Modified Oligonucleotide Linkages for Nuclease Resistance and Tolerability

Solution Overview

Problem

Existing antisense compounds face challenges in achieving optimal nuclease resistance, tolerability, and pharmacokinetics, limiting their therapeutic efficacy and safety.

Innovation Solution

Development of oligomeric compounds comprising modified oligonucleotides with specific internucleoside linking groups, such as Formula VIII and Formula XVII, which enhance properties like nuclease resistance and therapeutic index.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemically modified nucleosides are incorporated into antisense compounds, then nuclease resistance and affinity for target nucleic acid are enhanced, but tolerability and pharmacokinetics properties deteriorate

Engineering Contradiction:

Improvenuclease resistanceVSAvoidtolerability

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific modified internucleoside linking groups (Formulas VIII and XVII) at particular positions within the oligonucleotide sequence, rather than uniformly modifying the entire molecule. This allows enhancement of nuclease resistance at critical sites while maintaining tolerability in other regions. The modified linking groups are strategically placed to provide localized protection against nucleases without causing systemic toxicity throughout the molecule.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs composite materials by combining different types of nucleosides and internucleoside linking groups within the same oligonucleotide molecule. The composite structure includes modified nucleosides with specific internucleoside linking groups (Formulas VIII and XVII) integrated into the oligonucleotide backbone, creating a heterogeneous structure that provides both nuclease resistance and acceptable tolerability through the synergistic combination of different chemical components.

Inventive Principle:

Principle #40Composite materials

2Reliability

If chemically modified nucleosides are incorporated into antisense compounds, then affinity for target nucleic acid is enhanced, but pharmacokinetics properties deteriorate

Engineering Contradiction:

Improveaffinity for target nucleic acidVSAvoidpharmacokinetics

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent applies local quality by introducing specific modified internucleoside linking groups (Formulas VIII and XVII) at particular positions within the oligonucleotide sequence, rather than uniformly modifying the entire molecule. This allows enhancement of nuclease resistance at critical sites while maintaining tolerability in other regions. The modified linking groups are strategically placed to provide localized protection against nucleases without causing systemic toxicity throughout the molecule.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs composite materials by combining different types of nucleosides and internucleoside linking groups within the same oligonucleotide molecule. The composite structure includes modified nucleosides with specific internucleoside linking groups (Formulas VIII and XVII) integrated into the oligonucleotide backbone, creating a heterogeneous structure that provides both nuclease resistance and acceptable tolerability through the synergistic combination of different chemical components.

Inventive Principle:

Principle #40Composite materials

3Reliability

If modified internucleoside linking groups are introduced, then therapeutic index is improved, but molecular complexity increases

Engineering Contradiction:

Improvetherapeutic indexVSAvoidmolecular complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by systematically varying the parameters of internucleoside linking groups (Formulas VIII and XVII), including the identity of R1, T, R2, R3, R4, and R5 substituents. By changing these chemical parameters, the patent optimizes the balance between therapeutic index and molecular complexity. The modified linking groups provide enhanced therapeutic properties through controlled variation of chemical parameters rather than introducing entirely new molecular architectures.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12595482B2Linkage modified oligomeric compounds and uses thereof

Publication Date: 2026.04.07 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.