缺血性心臟病基因治療

1、缺血性心臟病基因治療現(xiàn)有治療藥物治療PCICABG 具有局限性！ 無(wú)法血運(yùn)重建 細(xì)胞喪失生物學(xué)治療基因治療、細(xì)胞成形術(shù)優(yōu)化現(xiàn)有的治療為終末期患者提供新的治療途徑基因治療的目的在于修復(fù)、替代體內(nèi)突變、缺失的基因或加強(qiáng)某些被不良抑制基因的功能，或抑制某些不當(dāng)過(guò)強(qiáng)表達(dá)基因的功能，以達(dá)到使機(jī)體異常的功能、代謝得以改善、恢復(fù)的目的。Angiogenesis StatusSince 1999 a massive wave of angiogenesis-stimulating drugs in clinical trials: 5 drugs for coronary artery disease; 6

2、5 drugs for peripheral vascular disease; 2 drugs for stroke; 10 drugs for wound healing;Laser Doppler blood flow in ischemic hindlimb model血管內(nèi)皮生長(zhǎng)因子（ VEGF）： 形成最初的血管叢 血管生成細(xì)小，有滲漏基因治療：VEGF-121進(jìn)行了人下肢缺血性治療的二期臨床試驗(yàn)(863)血管生成素（Ang）： 穩(wěn)定新生血管壁 血管口徑增大VEGF165和Ang1基因 促血管生成和抗缺血研究研究?jī)?nèi)容構(gòu)建Ad5-VEGF165和Ad5-Ang1 聯(lián)合轉(zhuǎn)染促血管生成作

3、用研究 聯(lián)合轉(zhuǎn)染抗心肌缺血作用研究機(jī)制探討研究結(jié)果更強(qiáng)的促血管生成作用 進(jìn)一步減少心肌梗死面積Ang1組和聯(lián)合組與對(duì)照組均有顯著性差異，但VEGF組無(wú)顯著性差異；Ang1組和聯(lián)合組與VEGF組均有顯著性差異高調(diào)心肌Bcl-2，抗凋亡單獨(dú)轉(zhuǎn)染組以及聯(lián)合組PI3K活性均比對(duì)照組顯著性增高；聯(lián)合組比VEGF單獨(dú)轉(zhuǎn)染組顯著升高，但與Ang1組無(wú)差異。進(jìn)一步活化心肌PI3K信號(hào)腺病毒介導(dǎo)肝細(xì)胞生長(zhǎng)因子治療缺血性心臟病(863,973) HGF在心血管方向的研究現(xiàn)狀抗心肌細(xì)胞凋亡，促進(jìn)血管新生，抗心肌組織纖維化促梗死周遍區(qū)心肌肥厚可能改善梗死后室壁擴(kuò)張，有待進(jìn)一步研究體外實(shí)驗(yàn)中發(fā)現(xiàn)HGF誘導(dǎo)骨髓干細(xì)胞分化

4、成心肌細(xì)胞以及能誘導(dǎo)特異的前體細(xì)胞沿濃度梯度定向遷移至梗死區(qū) 通過(guò)阻NFkappaB旁路，起到抗炎作用 研究目的考察經(jīng)非梗死相關(guān)動(dòng)脈轉(zhuǎn)染Ad5-HGF對(duì)梗死后心衰的改善作用 研究轉(zhuǎn)染Ad5-HGF后，局部心肌中CD117+干細(xì)胞動(dòng)員情況對(duì)比經(jīng)非梗死相關(guān)動(dòng)脈移植骨髓間充質(zhì)干細(xì)胞（BM-MSCs）或轉(zhuǎn)染Ad5-HGF對(duì)心梗死后心衰治療作用 實(shí)驗(yàn)技術(shù)方法對(duì)照組急性心梗模型建立MSCs培養(yǎng)移植（4周后）門控心肌顯像，冠狀動(dòng)脈造影處死，免疫組織化學(xué)Ad5-HGF組BM-MSCs組 3周后再次心肌顯像，冠脈造影開胸結(jié)扎前降支，建立模型門控心肌核素顯像A:對(duì)照組4周和7周對(duì)比B:Ad5-HGF 組4周和7周

5、對(duì)比 心 功 能冠狀動(dòng)脈造影：側(cè)支循環(huán)分析A:對(duì)照組4周和7周對(duì)比B:Ad5-HGF 組4周和7周對(duì)比 免疫組化ELISA法檢測(cè)心肌組織中HGF蛋白表達(dá) 因子陽(yáng)性血管A: BM-MSCs治療組 B: Ad5-HGF治療組 SMA陽(yáng)性血管A: BM-MSCs治療組B: Ad5-HGF治療組 CD117+細(xì)胞結(jié)果 A:對(duì)照組B：Ad5-HGF 組連續(xù)切片CD117和C-Met抗體免疫組織化學(xué)檢測(cè) A：顯示細(xì)胞呈CD117+ B：顯示細(xì)胞也呈C-Met+ 結(jié) 論經(jīng)冠脈轉(zhuǎn)染Ad5-HGF能使心肌高度表達(dá)HGF蛋白， HGF對(duì)心肌梗死慢性期的側(cè)枝循環(huán)形成，心肌灌注及心功能均有改善作用 經(jīng)非梗死相關(guān)動(dòng)脈移

