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

• Published in: Molecular therapy Vol. 30; no. 3; pp. 1329 - 1342
• Main Authors: Yenilmez, Batuhan, Wetoska, Nicole, Kelly, Mark, Echeverria, Dimas, Min, Kyounghee, Lifshitz, Lawrence, Alterman, Julia F., Hassler, Matthew R., Hildebrand, Samuel, DiMarzio, Chloe, McHugh, Nicholas, Vangjeli, Lorenc, Sousa, Jacquelyn, Pan, Meixia, Han, Xianlin, Brehm, Michael A., Khvorova, Anastasia, Czech, Michael P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-03-2022; American Society of Gene & Cell Therapy
• Subjects: Animals; Diacylglycerol O-Acyltransferase - genetics; Diacylglycerol O-Acyltransferase - metabolism; Disease Models, Animal; Fibrosis; Inflammation - metabolism; Liver - metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; NAFLD; NASH; non-alcoholic fatty liver disease; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - therapy; Non-alcoholic steatohepatitis; Obesity - genetics; Obesity - therapy; Oligonucleotide therapy; Original; RNAi Therapeutics; Triglycerides - metabolism; Triglycerides - therapeutic use; RNAi therapeutics; NAFLD; non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; NASH; Oligonucleotide therapy
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2021.11.007

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.
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Liver fat overload in obesity and type 2 diabetes can proceed to severe inflammation, fibrosis, and liver failure. A chemically stabilized, GalNAc-conjugated siRNA targeting lipid synthesis enzyme DGAT2 was identified that decreases liver fat by 85% following single subcutaneous injection in mice; however, inflammation and scarring are surprisingly unaffected.