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

Abstract

Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small and large animal models. However, the initial clinical results yielded only modest or no improvement in clinical endpoints. The presence of neutralizing antibodies and cellular immune responses directed against the viral vector and/or the gene-modified cells, the insufficient gene expression levels, and the limited gene transduction efficiencies accounted for the overall limited clinical improvements. Nevertheless, further improvements of the gene delivery technology and a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure. In particular, improved vectors based on emerging cardiotropic serotypes of the adeno-associated viral vector (AAV) are particularly well suited to coax expression of therapeutic genes in the heart. This led to new clinical trials based on the delivery of the sarcoplasmic reticulum Ca2+-ATPase protein (SERCA2a). Though the first clinical results were encouraging, a recent Phase IIb trial did not confirm the beneficial clinical outcomes that were initially reported. New approaches based on S100A1 and adenylate cyclase 6 are also being considered for clinical applications. Emerging paradigms based on the use of miRNA regulation or CRISPR/Cas9-based genome engineering open new therapeutic perspectives for treating cardiovascular diseases by gene therapy. Nevertheless, the continuous improvement of cardiac gene delivery is needed to allow the use of safer and more effective vector doses, ultimately bringing gene therapy for heart failure one step closer to reality.

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

“…23 Most therapeutic applications of miRNA require packaging the nucleic acid in a vector or nanovehicle, example of which include adenovirus (AV), adeno-associated virus (AAV), liposomes, polycationic polymers, and organic/ inorganic nanoparticles. [24][25][26][27][28][29] Kota et al, for example, showed that miR-26a, a downregulated miRNA in hepatocellular carcinoma, could be delivered to liver cancer cells using AAV where it induced tumor-specific apoptosis in a mouse model of liver cancer. 30 Moreover, our group developed a poly(lactic-coglycolic acid)/polyetherimide/hyaluronan (PLGA/PEI/HA)-based vehicle as a carrier of miR-145 and further showed that PLGA/PEI/HA/miRNA complexes were delivered efficiently to tumor cells within colon carcinoma xenografts in mice where they exhibited significant antitumor effects.…”

Polyethyleneimine-coated quantum dots for miRNA delivery and its enhanced suppression in HepG2 cells

“…Cells were viewed by fluorescence microscopy at different time points after transfection (24,48, and 72 h), and imaged based on fluorescein isothiocyanate (FITC) channels. Finally, the cells were harvested after being transfected for 72 h, and the total RNA was extracted with Trizol according to the manufacturer's instruction.…”

Nucleic Acid Delivery for Endothelial Dysfunction in Cardiovascular Diseases

“…Among the several angiogenic factors studied, the initial gene therapy trials evaluated the effect of angiopoietins, FGF, HIF-α, and VEGF-A in the treatment of either ischemia-induced vascular conditions or peripheral occlusive disorders. 40 The VEGF family of growth factors is crucial in regulating several endothelial functions including vasodilation and nitric oxide release, recruitment of circulating progenitor cells, regulation of vascular permeability, and endothelial proliferation and migration, 41 making it particularly well-suited for gene therapy targeting endothelial dysfunction.…”

“…40 An example of DNA-based gene therapy using proangiogenic VEGF is the ongoing KAT301 clinical trial. 40 This trial is evaluating the safety and efficacy of the adenoviral vector-mediated delivery of VEGF-D, a mature form of VEGF, delivered using the NO-GA-mediated transendocardial injection system in patients with severe coronary heart disease (NOGA® XP Cardiac Navigation System, Biologics Delivery Systems Group, Cordis Corporation, Miami Lakes, FL). 42 Preliminary results at 3 months demonstrated increased myocardial perfusion with intramyocardial delivery of VEGF-D in segments with the lowest perfusion reserve, thus justifying a phase II/III evaluation.…”