Gene therapy via inducible nitric oxide synthase: a tool for the treatment of a diverse range of pathological conditions

Abstract

Nitric oxide (NO(.)) is a reactive nitrogen radical produced by the NO synthase (NOS) enzymes; it affects a plethora of downstream physiological and pathological processes. The past two decades have seen an explosion in the understanding of the role of NO(.) biology, highlighting various protective and damaging modes of action. Much of the controversy surrounding the role of NO(.) relates to the differing concentrations generated by the three isoforms of NOS. Both calcium-dependent isoforms of the enzyme (endothelial and neuronal NOS) generate low-nanomolar/picomolar concentrations of NO(.). By contrast, the calcium-independent isoform (inducible NOS (iNOS)) generates high concentrations of NO(.), 2-3 orders of magnitude greater. This review summarizes the current literature in relation to iNOS gene therapy for the therapeutic benefit of various pathological conditions, including various states of vascular disease, wound healing, erectile dysfunction, renal dysfunction and oncology. The available data provide convincing evidence that manipulation of endogenous NO(.) using iNOS gene therapy can provide the basis for future clinical trials.

Antitumoral gene-based strategy involving nitric oxide synthase type III overexpression in hepatocellular carcinoma

“…3,4 Low levels of NO generated by NOS-1 and NOS-3 are related to tumour progression through induction of DNA mutagenesis, angiogenesis and invasiveness, but high NO generation (µM range) generated by NOS-2 are associated with increased DNA damage, oxidative/nitrosative stress, apoptosis induction and mitochondrial damage. 5 The biological activity of NO is cGMPindependent and cGMP-dependent pathways which act in normal physiology and pathological conditions. 6 A profound alteration of S-nitrosylation protein pattern is observed during induction of apoptosis by NOS-3 overexpression in hepatoma cells.…”

Inhibition of neointimal hyperplasia in a rabbit vein graft model following non-viral transfection with human iNOS cDNA

“…Increased NO levels in vein graft tissues would help to restrict the development of IH by promoting endothelial cell growth and survival, inhibition of vascular smooth muscle cell proliferation and migration, inhibition of platelet adherence and leukocyte chemotaxis. 20, 27 All three NOS isoforms have been transferred into blood vessels for various vascular disorders but iNOS is often preferred as it generates >100-fold higher levels of NO than the constitutive isoforms, endothelial NOS and neuronal NOS. 27 Clinical gene therapy trials are in progress for in-stent restenosis, with the iNOS gene delivered by a lipoplex.…”

Nitric oxide based strategies for applications of biomedical devices

“…Generally, current NO-based therapies can be classified into two categories: materials that directly release active NO or act as NO redox catalysts, and drugs that regulate the enzymatic production of NO from the body. In addition, several promising strategies are based on altering NOS activity to regulate endogenous NO concentrations [17][18][19][20][21]. Many studies have focused on constructing NO-releasing and NO-generating materials.…”