JP2020516301A - 骨髄応答および免疫応答の予測のためのsh2bアダプタータンパク質3 - Google Patents
骨髄応答および免疫応答の予測のためのsh2bアダプタータンパク質3 Download PDFInfo
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Abstract
Description
i.被験体からの血液サンプリング
ii.SH2B3遺伝子発現の測定、好ましくはRT−PCRおよび/またはqPCRによる
iii.レスポンダーであるかまたはノンレスポンダーであるかの分類
を含む。
(i)被験体からの血液サンプリング、
(ii)好ましくはRT−PCRおよび/またはqPCRによる、SH2B3遺伝子発現の測定、
(iii)測定された量をベースライン値および/または参照値と比較すること、
(iv)レスポンダーまたはノンレスポンダーへの分類
を含む。
心筋内CD133+精製自己骨髄性幹細胞(BMSC)移植が、急性PCIおよび二次的な冠動脈バイパス術による冠動脈血行再建で順に処置された、ST上昇型心筋梗塞(STEMI)および冠動脈3枝病変疾患の後の、左室駆出率(LVEF)の低下を伴う左室心機能の回復のための冠動脈バイパスグラフト(CABG)血管再生への補助的方法として調べられた。安全性および有効性に関する先のトライアル(フェーズI、IIa、IIb)は、向上された左室駆出率(LVEF)、および、補助的なCD133+ BMSC処置の冠動脈血管再建術への臨床的安全性を示した。無作為化二重盲検プラセボ対照臨床試験が、臨床的安定性、有効性、および、インターベンションCD133+ BMSC移植による心臓の修復機序と関連するCD133+骨髄性幹細胞を同定するためのバイオマーカーを評価するためにデザインされた。
事後解析:主要エンドポイントレスポンダー(R:ΔLVEFが5%以上)群は、ΔLVEFにおいて大きな増加を示した(17.6% 6か月/0、プラセボ対CD133+:+13.9対+19.1%、p=0.066)。ノンレスポンダー(NR)(LVEF<5% 6か月/0)(CD133+で36%およびプラセボで43.5%)は、末梢血液において、増加されたSH2B3 mRNA発現(p=0.032片側p値/p=0.073両側p値、NR対R)、増加したEPO(p=0.02、NR対R)の存在下の減少した血小板(p=0.004、NR対R)およびEPC(NR対R、CD133+117+、p=0.027)によって術前に特徴づけられた。長期生存は、NRにおいて低下した(カプランマイヤー法、R対NR、HR 0.3、p=0.067)。機械学習を用いて、レスポンダーまたはノンレスポンダーの患者の区別を可能にする10個の術前パラメータが同定された。
SH2B3遺伝子発現の測定が全血のサンプリング、その後のRT−PCRによって行われた。
末梢血液(EDTA血液)の未変性のサンプルが、LightCycler(登録商標) 480 システムII(Roche Deutschland Holding GmbH)を用いた定量リアルタイムPCRに用いられた。
未変性のヒト組織サンプルが、全血サンプルの代わりに用いられた。SH2B3の測定が、実施例2または3で記載されているようにRT−PCRによって行われた。
培養されたヒトまたは非ヒト細胞および組織が、全血サンプルの代わりに用いられた。SH2B3の測定が、実施例2または3で記載されているようにRT−PCRによって行われた。
遺伝子組み換えのヒトまたは非ヒト細胞、組織および器官が、全血サンプルの代わりに用いられた。SH2B3の測定が、実施例2または3で記載されているようにRT−PCRによって行われた。
CD=分化抗原群
CABG=冠動脈バイパスグラフト
BM=骨髄
QC=BMから単離されたCD133+内で行われる品質維持
LVEF=左室駆出率
MNC=単核細胞
PB=末梢血液
IHG=ISHAGEガイドラインに従って行われる分析
EPC=内皮前駆細胞、EPCパネル、PB中で測定されるCD
CEC=循環内皮細胞、CECパネル、PB中で測定されるCD
SCF=幹細胞因子
VEGF=血管内皮増殖因子
VEGFR2/KDR/VEGF−REC=血管内皮増殖因子レセプター2/キナーゼ挿入ドメインレセプター
末梢血液中の誘導されたSH2B3発現の組織再生に対する影響が以下の表2に示されている。
Claims (35)
- 診断マーカーとしての使用のためのSH2B3。
- 骨髄応答および免疫応答の予測のための診断における使用のためのSH2B3。
- SH2B3遺伝子の発現が、RNAのレベルで、より好ましくはmRNAのレベルで測定される、請求項1または2記載の使用のためのSH2B3。
- 骨髄性幹(前駆)細胞または非骨髄性幹(前駆)細胞および/または血液細胞および/または免疫細胞および/または血管細胞および/または組織細胞の増殖および炎症応答の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- インテグリンレセプターまたはエリスロポエチン(EPO)レセプターまたは幹細胞因子(CD105)またはVEGF−REC(CD309)または幹細胞増殖因子(CD117)またはノッチレセプターの内皮活性化または抑制の発現の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- インテグリンレセプターもしくはエリスロポエチンレセプターもしくは幹細胞因子(CD105)もしくはVEGF−REC(CD309)もしくはCXCR4(CD184)もしくは幹細胞増殖因子(CD117)もしくはノッチ受容体の骨髄性幹(前駆)細胞(MSCのCD133+)活性化または抑制の発現の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- EPOおよびVEGFの末梢血液への遊走の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 末梢血液中への、炎症性サイトカインの遊走の予測、好ましくは、TNFアルファ、IP−10、インターロイキンの遊走の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- EPOおよびVEGFの末梢血液中への遊走への(幹)細胞応答の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 