Modified dsRNA for Hepatocyte-Targeted APOC3 Silencing

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Solution Overview

Problem

Conventional small-molecule drugs and biomacromolecule formulations are ineffective in targeting non-druggable proteins associated with diseases, necessitating the development of effective RNA interference methods for therapeutic delivery to specific cells, particularly hepatocytes, to inhibit the expression of proteins like APOC3 that contribute to conditions such as cardiovascular disease and diabetes.

Innovation Solution

Designing double-stranded ribonucleic acid (dsRNA) with specific chemical modifications, including 2′-fluoro and 2′-methoxy nucleotides, and incorporating a chemical modification represented by formula (I) at certain nucleotide positions to enhance targeting and delivery to hepatocytes through asialoglycoprotein receptors, thereby inhibiting the expression of APOC3.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional small-molecule drugs and biomacromolecule formulations are used, then drug delivery is possible, but they cannot effectively target non-druggable proteins associated with diseases

Engineering Contradiction:

Improvetargeting effectivenessVSAvoidapplicability to non-druggable proteins

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the chemical parameters of the RNA molecule by introducing specific modifications (2'-fluoro and 2'-methoxy nucleotides at defined positions) to create a dsRNA structure that can effectively target non-druggable proteins through RNA interference, overcoming the limitations of conventional drugs

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite structure by combining chemically modified nucleotides (2'-fluoro and 2'-methoxy) within the dsRNA framework to produce a molecule with enhanced therapeutic properties for targeting previously non-druggable proteins

Inventive Principle:

Principle #40Composite materials

2Reliability

If dsRNA is delivered to achieve therapeutic RNA interference effect, then gene expression can be silenced, but delivery to specific cells in vivo is needed

Engineering Contradiction:

Improvetherapeutic effectVSAvoiddelivery complexity

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent uses asialoglycoprotein receptors on hepatocyte surfaces as intermediaries to facilitate the delivery of dsRNA to specific liver cells, enabling targeted delivery without complex delivery systems

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the chemical parameters of the dsRNA by incorporating specific nucleotide modifications that enhance the molecule's ability to interact with cellular receptors and improve in vivo delivery efficiency to hepatocytes

Inventive Principle:

Principle #35Parameter changes

3Reliability

If higher activity of dsRNA is achieved, then better therapeutic effect or lower dosage is possible, but lower dosage means lower toxicity

Engineering Contradiction:

Improvetherapeutic effectVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent optimizes the chemical parameters of dsRNA by precisely positioning 2'-fluoro and 2'-methoxy nucleotide modifications to achieve maximum therapeutic activity at lower dosages, thereby reducing toxicity while maintaining efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local chemical modifications at specific positions within the dsRNA sequence rather than uniform modification throughout, creating regions of enhanced activity that improve therapeutic effect while minimizing overall dosage requirements and associated toxicity

Inventive Principle:

Principle #3Local quality

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 modified dsRNA effectively silences APOC3 expression in the liver, reducing triglyceride levels and addressing associated diseases like cardiovascular disease and diabetes by improving therapeutic efficacy and reducing dosage-related toxicity.

Implementation Method 1

incorporating a chemical modification represented by formula (I) at certain nucleotide positions to enhance targeting and delivery to hepatocytes through asialoglycoprotein receptors

Methodology Applied

Scientific EffectReceptor-ligand binding: Adsorption

Implementation Method 2

RNA interference (RNAi) is an effective way to silence gene expression... proper dsRNAs can be designed according to the mRNAs encoding these proteins to specifically target and degrade the target mRNAs, thereby inhibiting the production of the related proteins

Methodology Applied

Scientific EffectRNA interference:

Data Source

PatentUS20260076990A1Dsrna, use thereof and preparation method therefor

Publication Date: 2026.03.19 TUOJIE BIOTECH (SHANGHAI) CO LTD

AI summary

Provided are a dsRNA, and the use thereof and a preparation method therefor. Further provided are a pharmaceutical composition, a cell or a kit containing the dsRNA. The dsRNA can interfere with the expression of APOC3, and prevent and/or treat related diseases.