Modified Antisense Oligonucleotides for HBV With Lower Liver Toxicity

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Solution Overview

Problem

Current antisense oligonucleotides (ASOs) used to treat hepatitis B virus (HBV) face safety issues such as liver toxicity, necessitating the development of ASOs with improved safety profiles and increased efficacy.

Innovation Solution

Development of modified antisense oligonucleotides (ASOs) that are complementary to specific nucleotide sequences within the HBV genome, incorporating phosphorothioate linkages, 2′-O-methoxyethyl nucleotides, and optionally containing abasic monomers, with specific wing and central regions comprising locked nucleotides, to enhance targeting and reduce toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antisense oligonucleotides are used to treat HBV, then viral RNA degradation and HBsAg reduction are achieved, but liver toxicity occurs

Engineering Contradiction:

Improveefficacy in reducing HBsAgVSAvoidliver toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The ASO is divided into distinct functional regions: a central gap region (positions 5-10) comprising DNA nucleotides that recruit RNase H for RNA degradation, and 5′/3′ wing regions comprising modified nucleotides (2′-MOE, LNA) that provide enhanced binding affinity and stability. This local differentiation of nucleotide types in different regions resolves the contradiction by concentrating degradative function in the center while shielding toxic effects through modified wings.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The ASO employs a composite structure combining multiple nucleotide types (DNA, 2′-MOE, LNA) and linkage types (phosphodiester, phosphorothioate) within a single molecule. This composite approach allows simultaneous optimization of RNA binding (via modified nucleotides), degradation mechanism (via central DNA gap), and reduced immunogenicity/toxicity (via phosphorothioate linkages and modified wings), thereby achieving efficacy while minimizing liver toxicity.

Inventive Principle:

Principle #40Composite materials

2Object-affected harmful factors

If ASOs with modified nucleotides are introduced to reduce toxicity, then safety profile improves, but molecular complexity increases

Engineering Contradiction:

ImprovetoxicityVSAvoidmolecular structure complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The ASO is segmented into functionally distinct modules: a central gap region (5-10 nucleotides) for RNase H recruitment, 5′-wing regions for stability and affinity, and 3′-wing regions for binding enhancement. Each segment uses specific modified nucleotides optimized for its function. This segmentation reduces overall molecular complexity by assigning specific roles to each region, making the complex molecule more predictable and designable while maintaining reduced toxicity through localized modifications.

Inventive Principle:

Principle #1Segmentation

3Reliability

If abasic monomers are incorporated to enhance immune activation, then TLR8 activity increases, but structural stability may be compromised

Engineering Contradiction:

Improveimmune activation efficacyVSAvoidoligonucleotide stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The abasic monomer acts as an intermediary element positioned within the central gap region (e.g., position 7) that specifically activates TLR8 receptors to enhance immune response. Its strategic placement among stabilizing DNA nucleotides and phosphorothioate linkages allows it to fulfill its immune-activating function while the surrounding stable structural elements compensate for any stability reduction, thereby resolving the contradiction between immune activation and structural stability.

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 ASOs demonstrate improved safety and efficacy in reducing HBV viral load and antigen levels, with reduced liver toxicity and enhanced immune activation, as evidenced by increased toll-like receptor 8 (TLR8) activity.

Implementation Method 1

antisense oligonucleotides (ASOs) that are complementary to specific nucleotide sequences within the HBV genome

Methodology Applied

Scientific EffectBase pairing: Chemical Bonding

Implementation Method 2

comprises at least one phosphorothioate linkage

Methodology Applied

Scientific EffectPhosphorothioate linkage: Chemical Bonding

Implementation Method 3

comprises at least one 2′-O-methoxyethyl nucleotide

Methodology Applied

Scientific Effect2′-O-methoxyethyl modification: Chemical Bonding

Implementation Method 4

with specific wing and central regions comprising locked nucleotides

Methodology Applied

Scientific EffectLocked nucleotide: Chemical Bonding

Implementation Method 5

enhanced immune activation, as evidenced by increased toll-like receptor 8 (TLR8) activity

Methodology Applied

Scientific EffectToll-like receptor activation: Enzyme

Data Source

PatentUS20250368996A1Modified antisense oligonucleotides for treating hepatitis b virus

Publication Date: 2025.12.04 ALIGOS THERAPEUTICS INC

AI summary

Provided herein are antisense oligonucleotides and compositions that include the disclosed ASOs. The disclosed ASOs and compositions can be used for treating hepatitis B.