Designing a new therapeutic approach using exosomal miRNAs to target metabolic disease: APOB and PCSK9 inhibition effects in reducing atherosclerosis risk as a model system

• Grant number: 19/16858-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2019
• End date: May 02, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Mario Jose Abdalla Saad
• Grantee: Tamires Marques Zanotto
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 20/12766-1 - Designing a new therapeutic approach using exosomal miRNAs to target metabolic disease: ApoB and PCSK9 inhibition effects in reducing atherosclerosis risk as a model system, BE.EP.PD

Abstract

MicroRNAs are small non-coding RNAs that can regulate gene expression by inhibiting translation or promoting mRNA degradation. miRNAs can be released into the circulation where they are carried by ribonucleoproteins, such as Agonaute-2, or lipoproteins, like HDL, or in extracellular vesicles or exosomes. Studies have shown an advantage of exosomes over artificial liposomes for RNA transport due to their higher capacity of endocytosis and protection against phagocytosis. In addition, although there is a basal release of miRNAs, several publications have shown that exosome trafficking and release of the cargo can increase with certain stimuli, including by inflammatory states. Recent work from the hosting lab has provided important evidence about the existence of an adipose tissue-liver communication axis based on circulating exosome-contained miRNAs. The aim of this study is to further explore this communication axis, including the miRNA loading mechanism in exosomes, and investigate whether exosomal miRNAs could be used to treat metabolic diseases originated in the liver. As a model case, we have selected hypercholesterolemia and atherosclerosis for two reasons: first because exosomes secreted by fat have been shown to target the liver and most of the cholesterol-carrying lipoproteins are derived exclusively from hepatocytes; secondly because this condition is one of the main causes of morbidity in Diabetes by leading to myocardial infarction, stroke, heart failure, heart failure, and Cardiovascular Disease (CVD). Atherosclerosis originates from cholesterol deposition and plaque accumulation in the arteries. Cholesterol is mostly transported by LDL lipoproteins, whose main protein component is apolipoprotein B-100. Several studies have already shown the important role of ApoB-100 inhibition as a target for Dyslipidemia and cardiovascular risk therapy. In addition, we also aim to target the proprotein convertase subtilisin/kexine type 9 (PCSK9), which is an enzyme that degrades LDL-receptor in hepatocytes. Knocking down PCSK9 leads to increased LDL receptor levels, leading to lower LDL-cholesterol in the circulation. Taken together, we propose the development of an innovative therapeutic design for the treatment of this metabolic pathology by making use of the high efficiency of miRNAs in inhibiting specific targets and the novel adipose tissue-liver communication axis via circulating exosomes. We may also try to target other liver-related metabolic abnormalities if time permits or if the above targets do not yield effect results. (AU)