MicroRNA Mimics for the Treatment of Cardiometabolic Diseases

Background & Unmet Need

• Impaired cholesterol and fat metabolism contributes to many cardiometabolic diseases, including obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) and atherosclerosis.
• Numerous regulatory factors have been found to modulate metabolic regulation of lipids, and are thus attractive therapeutic targets
• The sterol regulatory element-binding protein-2 (SREBP-2) directed transcription of low-density lipoprotein (LDL) receptor is essential for the removal of atherogenic LDL from circulation
• Post-translationally, LDLR-mediated cholesterol uptake is limited by SREBP-2- and LXR-induced counter mechanisms
• However, coordinated cellular mechanisms that restrict or prevent LDLR from degradation upon transcription remain uncharacterized
• Unmet Need: Improved understanding of LDLR regulation to inform development of novel treatments

Technology Overview

• The Technology: miRNA-33a-3p mimics that lower LDL and reduced hepatic steatosis for the treatment of cardiometabolic diseases such as NAFLD
• The Discovery: miRNA-33a, encoded within the SREBP-2 gene, acts to promote LDLR expression and LDL-uptake through direct targeting of PCSK9, IDOL and ANGPTL3.
• PoC Data: Liver-targeted delivery of miRNA-33a-3p mimics into mouse models of diet-induced obesity resulted in reduced hepatic and circulating PCSK9 levels as well as serum ANGPTL3 levels
• miRNA-33a-3p mimics significantly lower LDL, and ameliorate hepatic steatosis while increasing HDL
• miRNA-33a-3p mimics therefore represent alternative therapeutic inhibitors of PCSK9, ANGPTL3, and LDL-cholesterol for reducing hypercholesterolemia and steatohepatitis

Technology Applications

• Treatment and prevention of cardiometabolic diseases and NAFLD/NASH
• Reduction of hypercholesterolemia and hypertriglyceridemia in patients with atherosclerosis and insufficient response to statins and dietary changes alone

Technology Advantages

• miRNAs can regulate multiple genes in the same biological process with as individual ~22 nucleotide transcripts
• miRNAs can be administered in a tissue-targeted manner to enhance specificity and efficacy while minimizing side effects
• miRNA-33a-3p successfully reduced LDL-cholesterol and hepatic steatosis in a mouse model of obesity