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

B. Yenilmez, N. Wetoska, M. Kelly, D. Echeverria, K. Min, L. Lifshitz, JF. Alterman, MR. Hassler, S. Hildebrand, C. DiMarzio, N. McHugh, L. Vangjeli, J. Sousa, M. Pan, X. Han, MA. Brehm, A. Khvorova, MP. Czech

. 2022 ; 30 (3) : 1329-1342. [pub] 20211111

Language English Country United States

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22019236

Grant support
R01 DK103047 NIDDK NIH HHS - United States
R35 GM131839 NIGMS NIH HHS - United States
S10 OD020012 NIH HHS - United States
UL1 TR001453 NCATS NIH HHS - United States

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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$a Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%-90%, p < 0.0001) in wild-type and NSG-PiZ "humanized" mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.
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$a Wetoska, Nicole $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA
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$a Kelly, Mark $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA
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$a Echeverria, Dimas $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA; RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA
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$a Min, Kyounghee $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA
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$a Lifshitz, Lawrence $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA
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$a Hassler, Matthew R $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA; RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA
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$a Hildebrand, Samuel $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA; RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA
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$a DiMarzio, Chloe $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA
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$a Vangjeli, Lorenc $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA; RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA
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$a Sousa, Jacquelyn $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA; RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA
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$a Pan, Meixia $u Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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$a Han, Xianlin $u Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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$a Brehm, Michael A $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA
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$a Khvorova, Anastasia $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA; RNA Therapeutics Institute, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA. Electronic address: anastasia.khvorova@umassmed.edu
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$a Czech, Michael P $u Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA. Electronic address: michael.czech@umassmed.edu
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