An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis.

Abstract

Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%-90%, p < 0.0001) in wild-type and NSG-PiZ "humanized" mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.

• Authors: Batuhan Yenilmez, Nicole Wetoska, Mark Kelly, Dimas Echeverria, Kyounghee Min, Lawrence Lifshitz, Julia F Alterman, Matthew R Hassler, Samuel Hildebrand, Chloe DiMarzio, Nicholas McHugh, Lorenc Vangjeli, Jacquelyn Sousa, Meixia Pan, Xianlin Han, Michael A Brehm, Anastasia Khvorova, Michael P Czech
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 30 Issue 3 Pg. 1329-1342 (03 02 2022) ISSN: 1525-0024 [Electronic] United States
• PMID: 34774753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Triglycerides
• DGAT2 protein, mouse
• Diacylglycerol O-Acyltransferase

Topics

• Animals
• Diacylglycerol O-Acyltransferase (genetics, metabolism)
• Disease Models, Animal
• Fibrosis
• Inflammation (metabolism)
• Liver (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Non-alcoholic Fatty Liver Disease (drug therapy, therapy)
• Obesity (genetics, therapy)
• RNAi Therapeutics
• Triglycerides (metabolism, therapeutic use)