The Road Ahead: Working Towards Effective Clinical Translation of Myocardial Gene Therapies

Abstract

During the last two decades the fields of molecular and cellular cardiology, and more recently molecular cardiac surgery, have developed rapidly. The concept of delivering cDNA encoding a therapeutic gene to cardiomyocytes using a vector system with substantial cardiac tropism, allowing for long-term expression of a therapeutic protein, has moved from hypothesis to bench to clinical application. However, the clinical results to date are still disappointing. The ideal gene transfer method should be explored in clinically relevant animal models of heart disease to evaluate the relative roles of specific molecular pathways in disease pathogenesis, helping to validate the potential targets for therapeutic intervention. Successful clinical cardiovascular gene therapy also requires the use of nonimmunogenic cardiotropic vectors capable of expressing the requisite amount of therapeutic protein in vivo and in situ. Depending on the desired application either regional or global myocardial gene delivery is required. Cardiac-specific delivery techniques incorporating mapping technologies for regional delivery and highly efficient methodologies for global delivery should improve the precision and specificity of gene transfer to the areas of interest and minimize collateral organ gene expression.

Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation

“…Several factors could have influenced the negative results obtained in the clinical trials using angiogenic factors compared with the promising preclinical data or earlier clinical trials. 134 , 135 The clinical data were only conclusive when the later studies were randomized and blinded compared with the initial ones. This suggested a strong placebo effect, in part due to the strict selection of patients, the delivery method used (intramuscular injection can increase the production of growth factors), or a possible bias by lack of a blinded protocol.…”

Liquid jet delivery method featuring S100A1 gene therapy in the rodent model following acute myocardial infarction

“…Despite this level of interest in S100A1, achieving sufficient myocardial delivery within safety limits is a major translational problem. Although there are very positive results presented in transgenic models 7 , 8 the relationships between: delivery route, vector selection, the resultant in vivo pharmacodynamics, and associated host response risks are not clearly established 9 , 10 . Sequential studies in larger species do not provide a quantitative relationship between the necessary transfer levels in the cardiac tissue counterbalanced by host response risks resulting - at least in part - from excessive off target expression 11 .…”

Anti-inflammatory loaded poly-lactic glycolic acid nanoparticle formulations to enhance myocardial gene transfer: an in-vitro assessment of a drug/gene combination therapeutic approach for direct injection

“…Despite the availability of effective transgene-vector systems, one major rate limiting problem is with achieving safe and efficient myocardial gene transfer in the clinic [ 13 , 14 ]. Due to size scale and more complex membrane barriers, these issues do not emerge in smaller animal studies yet are a major challenge in larger organisms [ 15 , 16 ].…”