JP2020527710A - 心臓血管再生に対する応答の予測方法 - Google Patents
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Abstract
Description
(i)被験体のサンプル中の次のバイオマーカーのそれぞれの量を測定する工程であって、該バイオマーカーは、成長因子、リンパ球アダプタータンパク質、糖タンパク質、脳性ナトリウム利尿ペプチド(BNP)、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(MNC)および亜集団、およびMNC亜集団上の受容体/リガンド発現の群より選択される、
(ii)測定された量をベースライン値および/または参照と比較すること、
(iii)比較結果に基づき、被験体における心臓血管修復への応答が期待されるか、期待されないか、またはであるかを予測すること
を含む方法に関する。
(i)本発明に係るバイオマーカーの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、
(ii)比較の結果に基づいて、被験体における心臓血管再生への応答が期待されるか、基体されないか、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。
心筋梗塞や虚血性心筋症後の心不全患者における心臓再生の誘導は、幹細胞治療を含む複数のアプローチを用いて標的にされてきた。これに関し、有効性の欠如と応答予測可能性の欠如は、治療の標準化と成功のための主な障害となってきた。
事前特定:明確な造血および内皮CD133+EPCの亜集団および血管新生能は、インビトロCFU−EC、CFU−Hillのおよびインビボマトリゲルプラグアッセイ(Matrigel plug assay)ならびにEPC(同時染色パネルCD133、34、117、184、309、105、45)および循環内皮細胞(CEC)(同時染色のパネル:CD31、146、34、45、105、184、309)のパネル一覧を同時染色することに対して、4レーザーフローサイトメトリー法(LSR II、ベクトン デッキンソン、ハイデルベルク、ドイツ)を使用する共発現解析を施行した骨髄(BM)および末梢血(PB)における39人の患者のコホートにおいて試験した。NT−proBNPならびにウイルス分析は、末梢血血清におけるIgGおよび抗原分析により、エプスタイン−バール−ウイルス(EBV)、サイトメガロウイルス(CMV)およびパルボウイルスに関して行った。最終的なデータの閉鎖前に事後解析を、血清血管新生因子およびサイトカインについて行った。
事後分析:BM亜集団分析および末梢血(PB)におけるSH2B3 mRNA RT−PCR:BM CD133+およびPBMNCサンプルを使用したサイトメトリービーズアレイ(CBA)および酵素結合免疫吸着アッセイ(ELISA)およびRT−PCRにおいて研究されたバイオマーカーの方法と分析。
サンプルサイズ計算では、センターによる一次解析の層化は無視された。一次解析に使用された共分散分析(ANCOVA)の代わりに、等分散を有する2標本t検定のシナリオが検討された。サンプルサイズは、両側第1種の誤り(type I error)(α)5%、第2種の誤り(type II error)(β)10%(すなわち、検定力90%)と仮定して測定された。4〜5%の2つの治療アームの間における術後6ヶ月時でのLVEFの差のシナリオは、臨床的に適切な差とみなされた。4.5の差および7.5の標準偏差で、群あたり少なくともn=60の患者が必要とみなされ、そして、さらに15%のドロップアウト率で、合計少なくとも142人の患者がランダム化されるべきであった。サンプルサイズは、市販のプログラムnQuery Advisor 5.0、セクション8、表MTT0−1(Hofmann WK, de Vos S, Elashoff D, et al., Lancet 2002; 359(9305):481-6)を用いて計算された。計算は、中心および非心t分布を用いて実施され、非心パラメータは、√n δ/√2であり、δは、効果の大きさ|μ1−μ2|/σ(O'Brien R G, Muller K E, Signified power analysis for t-tests through multivariate hypothesis. In L K Edward (Ed.) Applied analysis of variance in behavioral science, 1993, New York, Marcel Dekker)として定義される。
安全性解析対象集団(safety set)の患者群(SAS)とパー・プロトコル・セット(per-protocol set)の患者群(PPS)における患者のベースライン特性の分析は、予め指定されたコホート分析の説明に従った、SAS(n=77)およびPPS(n=58)プラセボ対CD133+。主要評価項目アウトカムに影響を与える要因を分析するために追加的に事後分析を実施した。このため、患者はレスポンダー(180日目でLEVFの増加>5%)または、およびノンレスポンダー(180日目でLEVFの増加<5%)として群分けされた。この事後解析によると、35/58(60.3%)の患者が治療レスポンダーであり、そして23/58(39.7%)でLEVFが改善しなかった。このレスポンダー/ノンレスポンダー(NR)比は、プラセボ群57/43%(R/NR:17/13患者(pt))およびCD133+群64/36%(R/NR:18/10pt.)とそれぞれ同様であった(プラセボ対CD133+:p=0.373)。
