Selective Antisense Oligonucleotide Gapmers for Target mRNA Modulation

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Solution Overview

Problem

Existing antisense compounds face challenges in effectively modulating target nucleic acids, particularly in achieving specific and efficient modulation of protein expression by binding to target mRNA, with limitations in cleavage, splicing, and polyadenlyation processes.

Innovation Solution

Development of oligomeric compounds comprising modified oligonucleotides with specific nucleobase sequences and motifs, such as gapmer motifs, to enhance binding and modulation of target mRNA, including phosphorothioate and methylphosphonate internucleoside linkages, and 5′-Me-DNA modifications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If existing antisense compounds are used to modulate target nucleic acids, then protein expression can be modulated, but the specificity and efficiency in reducing target protein expression is limited

Engineering Contradiction:

Improvespecificity in reducing target protein expressionVSAvoidefficiency in reducing target protein expression

Core Design Contradiction:

Measurement precisionVSProductivity

Solution Approach 1:

The patent applies local quality by creating oligonucleotides with heterogeneous structures where different regions have different properties: the gapmer motif region provides high binding affinity and specificity to target mRNA, while modified regions (with phosphorothioate or methylphosphonate linkages) provide enhanced stability and resistance to nucleases. This localized functional differentiation resolves the contradiction by concentrating specificity in the gapmer region while efficiency is enhanced by the stable modified regions.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs composite materials by combining different types of nucleosides and linkages within a single oligonucleotide molecule. The composite structure includes natural nucleosides in the gapmer motif region for high complementarity and binding, combined with modified nucleosides containing phosphorothioate or methylphosphonate linkages for enhanced stability. This composite approach simultaneously improves both specificity (through the gapmer region) and efficiency (through the stable modified regions).

Inventive Principle:

Principle #40Composite materials

2Reliability

If antisense compounds bind to target mRNA to modulate protein expression, then cleavage or splicing modulation can occur, but the compounds face limitations in achieving effective and selective modulation

Engineering Contradiction:

Improveselectivity of modulationVSAvoidcomplexity of oligonucleotide structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the oligonucleotide into distinct functional segments: a gapmer motif segment (typically 8-12 nucleotides) that provides high-affinity binding and specificity to the target mRNA, and modified segments flanking the gapmer that provide stability and nuclease resistance. This segmentation allows the molecule to achieve high selectivity through the specific gapmer region while the modified segments can be optimized for stability without compromising selectivity, thus managing complexity through functional modularization.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies universality by designing the gapmer motif as a universal high-affinity binding element that can be applied to different target sequences while maintaining consistent specificity and mechanism of action. The modified regions with phosphorothioate or methylphosphonate linkages serve as universal stability-enhancing components that can be incorporated into various oligonucleotide designs. This multi-functionality approach allows the same structural principles to achieve both selectivity and stability across different applications without increasing inherent complexity.

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 demonstrate enhanced specificity and efficiency in reducing target protein expression, with selectivity shown through lower EC50/ED50 values compared to non-targets, and potential therapeutic applications in treating diseases like Huntington's disease.

Implementation Method 1

antisense compounds have been shown to modulate protein expression by binding to a target messenger RNA (mRNA) encoding the protein

Methodology Applied

Scientific EffectHybridization:

Implementation Method 2

oligonucleotides comprise a region having a gapmer motif... phosphorothioate and methylphosphonate internucleoside linkages

Methodology Applied

Scientific EffectChemical modification:

Data Source

PatentUS20250270554A1Selective Antisense Compounds and Uses Thereof

Publication Date: 2025.08.28 IONIS PHARMACEUTICALS INC

AI summary

The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount, activity, or expression of the target nucleic acid in a cell. In certain embodiments, hybridization results in selective modulation of the amount, activity, or expression of a target Huntingtin gene or Huntingtin transcript in a cell.