被験体において、疾患治療、特に組織修復、好ましくは心修復に対する応答が、期待されるか、期待されないか、または両価であるかどうかを予測すること
を含む方法。 - (i)被験体の試料において、SH2B3-遺伝子および/またはSH2B3-遺伝子発現をバイオマーカーとして測定することであって、SH2B3-遺伝子および/またはSH2B3-遺伝子発現が突然変異体を含み、
(ii)測定されたSH2B3-遺伝子および/またはSH2B3-遺伝子発現突然変異体を基準値および/または参照と、好ましくは基準値および/または体細胞変異遺伝子および/または遺伝子発現をもたないSH2B3無病型もしくは個体の参照細胞の参照と比較すること、
(iii)比較結果に基づき、被験体において、疾患治療、特に組織修復、好ましくは心修復に対する応答が、期待されるか、期待されないか、または両価であるかどうかを予測すること
を含む、請求項1記載の疾患治療、特に心臓血管再生に対する応答の予測方法。 - SH2B3-遺伝子および/またはSH2B3-遺伝子発現がノックアウト遺伝子および/またはノックアウト遺伝子発現変異体である請求項2記載の方法。
- SH2B3-遺伝子および/またはSH2B3-遺伝子発現変異体が、SH2B3-遺伝子および/またはSH2B3-遺伝子発現変異体1および/またはSH2B3-遺伝子および/またはSH2B3-遺伝子発現変異体2の少なくとも1つの突然変異を含む請求項2および/または3記載の方法。
- SH2B3-遺伝子および/またはSH2B3-遺伝子発現変異体が、配列番号1および/または配列番号2記載の配列を含む請求項2、3および/または4記載の方法。
- LNKタンパク質発現および/またはSH2B3-遺伝子および/またはSH2B3-遺伝子発現変異体の機能の分析をさらに使用する請求項1~5のいずれか1項に記載の方法。
- 1つまたはそれ以上のバイオマーカーをさらに使用し、そのさらなるバイオマーカーが、血管新生因子、生存因子、ケモカイン、循環内皮前駆細胞(EPC)、循環内皮細胞(CEC)、循環血小板、循環単核細胞および亜集団、MNC亜集団上の受容体/リガンド発現、および/または全ゲノム配列RNAからなる群より選択される請求項1~6のいずれか1項に記載の方法。
- バイオマーカーが、好ましくはPLCG1、EPO、LPCAT2、GRB2、AP1B1、AFAP1、KLF8、MARK3、REX1BD、SACM1L、PDGFRB、VEGF、BEX3、デルタ_CT_SH2B3、ZNF205、LTB、EMG1、CD34+細胞/ml PB、BAZ1A、および/またはCD133+細胞/ml PBから、より好ましくはPLCG1、EPO、LPCAT2、GRB2、AP1B1、AFAP1、KLF8、MARK3、REX1BD、SACM1L、PDGFRB、および/またはVEGFから選択される請求項1~7のいずれか1項に記載の方法。
- 予測正確性の感度および特異度が約90%超、好ましくは約92%超、より好ましくは約93%超、最も好ましくは約94%超である請求項1~8のいずれか1項に記載の方法。
- PLCG1、LPCAT2、GRB2、AP1B1、AFAP1、KLF8、MARK3、REX1BD、SACM1L、PDGFRB、BEX3、ZNF205、EMG1、BAZ1A、および/またはLTBがRNAレベルで測定され、および/またはEPOおよび/またはVEGFがタンパク質レベルで測定される請求項1~9のいずれか1項に記載の方法。
- 幹細胞治療に対する応答、および/または血管新生応答の誘導、および/または心筋梗塞、脳卒中および末梢虚血性血管疾患を含む心臓血管疾患の組織修復の術前予測のために使用される請求項1~10のいずれか1項に記載の方法。
- 試料が心臓病および/または動脈硬化に罹患している被験体から採取される請求項1~11のいずれか1項に記載の幹細胞治療に対する応答の予測方法。
- 少なくとも2、3、4、5、6、またはそれより多くの時点の比較結果のプロファイリングを含む請求項1~12のいずれか1項に記載の方法。
- 臨床診断パラメータの使用をさらに含む請求項1~13のいずれか1項に記載の方法。
- 血管新生応答のプロファイリングのために使用される請求項1~14のいずれか1項に記載の方法。
- RNAおよび/またはmRNA配列、および/またはマイクロRNAおよび/または非コーディングRNAなどの機能的RNA、および/または疾患シグネチャーを含むSNPを分析することをさらに含む請求項1~15のいずれか1項に記載の方法。
- RNAおよび/またはDNA配列決定分析および/またはネットワーク経路分析薬物動態および薬理遺伝学データの分析をさらに含む請求項1~16のいずれか1項に記載の方法。
