Modified Oligonucleotide Compositions for Stable mRNA Silencing

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Solution Overview

Problem

There is a need for improved oligonucleotides that effectively reduce gene expression by targeting specific mRNA and protein levels.

Innovation Solution

Compositions comprising oligonucleotides, such as siRNA, with specific modifications like hydrophobic moieties, vinyl phosphonate, and phosphorothioate linkages, connected via phenyl or cyclohexyl linkers, are designed to target and reduce mRNA or protein levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional oligonucleotides are used to target mRNA, then gene expression reduction is achieved, but the efficiency and stability are insufficient

Engineering Contradiction:

Improvegene expression reduction efficiencyVSAvoidoligonucleotide stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent modifies the chemical parameters of the oligonucleotide backbone by introducing phosphorothioate linkages (replacing oxygen with sulfur) and vinyl phosphonate groups, which enhance both the stability against nucleases and the binding affinity to target mRNA, thereby simultaneously improving reliability and stability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite oligonucleotide structure combining multiple modified components: vinyl phosphonate terminal groups, phosphorothioate backbone linkages, and modified nucleosides (2'-fluoro, 2'-O-methyl), which work synergistically to enhance both stability and gene silencing efficiency

Inventive Principle:

Principle #40Composite materials

2Productivity

If oligonucleotides are modified with hydrophobic moieties and lipid connections, then delivery efficiency is improved, but the molecular complexity increases

Engineering Contradiction:

Improvedelivery efficiencyVSAvoidmolecular structure complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent introduces lipid moieties connected via phenyl or cyclohexyl linkers as intermediary structures that facilitate cellular uptake and delivery of the oligonucleotide, while the linkers act as flexible connectors that manage the structural complexity through modular design

Inventive Principle:

Principle #24Intermediary (Mediator)

3Stability of the object's composition

If phosphorothioate linkages are introduced to enhance stability, then resistance to degradation increases, but the manufacturing complexity increases

Engineering Contradiction:

Improveresistance to degradationVSAvoidsynthesis complexity

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The substitution of oxygen with sulfur in the phosphate backbone (phosphorothioate modification) changes the chemical parameter of backbone stability, providing enhanced resistance to nuclease degradation while maintaining compatibility with standard oligonucleotide synthesis methodologies

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250250568A1Modified oligonucleotides

Publication Date: 2025.08.07 EMPIRICO INC

AI summary

Disclosed herein are compositions comprising modified oligonucleotides. In some embodiments, the oligonucleotide includes a hydrophobic moiety. In some embodiments, the oligonucleotide includes a vinyl phosphonate. In some embodiments, the oligonucleotide includes modified oligonucleotide sugars such as 2′ modified ribose molecules. In some embodiments, the oligonucleotide includes modified internucleoside linkages such as phosphorothioate linkages. In some embodiments, the oligonucleotide includes an siRNA. In some embodiments, the siRNA comprises a duplex region with overhangs on either end.