Vascular disease is caused by factors such as the inflammation and weakness of the veins and arteries and by the build-up of fatty deposits in blood vessels. Cardiovascular disease is the leading global cause of death, accounting for over 17 million deaths per year and growing. Cardiovascular and related diseases claims more deaths each year than all forms of cancers combined. Accordingly, there is a great deal of interest in trying to understand the mechanism behind vascular disease with an aim to developing materials and methods for treating the disease or preventing its onset. FIG. 1 provides an illustration of vascular pathology and shows how physical injury including endothelial damage and infiltration of inflammatory cells stimulate migration and proliferation of smooth muscle cells (SMCs).
Smooth muscle cell proliferation and migration is a necessary function during vascular development and in response to vascular injury. However, pathological proliferation and migration is a major factor in atherogenesis and restenosis. The distinction between physiological and pathological proliferation and migration is thought to be driven by modulation of vascular smooth muscle cell (VSMC) phenotypes. VSMCs exist in a wide range of phenotypes. In normal blood vessels the predominant phenotype is the contractile phenotype which regulates blood vessel diameter and blood flow. However, in response to injury, the contractile phenotype switches to the synthetic, migratory and proliferative phenotype. The response to injury is multicellular and involves a number of growth factors including platelet derived growth factor (PDGF). Where the migrating and proliferating VSMC fail to switch back to contractile phenotype, they instead induce pathogenic vascular remodelling and generate intimal vascular lesions.
Neointimal formation caused by SMC migration and proliferation is a hallmark in vascular pathology. Local cytokine (e.g. IL1α) and growth factor (e.g. PDGF) networks are known to regulate SMC phenotype in vascular disease[B,C] , for example via synergistic activation of the protein complex NFKB[D]. However, to date no therapeutic intervention has proved successful in targeting vascular remodelling.
Coronary artery bypass grafting (CABG) is the preferred treatment for patients with multi-vessel disease. However, 30 to 50% of grafted vessels fail due to stenotic occlusion within 5 to 10 years of treatment.
There is therefore a need for novel interventions that will permit vascular adaptation to insult but will prevent neointimal thickening. Success depends on a much deeper understanding of mechanisms responsible for the switch from migration mode to invasion mode.
High throughput RNA sequencing technologies have shown that non-coding RNA makes up the majority of transcribed RNA in the genome. Long non-coding RNAs (lncRNA) are a large and diverse class of transcribed RNA molecules with a length of more than 200 nucleotides that do not encode proteins. Their expression is believed to be developmentally regulated and lncRNA can be tissue- and cell-type specific.
LncRNA are thought to exert their function either by binding to DNA or RNA in a sequence specific manner or by binding to proteins. Some lncRNAs can modulate smaller regulatory RNAs such as microRNAs. LncRNAs are not defined by a specific function as they can apparently regulate gene expression and protein synthesis in a number of different ways. Post-transcriptional functions of lncRNA include regulating RNA processing events such as splicing, editing, localisation, translation and degradation.
With such wide ranging functions, it is not surprising that lncRNAs play a role in the development and pathology of disease. LncRNAs have been found to be differentially expressed in various types of cancers and have been found to be dysregulated in diseases such as cardiovascular disease, neurological disorders and immune mediated diseases.
Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state is implicated in diverse vascular pathologies including atherogenesis, plaque stabilisation, and neointimal hyperplasia. However, very little is known as to the role of long non coding RNA (lncRNA) during this process. The inventors have investigated a role for long non-coding (lnc)RNAs in VSMC biology and pathology.
USPTO Backgrounds
USPTO Backgrounds