Gene-Based Therapy for Hypertension – Do Preclinical Data Suggest a Promising Future?

Abstract

Many experimental studies have obtained a prolonged control of blood pressure through gene treatment. This consists in the administration of genes coding for vasodilator proteins (the ‘sense’ approach), or of nucleotide sequences that are complementary to the mRNA of vasoconstrictor proteins, which are consequently synthesized in smaller amounts (the ‘antisense’ approach). Examples of the sense approach include the genes encoding endothelial nitric oxide synthase and kallikrein. Examples of the second type of approach are the antisense oligodeoxynucleotides to angiotensin-converting enzyme and endothelin-1. Also, RNA molecules, such as ribozymes and small interfering RNAs, are capable to inhibit RNA function. Whole sense genes are usually administered through viral vectors, while antisense oligonucleotides may be administered with plasmids or liposomes. Both viral and non-viral vectors have advantages and disadvantages. Despite the still persisting limitations, the possibility exists that in the future some forms of genetic treatment will be extended to the clinical setting, allowing a prolonged control of essential hypertension and its end-organ sequelae.

Very Long Chain N 4 ,N 9 -Diacyl Spermines: Non-Viral Lipopolyamine Vectors for Efficient Plasmid DNA and siRNA Delivery

“…spermine (1,12-diamino-4,9-diazadodecane) (2,3). Other research groups are investigating a variety of alternative approaches, including: naked polynucleotides, gene gun (bound to gold particles), electroporation, and the use of a wide variety of cationic lipids (lipoplexes) (4)(5)(6)(7)(8) and cationic polymers (polyplexes), for reviews see: (9)(10)(11)(12). Structure-activity studies are required for non-viral vectors in siRNA delivery, as there is no immediate correlation between the efficiency of a vector used for both DNA and siRNA delivery (13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Effect of Small Hairpin RNA Targeting Endothelin-Converting Enzyme-1 in Monocrotaline-Induced Pulmonary Hypertensive Rats

“…Lentiviral delivery of siRNA represents a powerful tool for functional genomics. The advantages of lentivirus for gene transfer, especially to non-dividing cells, make the RNAi technique more accessible for specific in vivo silencing in mammalian cells (5). Effective methods for the delivery of siRNA/shRNA to allow a sufficient silencing effect in the target organ are yet to be developed (24).…”

“…siRNA is being explored as genetic inhibitors of gene expression, as well as potential therapeutics against inflammatory states, viral and hematological diseases, cancers and genetic disorders due to a dominant genetic effect, such as amyotrophic lateral sclerosis (4). Overall, these agents might be useful for a hypertensive state, but the efficacy of specific siRNA expression has not been tested in PAH (5). …”

20 Years of Hypertension Research using Genetically Modified Animals: No Clinically Promising Approaches in Sight

“…Gene therapy via gene transfer using viral or nonviral vectors has only been performed in animal experiments to date (Simonson et al, 2005;Nakamura et al, 2006). With regard to primary hypertension, such approaches still have no discernable clinical impact (Puddu, 2006). Other therapies, such as RNAi or stem cell therapy, are still at the stage of basic research (Melo et al, 2005;Nordlie et al, 2006).…”