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| Status |
Public on Dec 31, 2022 |
| Title |
An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 transplantation, with no approved therapeutics available. Despite years of research, the exact molecular mechanism of NASH progression is not well understood, but fat accumulation is believed to be 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 Gal-Nac conjugated siRNA targeting DGAT2 (Dgat2-1473) that upon injection elicits up to three 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 (> 50%, p:0.0008), resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat didn’t 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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| Overall design |
Liver samples from 4 mice for control (NTC) , 4 mice samples for treatment group (Dgat2-1473)
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| Contributor(s) |
Yenilmez B, Lifshitz L, Czech M, Khvorova A |
| Citation(s) |
34774753 |
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| Submission date |
Jun 27, 2021 |
| Last update date |
Apr 03, 2023 |
| Contact name |
Michael Czech |
| E-mail(s) |
[email protected]
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| Organization name |
University of Massachusetts Medical School
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| Department |
Program in Molecular Medicine
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| Street address |
373 Plantation Street
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| City |
Worcester |
| State/province |
Massachusetts |
| ZIP/Postal code |
01605 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA741794 |
| SRA |
SRP325785 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE178987_rsem_gene_expected_count.tsv.gz |
562.2 Kb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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