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Ubiquitination of hepatic APOC3 by GM47544 prevents hypertriglyceridemia and ameliorates atherosclerosis

ABSTRACT: Ubiquitination of hepatic APOC3 by GM47544 prevents hypertriglyceridemia and ameliorates atherosclerosis

PROVIDER: PRJNA974253 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24655558_1.fastq.gz	Fastqsanger.gz
	SRR24655558_2.fastq.gz	Fastqsanger.gz
	SRR24655559_1.fastq.gz	Fastqsanger.gz
	SRR24655559_2.fastq.gz	Fastqsanger.gz
	SRR24655560_1.fastq.gz	Fastqsanger.gz

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Ubiquitination of hepatic APOC3 by GM47544 prevents hypertriglyceridemia and ameliorates atherosclerosis

Project description:To investigate the function of lnc GM47544 in the regulation of triglyceride, we established AML-12 cell lines in which lnc GM47544 has been stably overexpressed by lentivirus. We then performed gene expression profiling analysis using data obtained from RNA-seq of AML-12-pLKO.1 (control) and AML-12-GM47544 (O/E).

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Discovery of Long-Acting APOC3 siRNA for Treating Patients with Hypertriglyceridemia

Project description:Apolipoprotein C-III (APOC3) plays a crucial role in triglyceride metabolism, and its high expression leads to hypertriglyceridemia, a condition associated with an increased risk of cardiovascular disease and acute pancreatitis. However, loss-of-function variants in APOC3 are linked to lower triglyceride levels and reduced incidence of coronary artery diseases. APOC3 mRNA, primarily synthesized by hepatocytes, is an ideal target for GalNAc-conjugated small interference RNA (siRNA) mediated gene silencing. Our research takes a unique approach, conducting systematic structure-activity relationship (SAR) studies to identify a long-acting APOC3 siRNA with a minimal number of 2’-F nucleotides. We evaluated the use of 5’-vinylphosphonate (5’-VP), 5’-methylene phosphonate (5’-MP), FHNA, and methane sulphonyl phosphoramidite backbone chemistry in APOC3 siRNA design and employed deoxynucleotides or 2’-O-methyl (OMe) to replace 2’-F residues. Additionally, we utilized 2’-O-methoxyethyl (MOE) nucleotides in conjunction with phosphorothioate modification to enhance metabolic stability. To ensure the preferential loading of the antisense strand, we strategically placed MOE nucleotides at specific sites in the antisense strand. These efforts led to the identification of APOC3 siRNA containing a novel chemical scaffold with a long duration of action (DOA) and tolerability in rodents and nonhuman primates. A comparative analysis of preclinical and clinical data of plozasiran surrogate suggests that our APOC3 siRNA may provide clinical benefits with less frequent exposure (>6 months apart), which could significantly improve the treatment of patients with hypertriglyceridemia.

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