Program in Molecular Medicine; RNA Therapeutics Institute; Graduate School of Biomedical Sciences
Cell Biology | Cellular and Molecular Physiology | Digestive System Diseases | Enzymes and Coenzymes | Molecular Biology | Nucleic Acids, Nucleotides, and Nucleosides | Therapeutics | Translational Medical Research
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.
NAFLD, NASH, Non-alcoholic steatohepatitis, Oligonucleotide therapy, RNAi therapeutics, non-alcoholic fatty liver disease, UMCCTS funding
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Copyright 2021 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Yenilmez B, Wetoska N, Kelly M, Echeverria D, Min K, Lifshitz L, Alterman JF, Hassler MR, Hildebrand S, DiMarzio C, McHugh N, Vangjeli L, Sousa J, Pan M, Han X, Brehm MA, Khvorova A, Czech MP. An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis. Mol Ther. 2022 Mar 2;30(3):1329-1342. doi: 10.1016/j.ymthe.2021.11.007. Epub 2021 Nov 11. PMID: 34774753; PMCID: PMC8899521. Link to article on publisher's site
Molecular therapy : the journal of the American Society of Gene Therapy
Yenilmez B, Wetoska N, Kelly M, Echeverria D, Min K, Lifshitz LM, Alterman JF, Hassler MR, Hildebrand SR, DiMarzio C, McHugh N, Vangjeli L, Sousa J, Brehm MA, Khvorova A, Czech MP. (2021). An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis. UMass Center for Clinical and Translational Science Supported Publications. https://doi.org/10.1016/j.ymthe.2021.11.007. Retrieved from https://escholarship.umassmed.edu/umccts_pubs/284
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