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".

Fig. 1

Cardiac gene delivery techniques.

Fig. 2

Direct methods of gene delivery. a. Epicardial. b. Endocardial. c. Intramyocardial.

Fig. 3

Advantages and limitations of direct gene delivery approach.

Fig. 4

Transvascular gene delivery. a. Selective coronary catheterization with antegrade delivery. b. Nonselective intracoronary delivery.

Fig. 5

Advantages and limitations of transvascular gene delivery approach.

Fig. 6

Ex vivo gene delivery.

Fig. 7

Cardiopulmonary bypass-mediated gene delivery. a. Gene delivery via conventional cardiopulmonary bypass. b. Gene transfer via cardiopulmonary bypass with complete cardiac isolation and recirculating delivery (MCARD).

Fig. 8

Advantages and limitations of ex vivo and cardiopulmonary bypass-mediated gene delivery approach.