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...

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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>
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		<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>
			<td></td>
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			<td>8 F introducer sheath</td>
			<td>Cordis</td>
			<td>504-608X</td>
			<td></td>
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			<td>Acetylsalicylic acid</td>
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			<td>Varying producer</td>
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			<td>Amiodarone</td>
			<td></td>
			<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>
			<td></td>
			<td></td>
			<td>Varying producer</td>
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			<td>Cefuroxime</td>
			<td></td>
			<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>
			<td></td>
			<td></td>
			<td></td>
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			<td>Cyclotron</td>
			<td>GE Healthcare</td>
			<td></td>
			<td></td>
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			<td>Dobutamine</td>
			<td></td>
			<td></td>
			<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>
			<td></td>
			<td></td>
			<td>Varying producer</td>
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			<td>Fentanyl</td>
			<td></td>
			<td></td>
			<td>Varying producer</td>
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			<td>Intramyocardial injection catheter</td>
			<td>Johnson &#38; Johnson</td>
			<td></td>
			<td></td>
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			<td>Iodine contrast agent</td>
			<td>Iomeron</td>
			<td></td>
			<td></td>
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			<td>Kitchen knife</td>
			<td></td>
			<td></td>
			<td>Varying producer</td>
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			<td>Lidocaine</td>
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			<td>Varying producer</td>
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			<td>Liquid nitrogen</td>
			<td></td>
			<td></td>
			<td>Varying producer</td>
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			<td>MgSO4</td>
			<td></td>
			<td></td>
			<td>Varying producer</td>
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			<td>Needle 18 G</td>
			<td>Cordis</td>
			<td>12-004943</td>
			<td></td>
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			<td>Perfusion pump</td>
			<td></td>
			<td></td>
			<td></td>
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			<td>PET-CT scanner</td>
			<td>Siemens Healthcare</td>
			<td></td>
			<td></td>
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			<td>Polytetrafluoroethylene tube</td>
			<td></td>
			<td></td>
			<td></td>
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			<td>Propofol</td>
			<td></td>
			<td></td>
			<td>Varying producer</td>
		</tr>
		<tr>
			<td>Scalpel no 11</td>
			<td>VWR</td>
			<td>SWAN0503</td>
			<td></td>
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			<td>Sublingual dinitrate</td>
			<td>Takeda</td>
			<td></td>
			<td></td>
		</tr>
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			<td>Ultrasound machine</td>
			<td>Philips</td>
			<td></td>
			<td></td>
		</tr>
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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 ...

The methods and imaging modalities used in this protocol constitute an excellent image of the safety and efficacy of gene therapy in ischemic heart before proceeding to clinical trials. The main advantages of this technique are the low invasiveness of the ischemia model, but also the precise targeting of the gene therapy to hypokinetic but still viable areas of the heart. Begin by performing the transthoracic echocardiography before ischemia operation, gene transfer, and euthanasia to evaluate any detectable pericardial fluid and determine the myocardial strain.Place the transducer in the third or fourth intercostal space under the armpit of the pig with a marker pointing to the sternum of the pig for accessing parasternal short axis views at the mitral valve level, papillary muscle, and apical levels. Then press acquire to save a clip. For performing the coronary angiography directly before ischemia operation use a 6-F catheter under fluoroscopic guidance with an iodine contrast agent to image the right coronary artery, the left ascending coronary artery, and the left anterior descending artery.For cine imaging in the autoinjector, set the bolus duration at three seconds, and the total volume for 21 milliliters, and then press single, and yes to administer iodine contrast agent into the left ventricle via a 5-F pigtail catheter. Perform cine imaging of the animal at rest and then administer dobutamine intravenously and escalating doses for the stress induction. Once the target heart rate of 160 beats per minute is achieved performs cine imaging and remove the pigtail catheter.To calculate the ejection fraction open the measurement software, select ventricular analysis of the image in question. Scroll the image to select a timeframe, one in diastole and one in systole, and then select a tool to draw ventricular outlines of each timeframe. For inducing the chronic myocardial ischemia, 14 days before gene transfer, place a coil to the left coronary artery, and glide the bottleneck stent to the left coronary artery, and place the stent distally to the first diagonal.Inflate the stent to nominal pressure in the artery, using an indeflator with a stent to lumen ratio of 1.3 for anchoring the bottleneck in place. After an additional 15 seconds, deflate the stent, retract the equipment from the artery, and ensure the correct placement of a bottleneck stent by angiography. After angiography and functional measurements under fluoroscopic guidance introduce a mapping catheter to the left ventricle via the femoral sheath for electro anatomical mapping, and collect at least 100 points from the left ventricle, and click accept to approve a point.In the final map, for viability, use a unipolar voltage over five millivolts as a criterion. And for hypokinesia, select a local linear shortening as low as possible, at least as low as 12%but preferably below 6%After euthanizing the animal, harvest the heart from the thoracic cavity. Once the harvested heart is rinsed place an 18-gauge needle above the aortic valve and attach the needle to a perfusion pump.Perfuse the heart with 750 milliliters of 1%paraformaldehyde. Use a sharp knife to slice the heart into one centimeter thick slices, and collect the samples from the gene transfer area into 4%paraformaldehyde and liquid nitrogen. Store the samples for staining in 4%paraformaldehyde for 48 hours at four degrees Celsius.The efficacy of the gene therapy was analyzed by measuring the circumferential strain, ejection fraction, and myocardial perfusion by 15O-water PET scan. The tissue samples can be collected directly from the gene transfer area, by comparing the heart to the electro anatomical map. The transgene expression and therapeutic angiogenesis were evaluated through immune histological analysis by analyzing the number of positive cells after Beta-galactosidase staining, and by analyzing the myocardial capillary area, after platelet/endothelial cell adhesion molecule-1 staining.It is important to confirm the placement of the bottleneck stent via angiogram and sample collection from the gene transfer area, which could be confirmed by comparing the heart to the electroanatomical map. Overall, it is crucial to make all measurements in the most reproducible way.

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