Segmented Antisense Oligonucleotides for HBV Antigen Reduction

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Solution Overview

Problem

Current HBV antisense oligonucleotides exhibit minimal efficacy in reducing serum HBsAg and HBeAg levels and pose safety concerns, necessitating improved therapeutic options for chronic hepatitis B.

Innovation Solution

Development of modified oligonucleotides with segmented gap structures and specific nucleoside modifications, including separator segments, to enhance binding and activity while minimizing toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional HBV antisense oligonucleotides are used, then they can target HBV transcripts, but they exhibit minimal efficacy in reducing serum HBsAg and HBeAg levels and cause safety concerns

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The oligonucleotide is divided into distinct functional segments: a 5' wing segment (nucleotides 1-6) with modified nucleosides for binding affinity, a central gap segment (nucleotides 7-17) of unmodified deoxynucleotides for RNase H recruitment, and a 3' wing segment (nucleotides 18-24) with modified nucleosides for stability. This segmentation allows each region to optimize its specific function while minimizing off-target effects and toxicity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Different nucleoside modifications are applied locally to specific regions of the oligonucleotide. The 5' and 3' wing segments contain modified nucleosides (2'-O-methoxyethyl, 2'-fluoro-arabinose, locked nucleic acid) to enhance binding affinity and stability, while the central gap segment uses unmodified deoxynucleotides to maintain RNase H recruitment capability. This local differentiation optimizes overall therapeutic efficacy while reducing toxicity.

Inventive Principle:

Principle #3Local quality

2Quantity of substance

If nucleoside therapies (entecavir, tenofovir) are used, then viral load is reduced, but HBeAg seroconversion and HBsAg loss rates remain low

Engineering Contradiction:

Improveviral load reductionVSAvoidseroconversion rate

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The oligonucleotide acts as an intermediary that recruits RNase H endonuclease to specifically cleave HBV transcripts. This enzymatic mediation enables direct degradation of viral mRNA, leading to both viral load reduction and enhanced seroconversion rates, overcoming the limitation of nucleoside therapies that only suppress replication without promoting immune-mediated seroconversion.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention replaces the mechanical inhibition mechanism of nucleoside analogs (which block polymerase) with an enzymatic degradation mechanism using RNase H. This substitution allows for more effective transcript destruction and promotes both viral load reduction and seroconversion by directly eliminating viral antigens, thereby enhancing the immune response.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Reliability

If antisense oligonucleotides with single gap segments are used, then they can reduce HBV expression, but they exhibit minimal efficacy and cause safety concerns

Engineering Contradiction:

ImproveHBV expression reductionVSAvoidsafety profile

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The oligonucleotide employs a composite structure combining different nucleoside types (modified and unmodified) in a specific arrangement. This composite design integrates the advantages of modified nucleosides (enhanced binding and stability) with unmodified deoxynucleotides (RNase H recruitment), achieving superior therapeutic efficacy and safety profile compared to homogeneous oligonucleotides.

Inventive Principle:

Principle #40Composite materials

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 oligonucleotides effectively reduce HBsAg and HBeAg levels, offering improved therapeutic efficacy with reduced toxicity and increased complementarity to HBV target sequences.

Implementation Method 1

increased complementarity to HBV target sequences

Methodology Applied

Scientific EffectNucleic acid complementarity:

Data Source

PatentUS20250215430A1Modulation of hepatitis b virus (HBV) expression

Publication Date: 2025.07.03 AUSPERBIO THERAPEUTICS INC

AI summary

Provided is a chimeric antisense compound comprising a modified oligonucleotide comprising 5′ W1-G1-S1-G2-W2 3′, wherein: W1 is a 5′ wing segment, W2 is a 3′ wing segment, G1 is a first gap segment, S1 is a first separator segment, and G2 is a second gap segment. Also provided is a method for decreasing HBV mRNA, DNA and protein expression. Such compounds and methods are useful to treat, prevent, or ameliorate HBV-related diseases, disorders or conditions.