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A MicroRNA Mimic for the Treatment of Familial Hypercholesterolemia and Atherosclerosis
Weill Cornell Medicine
Nucleotide
Cardiovascular disease, Metabolic disease
Hit To Lead or Lead Optimization
Background
• 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 Needs
Improved understanding of LDLR regulation to inform development of novel treatments
Technology Overview
• miRNA-33a-3p mimics that lower LDL and reduced hepatic steatosis for the treatment of cardiometabolic diseases such as NAFLD
• miRNA-33a, encoded within the SREBP-2 gene, acts to promote LDLR expression and LDL-uptake through direct targeting of PCSK9, IDOL and ANGPTL3
• 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
S. Hani Najafi-Shoushtari
PCT-US2022-029884 (2022.05.18)
"MicroRNA 33A controls SREBP-2 and LXR dependent regulation of the LDL receptor pathway". Ramachandran, V., et al. Atherosclerosis 2022, 355, 73
