Current strategies for myocardial gene delivery

Abstract

Existing methods of cardiac gene delivery can be classified by the site of injection, interventional approach and type of cardiac circulation at the time of transfer. General criteria to assess the efficacy of a given delivery method include: global versus regional myocardial transduction, technical complexity and the pathophysiological effects associated with its use, delivery-related collateral expression and the delivery-associated inflammatory and immune response. Direct gene delivery (intramyocardial, endocardial, epicardial) may be useful for therapeutic angiogenesis and for focal arrhythmia therapy but with gene expression which is primarily limited to regions in close proximity to the injection site. An often unappreciated limitation of these techniques is that they are frequently associated with substantial systemic vector delivery. Percutaneous infusion of vector into the coronary arteries is minimally invasive and allows for transgene delivery to the whole myocardium. Unfortunately, efficiency of intracoronary delivery is highly variable and the short residence time of vector within the coronary circulation and significant collateral organ expression limit its clinical potential. Surgical techniques, including the incorporation of cardiopulmonary bypass with isolated cardiac recirculation, represent novel delivery strategies that may potentially overcome these limitations; yet, these techniques are complex with inherent morbidity that must be thoroughly evaluated before safe translation into clinical practice. Characteristics of the optimal technique for gene delivery include low morbidity, increased myocardial transcapillary gradient, extended vector residence time in the coronary circulation and exclusion of residual vector from the systemic circulation after delivery to minimize extracardiac expression and to mitigate a cellular immune response. This article is part of a Special Section entitled “Special Section: Cardiovascular Gene Therapy”.

Myocardial Gene Transfer: Routes and Devices for Regulation of Transgene Expression by Modulation of Cellular Permeability

“…The available methods of cardiac gene delivery are typically classified by the site of injection, interventional approach, and the variation of cardiac circulation during transfer (Katz et al, 2011). Many clinical trials in cardiology and cardiac surgery have involved injecting the virus particle directly (intramyocardially) into the intended myocardial region.…”

Downregulation of the β1 adrenergic receptor in the myocardium results in insensitivity to metoprolol and reduces blood pressure in spontaneously hypertensive rats

“…Rats in the rAAV9-NC and rAAV9-Adrb1groups were injected with a single dose of 1×10 12 v.g./kg rAAV9-NC or rAAV9-Adrb1 into the myocardium via the pericardial cavity using the methods described previously (21,22). Briefly, SHR were anesthetized with 10% chloral hydrate (300 mg/kg), and each rat was placed in a supine position before connecting to an endotracheal tube.…”

Surgical Methods for Cardiac Gene Transfer

“…Over time, although, it became clear that both of these methods had severe limitations and did not adequately reflect all the potentially more novel technologies of gene delivery. A classification of existing cardiac gene delivery techniques was proposed that considers variations of heart perfusion during transfer, site and method of injection, and interventional approach [6]. These various gene delivery strategies each have their own barriers that must be overcome.…”