Date Published: April 3, 2018
Author(s): Michael G Katz, Anthony S Fargnoli, Roger J Hajjar, Charles R Bridges.
The concept of delivering nucleic material encoding a therapeutic gene to the heart has arduously moved from hypothesis to a variety of high potential clinical applications. Despite the promise however, the results achieved have yet to be realized due to several problems that persist in the clinic. One of these identified problems is the need for an efficient delivery method which facilitates complete cardiotropism and minimizes collateral effects. Additional parameters impacting gene delivery that most need to be improved have been identified as follows: (1) Increasing the contact time of vector in coronary circulation permitting transfer, (2) Sustained intravascular flow rate and perfusion pressure to facilitate proper kinetics, (3) Modulation of cellular permeability to increase uptake efficiency, and once in the cells (4) Enhancing transcription and translation within the transfected cardiac cells, and (5) Obtaining the global gene distribution for maximum efficacy. Recently it was hypothesized that use of cardiopulmonary bypass may facilitate cardiac-selective gene transfer and permit vector delivery in the arrested heart in isolated “closed loop” recirculating model. This system was named molecular cardiac surgery with recirculating delivery (MCARD). The key components of this approach include: isolation of the heart from systemic organs, multiple pass recirculation of vector through the coronary vasculature, and removing the residual vector from the coronary circulation to minimize collateral expression. These attributes unique to a surgical approach such as MCARD can effectively increase vector transduction efficiency in coronary vasculature.
In the previous 25 years, there has been a substantial increase in the understanding of the aims of gene therapy, development of transgenic models of various diseases and synthetically packaging nucleic material in a variety of biologic therapeutics. Recently in parallel with clinical development, there have been numerous organized efforts to improve gene delivery techniques specifically tailored for cardiovascular gene therapies. Three major conclusions from previously published data are as follows: (1) Even the best engineered vectors such as those containing cardiac-specific promoter cannot limit the delivery of viral capsids to collateral organs or non-target tissue in the heart, (2) The route of administration of gene transfer is equally or more important than the vector or promoter system in larger species, and (3) Optimal gene transfer can be defined in terms of transfer ratio to the target organ versus inadvertent collateral transfer to evaluate efficiency. Thus, as additional cardiac gene therapies have moved into clinical trials, the drug delivery aspects specific to gene therapies have thrived opening and entirely new device field.
The gene therapy parameters impacting delivery that most need to be improved have been identified as follows: (1) Increasing the contact time of vector in coronary circulation permitting transfer, (2) Sustained intravascular flow rate and perfusion pressure to facilitate proper kinetics, (3) Modulation of cellular permeability to increase uptake efficiency, and once in the cells (4) Enhance transcription and translation within the transfected cardiac cells, and (5) Obtaining the global gene distribution for maximum efficacy.
Selective coronary catheterization with antegrade delivery was first tested in a rabbit model . Today, it is the widely practiced technique utilized in clinical trials of heart failure gene therapy . The benefits of this method include the possibility of repeated vector deliveries to the whole myocardium with homogenous gene expression and its safety record in providing a minimal invasive, high throughput system. However, the limited transduction and varied results with systemic leakage leading to significant collateral organ uptake led researchers to identify parameters influencing the efficiency of intracoronary transfer. If the gene delivery flow through the selective antegrade coronary administration is, for example, 20% of the flow rate of normal coronary blood flow, then only 20% of the vector infused would recirculate on the second pass through the system and only 0.8% would recirculate on the fourth pass. Thus, each virus would pass through the coronary circulation an average of <1.3 times or essentially one-pass kinetics. It is estimated that using simple selective antegrade coronary infusion technique, more than 99% of the vector disappears into the systemic circulation . To address this obvious problem, there have been many new additional techniques to optimize selective antegrade coronary gene delivery including temporary interruption of coronary arterial flow , coronary venous blockade during gene transfer , changes of perfusion pressure and flow  and transient cardiac arrest and enhanced endothelial permeability with pharmacological agents . However, all these methods were not clinically relevant due to their aggressive means in either manipulating anatomy or inflating devices in compromised high risk vessels. As a response to address the shortcomings of catheter based systems, researchers hypothesized that utilizing advanced device concepts leveraging consistent flow perfusion would provide a better means to increase bioavailability and reduce first pass effects. The ultimate device concept of this proposal is “closed-loop” recirculatory systems, which allowed separation of the coronary vascular bed from the systemic . Recently it was hypothesized that use of cardiopulmonary bypass (CPB) may facilitate cardiac-selective gene transfer and allowing to make a vector delivery in stopped heart . Summarizing, it has been demonstrated that complete surgical isolation of the heart in situ, using CPB with high-pressure retrograde coronary sinus infusion with multiple-pass recirculation of vector through the heart results in an increase of several orders of magnitude in cardiac marker gene activities compared with controls, receiving retrograde infusion of adenovirus without CPB and without cardiac isolation . The principal strength of this technology includes a dramatic (>1000-fold) increase in transduction efficiency, the extension of vector residence time, the ability to manipulate endothelial permeability, the avoidance of an immune response to the vector and the ability to washout the vector post gene delivery limiting collateral organ exposure . “Closed loop” systems such as MCARD can provide robust gene expression with no detectable extra-cardiac transfer and no detrimental effects on major organ function. Despite these advantages however MCARD’s position in terms of applicability would only be for select adjunctive cardiac surgery procedures and not standalone due to its invasiveness. Therefore, a new conceived unaddressed market is adapting minimally invasive robotic surgery tools for delivery purposes.