Evidence map›Paper›PMID 34774753›Full record

ArticleMolecular therapy : the journal of the American Society of Gene Therapy2022

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

Batuhan Yenilmez, Nicole Wetoska, Mark Kelly, Dimas Echeverria, Kyounghee Min, Lawrence Lifshitz, Julia F Alterman, Matthew R Hassler, Samuel Hildebrand, Chloe DiMarzio and 8 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.

0numbers the graph read from it
0cells of the map it votes in
24citing papers in PubMed
5.1field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

24 citing papers in PubMed, 45 citations in OpenAlex.

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  14. Molecular therapy. Methods & clinical development · 2024
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 2 institutions in 1 country.

Batuhan YenilmezProgram in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA.
Nicole WetoskaProgram in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA.
Mark KellyProgram in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA.
Dimas EcheverriaProgram 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.
Kyounghee MinProgram in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA.
Lawrence LifshitzProgram in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA.
Julia F AltermanProgram 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.
Matthew R HasslerProgram 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.
Samuel HildebrandProgram 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.
Chloe DiMarzioProgram in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA.
Nicholas McHughProgram 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.
Lorenc VangjeliProgram 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.
Jacquelyn SousaProgram 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.
Meixia PanDepartment of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Xianlin HanDepartment of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Michael A BrehmProgram in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street Biotech Two, Suite 100, Worcester, MA 01605, USA.
Anastasia KhvorovaProgram 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.
Michael P CzechProgram 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.
University of Massachusetts Chan Medical School · USThe University of Texas Health Science Center at San Antonio · US

Funding

University of Massachusetts Center for Clinical Science and Translational SupplementUL1TR001453 · NCATS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI LUZURIAGA, KATHERINE F · 2015 to 2024
$39.0M
TRANSGENIC COREP30AG013319 · NIA · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI PETER J HORNSBY · 1995 to 2026
$30.6M
Paracrine Signaling by Kupffer Cells in Hepatic Insulin ResistanceR01DK103047 · NIDDK · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI CZECH, MICHAEL P · 2015 to 2023
$5.0M
Chemical engineering of therapeutic RNAs for extrahepatic deliveryR35GM131839 · NIGMS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ANASTASIA KHVOROVA · 2019 to 2026
$3.1M
Mid-Scale RNA Synthesis, Purification and Quality Control SystemS10OD020012 · OD · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI KHVOROVA, ANASTASIA · 2015 to 2015
$563k
NCATS NIH HHS UL1 TR001453NIA NIH HHS P30 AG013319NIDDK NIH HHS R01 DK103047NIGMS NIH HHS R35 GM131839NIH HHS S10 OD020012
6 · The paper itself

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.

Indexed as

Non-alcoholic Fatty Liver DiseaseAnimalsDiacylglycerol O-AcyltransferaseDisease Models, AnimalFibrosisInflammationLiverMiceMice, Inbred C57BLMice, ObeseObesityRNAi TherapeuticsTriglyceridesDGAT2 protein, mouseDiacylglycerol O-AcyltransferaseTriglyceridesNAFLDNASHnon-alcoholic fatty liver diseaseNon-alcoholic steatohepatitisOligonucleotide therapyRNAi therapeutics

Identifiers

PMID34774753
PMCPMC8899521
OpenAlexW3212131704

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.