Abstract
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.
Highlights
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
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
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 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
Summary
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. 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 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. 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. Decreases in bioavailability are a problem as subsequent gene therapy products not reaching the heart are either absorbed by collateral organs or inactivated by the immune system. Delivery systems addressing these concerns would offer substantial improvement for overall therapy with a key focus on several parameters
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