Name: large animal model for evaluating the efficacy of the gene therapy in ischemic heart
Uploaded: 2021-09-02T14:30:00
Description: Watch this Scientific Journal Video about Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart at JoVE.com

The authors would like to thank Maria Hedman, Tiina Laitinen, Tomi Laitinen, Pekka Poutiainen, Annika Viren, and Severi Sormunen for assistance and permitting 15O-PET imaging at Kuopio University Hospital; and Heikki Karhunen, Minna T&#246;rr&#246;nen, and Riikka Ven&#228;l&#228;inen from National Laboratory Animal Center for their assistance in animal work.
This study is supported by grants from Finnish Academy, ERC, and CardioReGenix EU Horizon 2020 grant.

The experiments presented here are performed using about 10-week-old female domestic pigs and are approved by the Animal Experiment Board in Finland. Animals weigh 30-40 kg at the beginning of the protocol, allowing the same procedural equipment and imaging modalities as possible for humans. Chronic ischemia is induced 14 days before the gene transfer, and the follow-up time after the gene transfer depends on the viral vector used. The study protocol is shown in Figure 1. This protocol can b...

<ol>
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T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+bottleneck+stent+model+for+chronic+myocardial+ischemia+and+heart+failure+in+pigs.">The bottleneck stent model for chronic myocardial ischemia and heart failure in pigs.</a> American Journal of Physiology. Heart and Circulatory Physiology. 305 (9), 1297-1308 (2013).</li><li>Greenberg, N. 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The timepoints of this protocol may be modified according to the viral vector used. Also, the immunohistological analyses may be selected according to the therapeutic gene. It is also possible to add more timepoints and endpoints to the protocol if needed.
This protocol comprises stages, which are essential to succeed and impossible to correct afterward. First, if one fails to induce appropriate ischemia, the animal must be excluded from further procedures and analyses. Standardization of the ...

Coronary artery disease is accountable for the vast proportion of mortality and disease burden worldwide1. Current treatment strategies are percutaneous interventions, pharmacological treatment, and bypass surgery2. However, despite the progression of these current therapeutics, many patients suffer from so-called refractory angina, underlining the unmet need for novel treatment approaches3. Gene therapy-mediated therapeutic angiogenesis could target this patient group.
Myocardial gene therapy is most often delivered by using different viral vectors, most commonly replication-deficient adenovirus4. As therapeutic genes, various angiogenic growth factors are used. The most substantially studied angiogenic growth factors are the vascular endothelial growth factors (VEGFs) that mediate their angiogenic signaling through vascular endothelial growth factor receptors (VEGFRs) and their co-receptors5. Several clinical trials have proved the benefit and safety of cardiac gene therapy and made this novel treatment method a realistic option for treating ischemic heart diseases6,7. However, this concept still needs enhancement of the therapeutic genes and viral vectors put to the test in large animal models before entering the clinics. The pig has been frequently used as a laboratory animal since its heart is very similar to the human heart. The size of the cardiovascular system of a pig allows the usage of similar catheter inventions as used in humans. All imaging modalities available for humans can be used in pigs8.
There are several large animal models for chronic ischemia. The most commonly used is the ameroid constrictor model9,10,11. The downside of this method is the invasiveness since thoracotomy is needed to access the coronary vasculature. Previously in our group, a mini-invasive bottleneck stent model for chronic myocardial ischemia has been developed12. This method is also used in this manuscript to induce myocardial ischemia.
The usability of ultrasound imaging has evolved substantially despite the age of the imaging modality. For example, myocardial strain is still mainly in research usage due to its novelty. Myocardial strain reflects changes in the contractile function of the heart better than the traditional M-mode ejection fraction measurement13. Thus, here in the large animal model, myocardial strain measurement is utilized. To evaluate the function of the heart, cardiac output is also measured by cine imaging of the left ventricle during angiography. Cardiac output is measured both at rest and under dobutamine-induced stress to evaluate myocardial function under stress.
In addition to the measurements of the heart function, information on myocardial perfusion is essential in gene therapy studies aiming at therapeutic angiogenesis. In this animal model, animals are imaged with 15O-labeled radiowater positron emission tomography (15H2O-PET) as this is the golden standard for measuring myocardial perfusion. 15H2O-PET has been previously validated for measuring perfusion of ischemic porcine heart14.
Thus, the methods and modalities mentioned above constitute an excellent perspective for evaluating the efficacy of gene therapy in the ischemic heart.