PPS有効性分析群(n=58)は、ベースラインLVEF 33.5%、SD ±6.26%[最小−最大 25−49]、n=58でMI後のポンプ機能低下(安静時MRIで測定)によって特徴付けられた。予め指定された主要評価項目:治療後6ヶ月の左心室機能は、+9.6%±SD11.3%[最小−最大 13−42]、p<0.001(n=58)のLVEFのかなりの増加を示した。CABGの血管再生による左心室機能の早い改善および遅い心筋逆リモデリングを判別するために、退院時の追加の中間MRI分析が、サブ群の患者(n=29)で利用可能であった。これにより、主に+6.5%,SD ±7.92%[最小−最大 11−23]、p=0.007(n=29)のΔLVEFの遅い(10〜180日)増加が明らかとなった。主要評価項目のANCOVA分析において、プラセボ群では、180日でベースラインLVEFが33.5%から42.3%に改善し(ΔLVEF +8.8%、SE ±2.17%[CI 38.0、46.6]、p<0.001;n=30)、そしてCD133+群のLVEFは、33.5%から43.9%に上昇した(ΔLVEF +10.4%、SE ±2.33%[CI 39.0、48.5]、p<0.001;n=28)。+2.58±SE 3.13%[CI -3.7−8.9]、p=0.414でのCD133+対プラセボの治療群差は、ANCOVA分析において統計的に有意ではなかった。CD133+幹細胞群は、プラセボコントロール群(10〜180日 ΔLVEF)+4.3%、SD ±8.8%[最小−最大 11−23]、p=0.077(n=15)に対して、主に+8.8%,SD ±6.38%[最小−最大 4−10],p=0.001(n=14)の遅い相(10〜180日 ΔLVEF)においてΔLVEFの改善を示した。
事後主要評価項目の解析において、治療レスポンダーは、180日での対ベースラインΔLVEFが5%より高いものとして定義された。58人の患者のコホートにおける35人のレスポンダーの広がりという結果は、180d/0での+17.1%;SE ±2.08%[CI 12.9.;21.3]、R対NR、p<0.0001(180d/0)、n=58のANCOBAにおけるΔLEVFの全体的な増加によって特徴付けられた。LVEFの増加はCD133+(+19.1%)対プラセボ(+13.9%)、p=0.099、n=35(データは示さず)であった。対照的に、ノンレスポンダーは、180d/0でのΔLVEFを0%、SE ±5.73%[CI 22.3;44.8]p=0.287だけ示した(プラセボ/NR +3.3%,CD133+/NR −2.4%)。
AE=有害事象
AESI=特別に関心のある有害事象
AHA=アメリカ心臓協会
ANCOVA=共分散の分析
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
EA=早期抗原
EBNA1=EBV−核抗原
EBV=エプスタインバービールス
EC=内皮細胞
ECG=心エコー
ELISA=酵素結合免疫吸着アッセイ
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
GMP=適性製造基準
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
IGFBP2/3=インスリン様成長因子−結合タンパク質2/3
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
IP−10=C−X−Cモチーフケモカイン10(CXCL10)としても知られている、インターフェロンガンマ誘導性タンパク質10
LMCA=左主冠状動脈
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
ML=機械学習
MNC=単核細胞
MRI=核磁気共鳴画像法
6MWT=6分歩行テスト
NT−proBNP=B−型脳性ナトリウム利尿ペプチド
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
PEI=ポール・エーリッヒ研究所
PPS=パー・プロトコル・セットの患者群
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
SH2B3=重要なアダプタ機能を有するSH2含有タンパク質に属する
SCF=幹細胞因子
STEMI=STセグメント上昇心筋梗塞
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
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
VEGFR2/KDR=血管内皮増殖因子受容体2/キナーゼ挿入ドメイン受容体
Claims (26)
- 心臓血管再生に対する応答の予測方法であって、
