Gene delivery to vascular endothelium using chemical vectors: implications for cardiovascular gene therapy

Abstract

The vascular endothelium is an attractive target for gene therapy because of its accessibility and its importance in the pathophysiology of a wide range of cardiovascular conditions. In general, viral methods have been shown to be very effective at delivering genes to endothelium. The immunogenicity and pathogenicity associated with viral vectors have led increased efforts to seek alternative means of 'ferrying' therapeutic genes to endothelium or to decrease the short-comings of viral vectors. This paper reviews developments in non-viral technology. In addition, discussion also covers the mechanisms whereby existing chemical vectors deliver DNA to cells. Understanding the pathways of vector internalisation and intracellular traffic is important in developing strategies to improve vector technology. The authors propose that the chemical vector may represent a robust and versatile technology to 'ferry' therapeutic genes to vascular endothelium in order to modify the endothelial dysfunction associated with many cardiovascular diseases.

Oligoproline-derived nanocarrier for dual stimuli-responsive gene delivery

“…The precipitated polymer was dried under vacuum. 1 H NMR spectra revealed 81% conjugation of ECT to mPEG. The molecular weight (M n ) and polydispersity (PDI) of polymer were 5300 and 1.05, respecively, as determined by gel permeation chromatography (GPC).…”

“…Advances in vascular gene delivery over the past decade have demonstrated potential in addressing clinical issues that arise from restenosis by directly controlling the behaviors of the problematic cell types. 1 To date, viral vectors are the most effective gene delivery platform due to their high transfection efficiency; however, safety issues such as immunogenicity and pathogenicity inhibit the broader clinical implementation of these systems. 2 , 3 To address these issues, cationic polymers and lipids have been explored as alternative delivery platforms due to their facile synthesis, tunable properties and demonstrated biosafety.…”

More trouble ahead; is gene therapy coming of age?

“…Developing non-viral technology may still, therefore, represent a logical alternative for the future of vector development if immunogenicity is a problem. For example, a recent gene therapy trial database has indicated that 25.3% of gene delivery uses either DNA-based methods alone or in combination with chemical vectors [47] . Indeed, using hydrodynamics-based gene delivery of E2F decoy, a singlecentre, randomised, controlled trial (the PREVENT trial) showed that intra-operative transfection of human bypass vein grafts with E2F-decoy oligodeoxy nucleotide was safe and feasible [48] .…”

“…For example, intravenous administration of the unmethylated CpG motif in the plasmid induces the production of large quantities of pro-inflammatory cytokines that are toxic and cause inhibition of transgene expression [50,51] . Methlylation of the CpG motif may represent a molecular approach to circumvent the problem [47] . Alternatively a transient use of immunosuppression may represent a viable choice [51] .…”

Transient embolization with microspheres of polyhydroxyalkanoate renders efficient adenoviral transduction of pancreatic capillaryin vivo

“…Subsequent studies also showed relatively efficient transduction of ECs by lentiviral vector and adeno-associated virus [14][15][16]. However, because of the quiescent nature of ECs, adenoviral vector (Ad) turned out to be the most efficient method amongst all viral and nonviral vectors for gene delivery to the vessel wall [17][18][19][20].…”