Cell Specific Therapy for Atherosclerosis in Diabetes

Need for a novel solution. Despite advances in the treatment of atherosclerotic cardiovascular disease (CVD), the risk of CVD remains higher in subjects with diabetes, in Australia and worldwide. Residual increased risk of CVD remains even after treatment of standard risk factors specifically hyperglycaemia. Therefore, there is an unmet clinical need to design novel therapies that can directly target the intrinsic pathobiology of atherosclerosis development. Off-target effects of systemically administered drugs have been a major hurdle in designing new therapies with desired efficacy and acceptable toxicity. Cell-specific drug delivery is an alternate exciting novel delivery approach that directs drug delivery to specific cells in pathological sites targeting the underlying pathophysiology of atherosclerotic plaque development. Endothelial/ macrophage directed nanotherapy. Endothelial cells are the first layer of vascular cells exposed to multiple factors embedded in blood stream. These factors include high glucose, cholesterol and shear stress by blood flow. Endothelial cell activation initiates the plaque formation process and thus represent an important target for cell specific therapeutics. In addition, macrophages play key roles in atherosclerosis and macrophage associated pro-atherosclerotic processes including inflammation and impaired cholesterol efflux are important targets for novel therapies for atherosclerosis. Targeted nanotherapeutics that can modulate the functions of macrophages and endothelial cells at the atherosclerotic lesions have shown great promise in preclinical models by improving therapeutic efficacy and reducing off-target effects. A range of active therapeutic agents including drugs that can target epigenetic mechanisms and transcription factors can be encapsulated in various types of nanocarriers including lipid nanoparticles (LNPs). Epigenetic mechanisms and transcription factors (TFs), through a cell-specific gene regulatory network play important role in the aetiology of several diseases including atherosclerosis. The application of systemic therapies that target epigenetic mechanisms and TFs has been limited due to the off-target effects that could potentially be overcome by directed drug delivery using LNPs. Hypothesis. We postulate that atherosclerosis would preferably be therapeutically mitigated by inhibiting specific epigenetic modifiers (EMi) and/or transcription factor (TFi) specifically in lesional macrophages/endothelial cells in diabetes. We will employ an innovative nanotherapeutic strategy to target epigenetic modifiers (EM) and TF within atherosclerotic lesions using macrophage/endothelial-targeting drug encapsulated LNPs (Mϕ/E-T-EMi/TFi-LNPs). The specific aims are: 1. To construct Mϕ/E-T-EMi/TFi-LNPs 2. To attenuate the development of diabetes associated atherosclerosis by conducting preclinical studies using Mϕ/E-T-EMi/TFi-LNPs 3. To identify post-treatment cell specific transcriptomic and epigenomic changes using single cell approaches.