(i)被験体のサンプル中の、成長因子、リンパ球アダプタータンパク質、糖タンパク質、脳性ナトリウム利尿ペプチド(BNP)、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、ならびにMNC亜集団上の受容体/リガンド発現の群より選択される、バイオマーカーのそれぞれの量を測定すること、
(ii)測定された量をベースライン値および/または参照と比較すること、
(iii)比較結果に基づき、被験体における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を予測すること
を含む方法。 - 予測精度の感度および特異性が約80%超である請求項1記載の方法。
- 成長因子が、好ましくはVEGFおよび/またはエリスロポエチンから選択され、リンパ球アダプタータンパク質が、好ましくはSH2B3から選択され、糖タンパク質が、好ましくはビトロネクチンから選択され、および脳性ナトリウム利尿ペプチドが、好ましくはNT−proBNPから選択される請求項1または2記載の方法。
- 方法がさらなるバイオマーカーを使用し、さらなるバイオマーカーが、サイトカイン、インターロイキン、インターフェロン、インスリン様成長因子結合タンパク質、インスリン様成長因子、ケモカインタンパク質および/またはマルチタンパク質E3ユビキチンリガーゼ複合体の群から選択される請求項1、2または3記載の方法。
- サイトカインが、好ましくはTNFから選択され、インターロイキンが、好ましくはIL−6、IL−8、および/またはIL−10から選択され、インターフェロンが、好ましくはヒトインターフェロンガンマ誘導性タンパク質10から選択され、インスリン様成長因子結合タンパク質が、好ましくはインスリン様成長因子結合タンパク質−2および/またはインスリン様成長因子結合タンパク質−3から選択され、インスリン様成長因子が、好ましくはIGF2から選択され、ケモカインタンパク質が、好ましくはSDF−1から選択され、および/またはマルチタンパク質E3ユビキチンリガーゼ複合体が、好ましくはSCFから選択される請求項4記載の方法。
- 方法が、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、心疾患および/または虚血性プレコンディショニングの、幹細胞治療に対する応答の術前予測および/または血管新生応答の誘導および/または組織修復のために使用される請求項1〜5のいずれか1項に記載の方法。
- サンプルが心疾患および/または動脈硬化症に罹患している被験体から採取される請求項1〜6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のための方法。
- 方法が、少なくとも2つ、3つ、4つ、5つ、6つまたはそれ以上の時点の比較の結果のプロファイリングを含む請求項1〜7のいずれか1項に記載の方法。
- 予測精度の感度および特異性が90%超である請求項8記載の方法。
- 方法が、臨床診断パラメータの使用をさらに含む請求項1〜9のいずれか1項に記載の方法。
- 方法が、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1〜10のいずれか1項に記載の方法。
- 方法が、診断指標を含む、RNAおよび/またはmRNA配列および/またはマイクロRNAおよび/またはノンコーディングRNAなどの機能的RNAおよび/またはSNPを分析することをさらに含む請求項1〜11のいずれか1項に記載の方法。
- 方法が、RNAおよび/またはDNA配列分析および/またはネットワーク経路分析を用いた薬物動態学および薬理遺伝学データ分析をさらに含む請求項1〜12のいずれか1項に記載の方法。
- 方法が、表現型の分析をさらに含む請求項1〜13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1〜14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1〜15のいずれか1項に記載の方法。
- サンプルが、血液、血清および/または血漿サンプル、および/または組織生検サンプルおよび/またはEPCなどの循環幹細胞のサンプルである請求項1〜16のいずれか1項に記載の方法。
- 心臓血管再生に対する応答を予測するための方法における使用のための、成長因子、リンパ球アダプタータンパク質、糖タンパク質、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(MNC)および亜集団、MNC亜集団上の受容体/リガンド発現および脳性ナトリウム利尿ペプチド(BNP)の群から選択されるバイオマーカーの組み合わせ。
- 成長因子が、好ましくはVEGFおよび/またはエリスロポエチンから選択され、リンパ球アダプタータンパク質が、好ましくはSH2B3から選択され、糖タンパク質が、好ましくはビトロネクチンから選択され、および脳性ナトリウム利尿ペプチドが、好ましくはNT−proBNPから選択される、心臓血管再生に対する応答の予測のための方法における使用のための請求項18記載のバイオマーカーの組み合わせ。
- 前記組み合わせが、サイトカイン、インターロイキン、インターフェロン、インスリン様成長因子結合タンパク質、インスリン様成長因子、ケモカインタンパク質および/またはマルチタンパク質E3ユビキチンリガーゼ複合体の群から選択される1つまたは複数のバイオマーカーをさらに含む請求項18または19記載のバイオマーカーの組み合わせ。