- 表現型検査の分析をさらに含む請求項1~17のいずれか1項に記載の方法。
- 幹細胞治療が、CD133陽性幹細胞の移植を含む請求項1~18のいずれか1項に記載の方法。
- 被験体がヒトである請求項1~19のいずれか1項に記載の方法。
- 試料が、血液、血清、および/または血漿試料、および/または組織生検試料、および/またはEPCなどの循環幹細胞の試料である請求項1~20のいずれか1項に記載の方法。
- 疾患治療、特に心臓血管再生に対する応答の予測方法における使用のための、SH2B3-遺伝子および/またはSH2B3-遺伝子発現突然変異体および/またはSH2B3-遺伝子および/またはSH2B3-遺伝子発現突然変異体のリンパ球アダプタータンパク質発現から選択されるバイオマーカー。
- バイオマーカーが、一つまたはそれより多くのさらなるバイオマーカーと組み合わせて使用され、さらなるバイオマーカーが、血管新生因子、生存因子、ケモカイン、循環内皮前駆細胞(EPC)、循環内皮細胞(CEC)、循環血小板、循環単核細胞および亜集団、MNC亜集団上の受容体/リガンド発現、および/または全ゲノム配列RNAの群から選択される、疾患治療、特に心臓血管再生に対する応答の予測方法における使用のための請求項22記載のバイオマーカー。
- バイオマーカーが、好ましくはPLCG1、EPO、LPCAT2、GRB2、AP1B1、AFAP1、KLF8、MARK3、REX1BD、SACM1L、PDGFRB、VEGF、BEX3、デルタ_CT_SH2B3、ZNF205、LTB、EMG1、CD34+細胞/ml PB、BAZ1A、および/またはCD133+細胞/ml PBから、より好ましくはPLCG1、EPO、LPCAT2、GRB2、AP1B1、AFAP1、KLF8、MARK3、REX1BD、SACM1L、PDGFRB、および/またはVEGFから選択される、疾患治療、特に心臓血管再生に対する応答の予測方法における使用のための請求項23記載のバイオマーカーの組み合わせ。
- PLCG1、LPCAT2、GRB2、AP1B1、AFAP1、KLF8、MARK3、REX1BD、SACM1L、PDGFRB、BEX3、ZNF205、EMG1、BAZ1A、および/またはLTBがRNAレベルで測定され、および/またはEPOおよび/またはVEGFがタンパク質レベルで測定される、疾患治療、特に心臓血管再生に対する応答の予測方法における使用のための請求項23または24記載のバイオマーカーの組み合わせ。
- RNAおよび/またはmRNA配列、および/またはマイクロRNAおよび/または非コーディングRNAなどの機能的RNA、および/または疾患シグネチャーを含むSNPを分析することをさらに含む、疾患治療、特に心臓血管再生に対する応答の予測方法における使用のための請求項22記載のバイオマーカーまたは請求項23~25のいずれか1項に記載のバイオマーカーの組み合わせ。
- 方法および/またはバイオマーカーが幹細胞治療に対する応答の術前予測のために使用され、幹細胞治療が冠動脈バイパス移植(CABG)手術、および/または虚血再灌流介入である、請求項1~21のいずれか1項に記載の方法、または請求項22記載のバイオマーカー、または請求項23~26のいずれか1項に記載のバイオマーカーの組み合わせ。
- 被験体の試料において請求項1~10のバイオマーカーの各々の量を測定するための検出試薬を含む、請求項1~21のいずれか1項に記載の方法を実施するのに適したキット。
- プロセッサ、およびプロセッサに連結された1つまたはそれより多くの機械学習(ML)モデルをコードするメモリを含むコンピュータ装置であって、プログラムがプロセッサに方法を実行させ、該方法が、
(iii)請求項1~10のいずれか1項による測定されたバイオマーカーを、基準値および/または参照と、好ましくは基準値および/または突然変異体をもたないSH2B3遺伝子および/またはSH2B3-遺伝子発現の参照と比較すること、
(iii)比較結果に基づき、被験体において、疾患治療、特に組織修復、好ましくは心臓血管再生に対する応答が、期待されるか、期待されないか、または両価であるかどうかを予測すること
を含むコンピュータ装置。 - (i)被験体の試料において、請求項1~10のいずれか1項に記載のバイオマーカーの各々の量を測定するための分析ユニット、および
(ii)請求項29記載のコンピュータ装置
を含む、請求項1~21のいずれか1項に記載の方法を実行するのに適した装置。
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