炎症性サイトカインまたは増殖因子の末梢血液中への遊走への(幹)細胞応答の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 末梢血液中における、薬剤、栄養素、(ナノ)粒子、マイクロ−RNA、タンパク質、融合溶液、および/または有毒な試薬の末梢血液レベルへの(幹)細胞応答の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 特には骨髄性幹細胞(CD133+)増殖および末梢のVEGF−RECへ結合するEPC(CD133+、CD117+、CD34+)の遊走による、血管新生刺激の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 特には骨髄性幹細胞(CD133+)増殖および血小板の遊走による、巨核球刺激または抑制の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 特には骨髄性幹細胞(CD133+)増殖ならびに赤血球、骨髄性細胞およびリンパ球の遊走による、血管新生増加刺激または抑制の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 内皮または脈管前駆細胞またはMSCの増殖刺激または増殖の抑制の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 幹細胞因子またはインテグリンレセプターまたは細胞接着レセプターの内皮活性化の発現の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- エリスロポエチンレセプターまたはVEGF−RECの内皮活性化の発現の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 白血球またはリンパ球インテグリンレセプター発現の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 末梢組織の修復および酸素化の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 骨髄応答または骨髄不全または骨髄性幹細胞増殖応答または血液細胞の骨髄遊走の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 血液細胞、免疫細胞、造血(CD133+)幹細胞、骨髄細胞または組織細胞または内皮細胞または非造血性幹細胞の炎症応答の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 骨髄性幹細胞増殖およびEPC CD133+の遊走の予測のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 末梢性虚血および炎症の処置における使用のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 血管修復、心筋再生およびアテローム性動脈硬化の治療における使用のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 心筋梗塞、虚血性心筋症、および冠動脈疾患の後の心不全を患う被検体の処置のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- LVEF修復の治療のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 心臓、血管、または非心血管性の組織再生、応答している患者の選択、および血管新生応答のモニタリングにおける請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 虚血性疾患、発作、末梢性虚血、(多発)外傷、蘇生、ショック、敗血性炎症反応症候群(SIRS)、および/または敗血症を患う被検体の処置のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- 感染性疾患、ウイルス性疾患、被爆、化学療法、薬物副作用、および/またはがんを患う被検体の処置のための請求項1〜3のいずれか1項に記載の使用のためのSH2B3。
- i.被験体からの血液サンプリング、
ii.好ましくはRT−PCRおよび/またはqPCRによる、SH2B3遺伝子発現の測定、
iii.レスポンダーまたはノンレスポンダーへの分類
を含む、SH2B3遺伝子発現を調べるための方法。 - 被検体の組織サンプリングを含む、請求項30記載の方法。
- 骨髄性幹細胞レスポンダー対ノンレスポンダーを含む、請求項30記載の方法。
- 炎症レスポンダー対ノンレスポンダーを含む、請求項30記載の方法。
- 前記被検体が、冠動脈疾患、アテローム性動脈硬化、セリアック病、一型糖尿病、感染性疾患、自己免疫疾患、および/または関節性リウマチを患っている、請求項30記載の方法。
- 前記分類が、共分散分析(ANCOVA)および/または2標本検定を介して行われる請求項30記載の方法。
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- 2018-04-10 CA CA3059647A patent/CA3059647A1/en not_active Abandoned
- 2018-04-10 CN CN201880024292.9A patent/CN110506125A/zh active Pending
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US20200115743A1 (en) | 2020-04-16 |
WO2018189198A1 (en) | 2018-10-18 |
CA3059647A1 (en) | 2018-10-18 |
AU2018251942A1 (en) | 2019-10-03 |
EP3610038A1 (en) | 2020-02-19 |
SG11201908331SA (en) | 2019-10-30 |
DE102017107661A1 (de) | 2018-10-11 |
CN110506125A (zh) | 2019-11-26 |
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