- サイトカインが、好ましくはTNFから選択され、インターロイキンが、好ましくはIL−6、IL−8および/またはIL−10から選択され、インターフェロンが、好ましくはヒトインターフェロンガンマ誘導性タンパク質10から選択され、インスリン様成長因子結合タンパク質が、好ましくはインスリン様成長因子結合タンパク質2および/またはインスリン様成長因子結合タンパク質3から選択され、インスリン様成長因子が、好ましくは、IGF2から選択され、ケモカインタンパク質が、好ましくはSDF−1から選択され、および/または、マルチタンパク質E3ユビキチンリガーゼ複合体が、好ましくはSCFから選択される請求項20記載のバイオマーカーの組み合わせ。
- 方法が、臨床診断データ、および/またはRNAおよび/またはmRNAおよび/またはマイクロRNAおよび/またはノンコーディングRNAなどの機能的RNAおよび/またはSNPの分析、および/または薬物動態学的データの分析、および/または表現型の分析をさらに含む、心臓血管再生に対する応答の予測のための方法における使用のための請求項18〜21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、前記幹細胞治療が、冠状動脈バイパス移植(CABG)を伴う請求項6または17記載の方法または請求項18〜21のいずれか1項に記載のバイオマーカーの組み合わせ。
- 請求項1〜17のいずれか1項に記載の方法を実行するために適合されたキットであって、前記被験体のサンプル中の、請求項1〜5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キット。
- プロセッサおよびプロセッサに結合された1つまたは複数の機械学習(ML)モデルをエンコードするメモリを含むコンピュータ装置であって、前記プログラムは、前記プロセッサに方法を実行させ、前記方法が、
(i)請求項1〜5のいずれか1項に記載のバイオマーカーの測定量をベースライン値および/または参照と比較し、
(ii)比較の結果に基づいて、被験体における心臓血管再生への応答が、予想されるか、予想されないか、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。 - 請求項1〜17のいずれか1項に記載の方法を実行するように適合された装置であって、
(i)被験体のサンプル中の、請求項1〜5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25記載のコンピュータ装置
を含む装置。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007511206A (ja) * | 2003-10-13 | 2007-05-10 | ヨハン ヴォルフガング ゲーテ−ウニヴェルジテート フランクフルト アム マイン | 骨髄前駆細胞(BMPs)および/または血液由来血中前駆細胞(BDPs)の心臓血管機能性を診断するためのインビトロでの方法 |
WO2007142288A1 (ja) * | 2006-06-07 | 2007-12-13 | The University Of Tokushima | エリスロポエチンを用いた虚血性疾患の治療 |
WO2009061382A2 (en) * | 2007-11-02 | 2009-05-14 | Marban Eduardo T | Cardiac stem cell and myocyte secreted paracrine factors and uses thereof |
US20130095060A1 (en) * | 2011-10-12 | 2013-04-18 | National Cheng Kung University | Pharmaceutical composition for promoting arteriogenesis, and preparation method and applications for the same |
JP2013520509A (ja) * | 2010-02-25 | 2013-06-06 | エイビーティー ホールディング カンパニー | 血管形成の調節 |
JP2016508129A (ja) * | 2012-12-20 | 2016-03-17 | セリャド エス.アー. | バイオマーカー方法および組成物 |
JP2017512988A (ja) * | 2014-03-26 | 2017-05-25 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 拡張機能障害を診断するためのigfbp7 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2666789C (en) * | 2006-10-18 | 2016-11-22 | Yong Zhao | Embryonic-like stem cells derived from adult human peripheral blood and methods of use |
RU2545757C2 (ru) * | 2008-10-30 | 2015-04-10 | Сантр Де Решерш Пюблик Де Ля Сантэ | Биомаркеры |
