Antisense Oligonucleotide Toehold Complex for Reduced Off-Target Toxicity

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Solution Overview

Problem

Existing antisense oligonucleotides face challenges with off-target toxicity due to hybridization-dependent and hybridization-independent mechanisms, which complicates their clinical use and application, and existing methods to reduce toxicity often compromise their efficacy.

Innovation Solution

A novel double-stranded nucleic acid complex, named BROTHERS, featuring a complementary toehold structure that allows for targeted and controlled binding with target RNA, reducing toxicity while maintaining antisense activity by using a complementary strand with nuclease resistance and optimized binding strengths.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If the number of non-naturally occurring nucleotides of ASO is adjusted to minimize binding strength with target RNA, then hybridization-dependent toxicity is reduced, but drug effect is lowered

Engineering Contradiction:

Improvehybridization-dependent toxicityVSAvoiddrug effect

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent introduces a complementary strand as an intermediary component that binds to the ASO to form a double-stranded structure. This intermediary complex reduces toxicity through steric hindrance and altered pharmacology while maintaining drug effect through controlled strand exchange mechanisms, resolving the contradiction between reduced binding strength and maintained efficacy

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent creates a composite nucleic acid structure combining ASO with a complementary strand to form a double-stranded complex. This composite structure exhibits properties different from either component alone, achieving both reduced toxicity and maintained drug effect through the synergistic interaction of the two strands

Inventive Principle:

Principle #40Composite materials

2Object-affected harmful factors

If one non-natural nucleic acid is introduced into the gap region of gapmer ASO to reduce toxicity, then toxicity is reduced, but changes in activity and toxicity cannot be predicted

Engineering Contradiction:

ImprovetoxicityVSAvoidpredictability of activity and toxicity changes

Core Design Contradiction:

Object-affected harmful factorsVSMeasurement precision

Solution Approach 1:

The patent systematically varies parameters such as complementary strand length, sequence composition, and binding strength to establish structure-activity-toxicity relationships. By controlling these parameters, the patent achieves predictable outcomes in both activity and toxicity reduction, resolving the unpredictability issue

Inventive Principle:

Principle #35Parameter changes

3Reliability

If HDO is used with overhang on the complementary strand to achieve in vivo gene suppressing effect, then antisense activity is achieved, but toxicity remains an issue

Engineering Contradiction:

Improveantisense activityVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local modifications to specific regions of the nucleic acid structure, particularly at the ends of the complementary strand. By controlling the presence or absence of overhangs at specific locations and modifying local sequences, the patent achieves antisense activity while reducing toxicity through localized structural control

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

BROTHERS complexes exhibit significantly reduced hepatotoxicity, nephrotoxicity, and mitochondrial toxicity, while maintaining effective antisense effects, offering a balanced approach to minimize off-target toxicity without compromising drug efficacy.

Implementation Method 1

a complementary strand comprising a sequence complementary to the antisense oligonucleotide

Methodology Applied

Scientific EffectHybridization:

Implementation Method 2

the complementary strand has nuclease resistance across its full length

Methodology Applied

Scientific EffectNuclease resistance:

Data Source

PatentUS20250297249A1Antisense oligonucleotide complex

Publication Date: 2025.09.25 LIID PHARM INC

AI summary

The present invention provides an antisense oligonucleotide complex which includes an antisense oligonucleotide and a complementary strand which includes a sequence which is complementary to said antisense oligonucleotide, said complex being characterized in that said antisense oligonucleotide has a single strand-structured toe hold, and said complementary strand has nuclease resistance throughout the entire length thereof. As a result, said complex exhibits an antisense effect and has reduced toxicity.