Modified Double-Stranded siRNA Analogs for Low Off-Target HBV Silencing

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Solution Overview

Problem

Current siRNA therapies for hepatitis B are ineffective in reducing hepatitis B virus surface antigen levels and suffer from off-target effects and safety issues, limiting their therapeutic potential.

Innovation Solution

Development of double-stranded siRNA analogs with modified nucleotides and conjugates, including sense and antisense strands, to enhance stability and target specificity, combined with pharmaceutically acceptable conjugating groups for improved delivery and reduced immunogenicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current siRNA is used for hepatitis B treatment, then the mechanism of RNA interference can inhibit target gene expression, but it cannot effectively reduce hepatitis B virus surface antigen levels and suffers from off-target effects

Engineering Contradiction:

Improveefficacy in reducing HBsAg levelsVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of siRNA molecules through various nucleotide modifications including 2'-O-methyl, 2'-fluoro, phosphorothioate linkages, and base modifications. These structural parameter changes enhance the stability, specificity, and efficacy of siRNA in reducing HBsAg levels while minimizing off-target effects through improved binding affinity and reduced non-specific interactions

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by creating chimeric siRNA molecules that combine different types of modified and unmodified nucleotides within the same molecule. This composite approach allows optimization of different regions of the siRNA for specific functions: modifications in the seed region reduce off-target effects, while modifications in other regions enhance stability and efficacy, achieving synergistic improvement in therapeutic performance

Inventive Principle:

Principle #40Composite materials

2Object-affected harmful factors

If nucleotide modifications are made to reduce off-target effects, then the risk of off-target is reduced, but the effectiveness of silencing is also reduced

Engineering Contradiction:

Improveoff-target riskVSAvoidsilencing effectiveness

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies local quality by implementing different modification strategies at different positions within the siRNA molecule. Specifically, the seed region (nucleotides 2-8 of the antisense strand) receives specific modifications like 2'-O-methyl or 2'-fluoro to reduce off-target effects, while other regions maintain modifications that preserve or enhance silencing effectiveness. This localized differentiation allows simultaneous optimization of specificity and efficacy

Inventive Principle:

Principle #3Local quality

3Reliability

If siRNA is used to inhibit viral gene expression, then the purpose of treating diseases is achieved, but the therapeutic safety window needs to be improved

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidsafety window

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes through extensive chemical modifications of siRNA including phosphorothioate backbone modifications, 2'-sugar modifications, and base modifications. These parameter changes improve pharmacokinetic properties, reduce immunogenicity, and enhance cellular uptake and stability, thereby expanding the therapeutic safety window while maintaining or improving antiviral efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs intermediary approaches by using modified nucleotide structures as mediators that bridge the gap between siRNA functionality and safety. These modified nucleotides act as intermediaries that maintain the RNA interference mechanism while reducing unwanted immune responses and improving cellular compatibility, thus expanding the therapeutic safety window

Inventive Principle:

Principle #24Intermediary (Mediator)

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 siRNA analogs demonstrate excellent anti-HBV activity, particularly in reducing HBsAg levels, with low off-target effects and improved safety profiles, as shown in in vitro and in vivo models.

Implementation Method 1

siRNA can partially complementarily pair with certain mRNA fragments, thereby regulating the expression of genes corresponding to the mRNA

Methodology Applied

Scientific EffectComplementary base pairing:

Data Source

PatentEP4671371A1Double-stranded sirna analogs comprising r and e and conjugates thereof

Publication Date: 2025.12.31 YAOPHARMA CO LTD

AI summary

Provided are a series of double-stranded siRNA analogs comprising R and/or E, conjugates thereof, salts of the conjugates, and uses.