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			<td>1% PFA</td>
			<td>VWR</td>
			<td>VWRC28794.295</td>
			<td>Prepared from paraformaldehyde powder</td>
		</tr>
		<tr>
			<td>15 % sucrose</td>
			<td>VWR</td>
			<td>VWRC27480.294</td>
			<td>Prepared from solid sucrose</td>
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			<td>4% PFA</td>
			<td>VWR</td>
			<td>VWRC28794.295</td>
			<td>Prepared from paraformaldehyde powder</td>
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			<td>5 F pigtail catheter</td>
			<td>Cordis</td>
			<td>534-550S</td>
			<td></td>
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			<td>6 F catheter AR2</td>
			<td>Cordis</td>
			<td>670-112-00</td>
			<td></td>
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			<td>6 F introducer sheath</td>
			<td>Cordis</td>
			<td>504-606X</td>
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			<td>8 F introducer sheath</td>
			<td>Cordis</td>
			<td>504-608X</td>
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			<td>Acetylsalicylic acid</td>
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			<td>Varying producer</td>
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			<td>Amiodarone</td>
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			<td></td>
			<td>Varying producer</td>
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			<td>Angiographic station</td>
			<td>GE Healthcare</td>
			<td></td>
			<td></td>
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			<td>Angiolaboratory set</td>
			<td>M&#246;lnlycke</td>
			<td></td>
			<td>designed for the needs of our angiolaboratory, contains sterile drapes, cups and swabs</td>
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			<td>Bisoprolol</td>
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			<td>Varying producer</td>
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			<td>Cefuroxime</td>
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			<td></td>
			<td>Varying producer</td>
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			<td>Clopidogrel</td>
			<td></td>
			<td></td>
			<td>Varying producer</td>
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			<td>Coroflex Blue stent</td>
			<td>B.Braun Medical</td>
			<td>5029012</td>
			<td>Catalog number depends on stent size</td>
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			<td>Crile forceps</td>
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			<td>Cyclotron</td>
			<td>GE Healthcare</td>
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			<td></td>
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			<td>Dobutamine</td>
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			<td>Varying producer</td>
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			<td>Electroanatomical mapping system</td>
			<td colspan="3">Biologics Delivery Systems, Johnson &#38; Johnson company</td>
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			<td>Enoxaparin</td>
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			<td>Varying producer</td>
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			<td>Varying producer</td>
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			<td>Intramyocardial injection catheter</td>
			<td>Johnson &#38; Johnson</td>
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			<td>Iodine contrast agent</td>
			<td>Iomeron</td>
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			<td>Needle 18 G</td>
			<td>Cordis</td>
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			<td>PET-CT scanner</td>
			<td>Siemens Healthcare</td>
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			<td>Polytetrafluoroethylene tube</td>
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			<td>Propofol</td>
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			<td>Scalpel no 11</td>
			<td>VWR</td>
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			<td>Sublingual dinitrate</td>
			<td>Takeda</td>
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			<td>Ultrasound machine</td>
			<td>Philips</td>
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			<td></td>
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large animal model for evaluating the efficacy of the gene therapy in ischemic heart

Coronary artery disease is one of the significant causes of mortality and morbidity worldwide. Despite the progression of current therapeutics, a considerable proportion of coronary artery disease patients remain symptomatic. Gene therapy-mediated therapeutic angiogenesis offers a novel therapeutic method for improving myocardial perfusion and relieving symptoms. Gene therapy with different angiogenic factors has been studied in few clinical trials. Due to the novelty of the method, the progress of myocardial gene therapy is a continuous path from bench to bedside. Therefore, large animal models are needed for evaluating the safety and efficacy. The more the large animal model identifies the original disease and the endpoints used in clinics, the more predictable outcomes are from clinical trials. Here, we introduce a large animal model for evaluating the efficacy of the gene therapy in the ischemic porcine heart. We use clinically relevant imaging methods such as ultrasound imaging and 15H2O-PET. For targeting the gene transfers into the desired area, electroanatomical mapping is used. The aim of this method is: (1) to mimic chronic coronary artery disease, (2) to induce therapeutic angiogenesis at hypoxic areas of the heart, and (3) to evaluate the safety and efficacy of the gene therapy by using relevant endpoints.

The success of the ischemia operation can be confirmed with this protocol by coronary angiogram and by determining the hypokinetic area by transthoracic ultrasound (Figure 1) before proceeding to the gene delivery. The state of the coronary occlusion can be evaluated by coronary angiogram, and the electroanatomical mapping ensures the ischemic and hibernating areas.
The efficacy of the gene therapy can be analyzed by measuring the circumferential strain, ejection ...

Watch this Scientific Journal Video about Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart at JoVE.com

Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart

Myocardial gene therapy for ischemic heart disease holds great promise for future therapeutics. Here, we introduce a large animal model for evaluating the efficacy of gene therapy in the ischemic heart.

Coronary artery disease is one of the significant causes of mortality and morbidity worldwide. Despite the progression of current therapeutics, a ...

