Direct Intramyocardial Gene Therapy With Vegf for Inoperable Coronary Artery Disease

Lathi, KG; Cespedes,; Losordo, D. W.; Vale, Peter R.; Jf, Symes; Isner, J M

doi:10.1097/00000539-199904001-00073

Cited by 3 publications

(2 citation statements)

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“…A thoracotomy approach to deliver therapeutics via IM injection ( 29 , 30 ) (i.e., right thoracotomy in current porcine model and left anterior thoracotomy in humans) carries associated risks and morbidity and could benefit from less invasive procedures involving smaller incisions with less rib spreading, the primary mediator of post-thoracotomy pain ( 31 – 33 ). Moreover, in patients with adhesions from prior cardiac surgery (e.g., coronary artery bypass grafting), certain regions of the heart may be completely inaccessible, which would preclude significant manipulation required to expose the areas of interest and perform IM injection.…”

Section: Discussionmentioning

confidence: 99%

Targeted Delivery for Cardiac Regeneration: Comparison of Intra-coronary Infusion and Intra-myocardial Injection in Porcine Hearts

Vekstein

Wendell

DeLuca

et al. 2022

Front. Cardiovasc. Med.

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BackgroundThe optimal delivery route to enhance effectiveness of regenerative therapeutics to the human heart is poorly understood. Direct intra-myocardial (IM) injection is the gold standard, however, it is relatively invasive. We thus compared targeted IM against less invasive, catheter-based intra-coronary (IC) delivery to porcine myocardium for the acute retention of nanoparticles using cardiac magnetic resonance (CMR) imaging and viral vector transduction using qPCR.MethodsFerumoxytol iron oxide (IO) nanoparticles (5 ml) were administered to Yorkshire swine (n = 13) by: (1) IM via thoracotomy, (2) catheter-based IC balloon-occlusion (BO) with infusion into the distal left anterior descending (LAD) coronary artery, (3) IC perforated side-wall (SW) infusion into the LAD, or (4) non-selective IC via left main (LM) coronary artery infusion. Hearts were harvested and imaged using at 3T whole-body MRI scanner. In separate Yorkshire swine (n = 13), an adeno-associated virus (AAV) vector was similarly delivered, tissue harvested 4–6 weeks later, and viral DNA quantified from predefined areas at risk (apical LV/RV) vs. not at risk in a potential mid-LAD infarct model. Results were analyzed using pairwise Student's t-test.ResultsIM delivery yielded the highest IO retention (16.0 ± 4.6% of left ventricular volume). Of the IC approaches, BO showed the highest IO retention (8.7 ± 2.2% vs. SW = 5.5 ± 4.9% and LM = 0%) and yielded consistent uptake in the porcine distal LAD territory, including the apical septum, LV, and RV. IM delivery was limited to the apex and anterior wall, without septal retention. For the AAV delivery, the BO was most efficient in the at risk territory (Risk: BO = 6.0 × 10−9, IM = 1.4 × 10−9, LM = 3.2 × 10−10 viral copies per μg genomic DNA) while all delivery routes were comparable in the non-risk territory (BO = 1.7 × 10−9, IM = 8.9 × 10−10, LM = 1.2 × 10−9).ConclusionsDirect IM injection has the highest local retention, while IC delivery with balloon occlusion and distal infusion is the most effective IC delivery technique to target therapeutics to a heart territory most in risk from an infarct.

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Section: Discussionmentioning

confidence: 99%

Targeted Delivery for Cardiac Regeneration: Comparison of Intra-coronary Infusion and Intra-myocardial Injection in Porcine Hearts

Vekstein

Wendell

DeLuca

et al. 2022

Front. Cardiovasc. Med.

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“…The Kuopio angiogenesis trial showed that intramyocardial injection of the recombinant VEGF gene on an adenoviral vector during percutaneous coronary angioplasty significantly increased myocardial perfusion when compared to delivery of the VEGF gene using a naked plasmid vector [ 31 ]. Moreover, phase I studies evaluating intramyocardial injection of plasmid-encoded VEGF DNA via thoracotomy in patients with end-stage coronary artery disease were associated with improvement of symptoms and blood flow to ischemic territories [ 27 , 28 , 29 ].…”

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview, Challenges, and Prospects

Sabra

Karbasiafshar

Aboulgheit

et al. 2021

IJMS

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Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field.

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Focal Angiogenic Therapy for Myocardial Ischemia

Symes

2010

Journal of Cardiac Surgery

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Background: Therapeutic angiogenesis, which involves the administration of angiogenic cytokines to stimulate collateral formation and improve myocardial perfusion, is being tested as an alternative treatment for patients with medically intractable angina who are no longer candidates for conventional revascularization techniques. Methods: Administration of recombinant protein formulations for these growth factors and transfection of the DNA itself have proven effective in animal models. At present, transfection of the DNA (gene therapy) appears preferable in that a single administration achieves a prolonged but transient, localized exposure of the ischemic tissues to the angiogen. The important technical aspects of surgical gene therapy via a mini thoracotomy incision are described. Results: Four Phase I clinical trials of angiogenic therapy recently have been reported, two involving administration of the recombinant protein combined with coronary bypass and two involving gene therapy alone. These studies have shown that this approach is relatively safe; the early evidence of efficacy is encouraging. The largest study reported six‐month follow‐up on 30 patients who received plasmid DNA for vascular endothelial growth factor‐165 (VEGF165) and documented improvement in angina, treadmill exercise tolerance, and myocardial perfusion in the majority of patients studied. Conclusions: These preliminary results will need to be supported by randomized clinical trials in which angiogenic therapy alone is compared to standard medical therapy or a placebo. Catheter‐based intramyocardial gene transfer and combined coronary arterial bypass grafting or transmyocardial laser revascularization plus gene therapy trials are also underway. If proven effective, angiogenic therapy may provide a relatively noninvasive modality for revascularization of ischemic myocardium not amenable to current techniques.

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Direct Intramyocardial Gene Therapy With Vegf for Inoperable Coronary Artery Disease

Cited by 3 publications

References 0 publications

Targeted Delivery for Cardiac Regeneration: Comparison of Intra-coronary Infusion and Intra-myocardial Injection in Porcine Hearts

Targeted Delivery for Cardiac Regeneration: Comparison of Intra-coronary Infusion and Intra-myocardial Injection in Porcine Hearts

Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview, Challenges, and Prospects

Focal Angiogenic Therapy for Myocardial Ischemia

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