Modified Internucleoside Linkages for Selective RNAi Seed Regions

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Solution Overview

Problem

Existing RNAi agents face challenges in achieving selective and potent modulation of gene expression due to limitations in internucleoside linkages, particularly in the seed region, leading to suboptimal efficacy and specificity.

Innovation Solution

Incorporation of modified internucleoside linking groups in the seed region of antisense RNAi oligonucleotides, which are not phosphodiester or phosphorothioate, to enhance selectivity and on-target potency compared to traditional linkages.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If traditional phosphodiester or phosphorothioate internucleoside linkages are used in the seed region, then the RNAi agent achieves basic target recognition, but selectivity and on-target potency are suboptimal

Engineering Contradiction:

ImproveselectivityVSAvoidon-target potency

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of internucleoside linkages in the seed region. Specifically, it uses non-phosphodiester and non-phosphorothioate linkages (such as methoxypropyl, methoxyethyl, or other modified linkages) to alter the physical and chemical properties of the RNAi agent, thereby improving selectivity and on-target potency compared to traditional linkages

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by introducing modified internucleoside linkages specifically in the seed region (nucleotides 2-8 from the 5' end) of the antisense oligonucleotide. This localized modification enhances the functional properties of the seed region, which is critical for RISC complex formation and target recognition, without affecting the entire oligonucleotide structure uniformly

Inventive Principle:

Principle #3Local quality

2Measurement precision

If modified internucleoside linkages are introduced in the seed region, then selectivity and on-target potency are improved, but the complexity of the oligonucleotide structure increases

Engineering Contradiction:

ImproveselectivityVSAvoidinternucleoside linkage structure

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent modifies the chemical parameters of the internucleoside linkages by introducing alternative linkages such as methoxypropyl (−OCH2CH2OCH3), methoxyethyl (−OCH2CH2OCH2CH3), or other modified linkages that differ from standard phosphodiester or phosphorothioate structures. These parameter changes enable improved selectivity and potency while managing structural complexity through systematic modification

Inventive Principle:

Principle #35Parameter changes

3Measurement precision

If non-phosphodiester/non-phosphorothioate linkages are used, then target recognition is enhanced, but compatibility with existing RNAi mechanisms may be compromised

Engineering Contradiction:

Improvetarget recognitionVSAvoidcompatibility with RISC mechanism

Core Design Contradiction:

Measurement precisionVSAdaptability or versatility

Solution Approach 1:

The patent modifies the chemical parameters of the internucleoside linkages to non-phosphodiester and non-phosphorothioate structures (such as methoxypropyl, methoxyethyl, or other modified linkages) that maintain compatibility with the RISC mechanism while enhancing target recognition. The modifications are designed to preserve essential functional properties required for RISC complex formation and activity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by introducing modified linkages specifically in the seed region (nucleotides 2-8 from the 5' end), which is the critical region for RISC complex formation and target recognition. This localized modification enhances compatibility with RISC mechanisms while improving target recognition, as the seed region is the primary interface with the target and RISC components

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 internucleoside linkages improve the selectivity and potency of RNAi agents, providing enhanced target recognition and modulation of gene expression.

Implementation Method 1

Such internucleoside linking groups as described herein may provide seed-region destabilization of RNA interference (RISC) complexes

Methodology Applied

Scientific EffectRISC complex destabilization:

Implementation Method 2

an antisense compound hybridizes to a target nucleic acid and modulates the amount, activity, and/or function of the target nucleic acid

Methodology Applied

Scientific EffectHybridization:

Implementation Method 3

target RNA degradation upon hybridization with a DNA-like antisense compound

Methodology Applied

Scientific EffectRNase H-based degradation:

Implementation Method 4

RNAi refers to antisense-mediated gene silencing through a mechanism that utilizes the RNA-induced silencing complex (RISC)

Methodology Applied

Scientific EffectRNA interference:

Implementation Method 5

MicroRNAs are small non-coding RNAs that regulate the expression of protein-coding RNAs

Methodology Applied

Scientific EffectMicroRNA binding:

Data Source

PatentUS20250346898A1Linkage Modified Oligomeric Compounds and Uses Thereof

Publication Date: 2025.11.13 IONIS PHARMACEUTICALS INC

AI summary

The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising a modified oligonucleotide having at least one modified internucleoside linking group.