在进行临床试验之前，本协议中使用的方法和成像方式构成了缺血性心脏基因治疗的安全性和有效性的良好图像。该技术的主要优点是缺血模型的低侵入性，而且还将基因治疗精确地靶向心脏运动功能减退但仍可行的区域。首先在缺血手术、基因转移和安乐死前进行经胸超声心动图检查，以评估任何可检测到的心包液并确定心肌应变。将换能器放置在猪腋下的第三或第四肋间隙，标记指向猪的胸骨，以进入二尖瓣水平、肌和顶端水平的胸骨旁短轴视图。然后按获取以保存剪辑。为了在缺血手术前直接进行冠状动脉造影，在透视引导下使用6-F导管和碘造影剂对右冠状动脉，左升冠状动脉和左前降动脉进行成像。对于自动注射器中的电影成像，将推注持续时间设置为3秒，总体积设置为21毫升，然后按单，是，通过5-F尾纤导管将碘造影剂注入左心室。对静息动物进行电影成像，然后静脉注射多巴酚丁胺并增加剂量以进行应激诱导。一旦达到每分钟160次的目标心率，就会进行电影成像并移除尾纤导管。要计算射血分数，请打开测量软件，选择相关图像的心室分析。滚动图像以选择一个时间范围，一个在舒张期，一个在收缩期，然后选择一个工具来绘制每个时间范围的心室轮廓。为了诱发慢性心肌缺血，在基因转移前14天，将线圈放在左冠状动脉上，并将瓶颈支架滑到左冠状动脉，并将支架远端放置在第一对角线上。使用支架与管腔比为 1.3 的平气机将支架充气至动脉中的标称压力，将瓶颈固定到位。再过 15 秒后，放气支架，将设备从动脉中收回，并通过血管造影确保正确放置瓶颈支架。在透视引导下进行血管造影和功能测量后，通过股骨鞘将导图导管引入左心室进行电解剖映射，并从左心室收集至少100个点，然后单击接受以批准一个点。在最终地图中，为了可行性，使用超过五毫伏的单极性电压作为标准。对于运动功能减退，选择尽可能低的局部线性缩短，至少低至12%，但最好低于6%对动物实施安乐死后，从胸腔中收获心脏。冲洗采集的心脏后，将 18 号针头放在主动脉瓣上方，并将针头连接到灌注泵上。用750毫升1%多聚甲醛灌注心脏。用锋利的刀将心脏切成一厘米厚的切片，将基因转移区的样本收集成4%多聚甲醛和液氮。将样品在4%多聚甲醛中在4摄氏度下储存48小时。通过15O水PET扫描测量周向应变、射血分数和心肌灌注来分析基因治疗的疗效。通过将心脏与电解剖图进行比较，可以直接从基因转移区域收集组织样本。通过分析β-半乳糖苷酶染色后的阳性细胞数量和分析血小板/内皮细胞粘附分子-1染色后的心肌毛细血管面积，通过免疫组织学分析评估转基因表达和治疗性血管生成。重要的是通过血管造影和从基因转移区域收集样本来确认瓶颈支架的位置，这可以通过将心脏与电解剖图进行比较来确认。总体而言，以最可重复的方式进行所有测量至关重要。

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在免疫缺陷小鼠的建立和传播人类视网膜母细胞瘤肿瘤

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在动物模型揭示神经，血液，创伤后应激障碍和行为相关因素的生物标志物

Identification of biomarkers representing the evolution of the pathophysiology of Post Traumatic Stress Disorder (PTSD) is vitally important, not only for ...

Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies

脓毒症动物模型，用于评估新型草药疗法

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. It has been routinely simulated in animals by several ...

A Novel Surgical Approach for Intratracheal Administration of Bioactive Agents in a Fetal Mouse Model

一种新的手术方法气管内注射生物活性剂在胎鼠模型

Prenatal pulmonary delivery of cells, genes or pharmacologic agents could provide the basis for new therapeutic strategies for a variety of genetic and ...

Osmotic Drug Delivery to Ischemic Hindlimbs and Perfusion of Vasculature with Microfil for Micro-Computed Tomography Imaging

药物输送到微型计算机断层扫描成像缺血后肢血管灌注与微滤渗透

Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to ...

An Isolated Working Heart System for Large Animal Models

一个孤立的工作心脏系统的大型动物模型

Since its introduction in the late 19th century, the Langendorff isolated heart perfusion apparatus, and the subsequent development of the working heart ...

A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS

一个快速的表型神经评分系统在ALS的SOD1-G93A小鼠模型评估疾病进展

The SOD1-G93A transgenic mouse is the most widely used animal model of amyotrophic lateral sclerosis (ALS). At ALS TDI we developed a phenotypic screening ...

Assessment of Plasma Coagulation on Liver Tissue in a Large Animal Model In Vivo

Assessment of Plasma Coagulation on Liver Tissue in a Large Animal Model In Vivo

大动物模型肝组织血浆凝固的评价

Plasma coagulation as a form of electrocautery is used in liver surgery for decades to seal the large liver cut surface after major hepatectomy to prevent ...