TWI492707B (zh) | 2009-05-20 | 2015-07-21 | 卡迪歐參生物科技有限公司 | 治療心臟疾病之藥品配方 |
GB201007159D0 (en) * | 2010-04-29 | 2010-06-09 | Nhs Blood & Transplant | Method for evaluating anglogenic potential |
CN101940591B (zh) * | 2010-08-27 | 2013-09-18 | 上海士腾生物技术有限公司 | 促血管再生或新生的制剂及其制备方法 |
CN101940594B (zh) | 2010-08-27 | 2013-12-04 | 上海士腾生物技术有限公司 | 用于治疗缺血性心血管疾病的制剂及其制备方法 |
US20150111224A1 (en) * | 2012-03-16 | 2015-04-23 | Fatih Arslan | Biomarkers for adverse cardiac remodeling |
-
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007511206A (ja) * | 2003-10-13 | 2007-05-10 | ヨハン ヴォルフガング ゲーテ−ウニヴェルジテート フランクフルト アム マイン | 骨髄前駆細胞(BMPs)および/または血液由来血中前駆細胞(BDPs)の心臓血管機能性を診断するためのインビトロでの方法 |
WO2007142288A1 (ja) * | 2006-06-07 | 2007-12-13 | The University Of Tokushima | エリスロポエチンを用いた虚血性疾患の治療 |
WO2009061382A2 (en) * | 2007-11-02 | 2009-05-14 | Marban Eduardo T | Cardiac stem cell and myocyte secreted paracrine factors and uses thereof |
JP2013520509A (ja) * | 2010-02-25 | 2013-06-06 | エイビーティー ホールディング カンパニー | 血管形成の調節 |
US20130095060A1 (en) * | 2011-10-12 | 2013-04-18 | National Cheng Kung University | Pharmaceutical composition for promoting arteriogenesis, and preparation method and applications for the same |
JP2016508129A (ja) * | 2012-12-20 | 2016-03-17 | セリャド エス.アー. | バイオマーカー方法および組成物 |
JP2017512988A (ja) * | 2014-03-26 | 2017-05-25 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 拡張機能障害を診断するためのigfbp7 |
Non-Patent Citations (4)
Title |
---|
CHRISTOF STAMM: "Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic", THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, vol. 133(3), JPN6022022517, March 2007 (2007-03-01), pages 717 - 725, ISSN: 0004793292 * |
SANG-MO KWON: "Pivotal Role of Lnk Adaptor Protein in Endothelial Progenitor Cell Biology for Vascular Regeneration", CIRCULATION RESEARCH, vol. 104(8), JPN6022022519, 24 April 2009 (2009-04-24), pages 969 - 977, ISSN: 0004793290 * |
SHERYL L CHOW: "Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure: A Scientific Sta", AHA SCIENTIFIC STATEMENT, vol. 35(22), JPN6022022518, 30 May 2017 (2017-05-30), pages 1054 - 1091, ISSN: 0004793291 * |
山崎 元成: "低左心機能症例における冠動脈バイパス術,術直後および中期遠隔期成績,予後因子の検討", 冠疾患誌, vol. 17, JPN6022022520, 2011, pages 8 - 15, ISSN: 0005021838 * |
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