6、植BM-MSCs或肝細(xì)胞生長(zhǎng)因子均能促進(jìn)梗死心臟心功能改善和促進(jìn)血管再生；BM-MSCs移植或Ad5-HGF轉(zhuǎn)導(dǎo)，未顯示何者更具優(yōu)勢(shì)。 HGF能增加動(dòng)員至缺血區(qū)的CD117+骨髓干細(xì)胞，并且該類細(xì)胞表達(dá)c-Met+；HGF改善心功能及心肌灌注的作用不僅僅是血管新生，可能還涉及到對(duì)干細(xì)胞的動(dòng)員召集作用。 文章被引用VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways . 2005 Gene TherapyAd-HGF

7、 Clinical Trial Phasein China 23 CHD patients, divided into 3 groups by different dose of Ad-HGF 5109pfu Ad-HGF11010pfu Ad-HGF21010pfu Ad-HGF Low dose group:6 casesMiddle dose group:6 casesHigh dose group:11cases11 patients only received HGF therapySafety2 patients have transient fever(38.0-38.5 0C)

8、 within one week after gene therapy，and recovered after 2-3 daysAll subjects have routine examination of blood, biochemical index, and tumor marker, all of them have no significant changeEfficiency Evaluate the efficiency in patients received HGF therapy onlyDiagnosis1.Coronary artery disease；2.unst

9、able angina Angina grading (Canada）Angiography：1.LAD proximal segment 90% stenosis；2.LCX proximal middle segment 80%，middle segment:total occluded ；3.RCA mild stenosisLAD、LCX with HGF After 5 weeksAngino grading（Canada）ECT ：after treatment, the perfusion of inferior wall improved, LV diameter dimini

10、shedPrepost Prepost Prepost PrepostPerfusion LVd Diagnosis 1.CHD；2. unstable angina Angina grading（Canada）Angiography 1.LAD proximal segment total occluded ；2.LCX middle and distal segment 90% stenosis；3.RCA proximal segment 70% stenosisLAD、LCX with HGFAfter 5 weeksAngina grading (Canada)ECT：anterio

11、r and posterior wall perfusion improvedPrepost Prepost Prepost PrepostPerfusionM-03 Name GSBI Sex male Diagnosis 1. CHD；2. Stable angina Angina grading（Canada）Angiography 1.LAD proximal segment 50% stenosis ，middle segment 30stenosis；2.LCX stenosis in stent ，distal segment mild irregular 3.RCA reste

12、nosis in stent ，proximal segment of stent 30-50% stenosis，distal 30%LAD,LCX with HGFAfter 5 weeksAngina grading (Canada)ECT：LV anterior, IVS, inferior wall perfusion significantly improved。LV diameter diminished.Prepost Prepost Prepost PrepostPerfusion LVd Diagnosis 1.CHD ；2.unstable anginaAngina gr

13、ading（Canada ） Angiography: LAD proximal and middle segment 70-80% stenosis ，LCX 70%，middle segment 80% stenosis，OM1proximal segment 80% stenosis，RCA proximal segment 70%，distal segment 90%LAD、LCX、RCA with HGFAfter 5 weeksAngina grading (Canada) ECT：anterior and posterior wall perfusion significant

14、improved 。Prepost Prepost Prepost PrepostPerfusionB-01 name XJLI Sex M Age 69Diagnosis CHD, AMI，Myocardial dysfunction，Hypertension，DM type 2 Angina grading（Canada）IIIAngiography: LM 90%，LAD、LCX 75-90% stenosis，RCA long stenosis，occluded in distal segmentLAD、LCX、RCA with HGFTreatment for 5 weekAngin

15、a grading（Canada）IIIECT：No significant improvmentPrepost Prepost PrepostB-03 name TZHE Sex M Age 71Diagnosis CHD、AMI，Hypertension、DM Angina grading （Canada）2Angiography LAD proximal segment 90%，middle segment total occlusion ，LCX distal segment 80% stenosis，RCA distal segment 60% stenosisLAD with HG

16、FTreatment for 5 weeksAngina grading (Canada): 1 ECT：Perfusion of anterior wall ,inferior wall and lateral wall significantly improved, cardiac chamber also diminished。Prepost Prepost Prepost PrepostPerfusion LVd ConclusionIn all 11 patients7 patients clinical syndrome improved5 patients myocardium perfusion