DGAT2-Targeting siRNA Duplex for Hepatic Triglyceride Reduction
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Solution Overview
Problem
Current treatments for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are inadequate in effectively inhibiting diacylglycerol acyltransferase-2 (DGAT2) expression, leading to uncontrolled triglyceride accumulation and inflammation in the liver, which can progress to cirrhosis and hepatocellular carcinoma.
Innovation Solution
Development of small interfering RNA (siRNA) molecules designed to specifically inhibit DGAT2 expression by forming a duplex region with complementary strands, potentially modified with 2'-methoxy or 2'-fluoro ribose and phosphorothioate linkages, administered alone or conjugated with ligand groups to enhance delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for NAFLD and NASH, then treatment coverage is provided, but DGAT2 expression inhibition is insufficient leading to uncontrolled triglyceride accumulation
Solution Approach 1:
The patent extracts and targets the specific DGAT2 gene expression pathway using siRNA technology, isolating this critical enzyme from the general metabolic processes. By designing siRNA molecules that specifically bind to DGAT2 mRNA, the treatment selectively inhibits triglyceride synthesis at the enzymatic level, achieving precise control over triglyceride accumulation without affecting other metabolic pathways.
Solution Approach 2:
The patent employs chemical modifications to the siRNA molecule parameters including 2'-O-methyl ribose modifications, phosphorothioate backbone linkages, and varying duplex lengths (19-25 base pairs). These parameter changes enhance the stability, cellular uptake, and target specificity of the siRNA, thereby improving DGAT2 inhibition effectiveness while reducing off-target effects and immune stimulation.
2Reliability
If siRNA is administered to inhibit DGAT2 expression, then triglyceride synthesis is reduced, but delivery efficiency and stability challenges arise
Solution Approach 1:
The patent creates composite siRNA structures by combining chemically modified nucleotides (2'-O-methyl modifications) with phosphorothioate backbone linkages. This composite approach integrates multiple functional properties: enhanced nuclease resistance, improved cellular uptake, and maintained RNAi activity. The composite material strategy allows the siRNA to withstand biological degradation while efficiently delivering gene silencing function to hepatic cells.
Solution Approach 2:
The patent uses modified nucleotide sequences as intermediaries between the administered siRNA and the target DGAT2 mRNA. The 2'-O-methyl modified ribose residues act as protective intermediaries that prevent premature degradation by nucleases during circulation, while the phosphorothioate linkages serve as stable intermediaries that facilitate cellular uptake and protect the siRNA structure until it reaches the target liver cells.
3Reliability
If siRNA molecules are designed with modified nucleotides and phosphorothioate linkages, then stability and specificity are improved, but molecular complexity increases
Solution Approach 1:
The patent applies chemical modifications locally rather than uniformly throughout the entire siRNA molecule. Specifically, 2'-O-methyl ribose modifications are placed at strategic positions (such as the 5' end of the sense strand and specific internal positions), and phosphorothioate linkages are introduced at key locations. This local quality approach provides enhanced stability and specificity at critical regions while minimizing overall molecular complexity and maintaining ease of synthesis.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The siRNA effectively reduces hepatic triglyceride levels, improves insulin sensitivity, and mitigates liver inflammation, offering a promising therapeutic approach for NAFLD and NASH by targeting DGAT2 inhibition.
Implementation Method 1
RNA interference (RNAi) is a highly conserved phenomenon in the evolution process, in which highly efficient and specific degradation of a homologous mRNA is induced by a double-stranded RNA (dsRNA)
Implementation Method 2
the sense strand and the anti-sense strand include a duplex region formed by reverse complementarity
Data Source
Figure 1~2
AI summary
The present invention relates to the technical field of genetic engineering, and in particular, to a small interfering RNA for inhibiting the expression of diacylglycerol acyltransferase-2 (DGAT-2) and the use thereof in the preparation of a drug for treating diseases related to the expression of DGAT2.