Modified Antisense Oligomers for Nuclease Resistance and Target Affinity

Solution Overview

Problem

Existing antisense compounds face limitations in terms of nuclease resistance, pharmacokinetics, and target affinity, which affect their therapeutic efficacy and safety profiles, particularly in achieving high maximum tolerated doses and therapeutic indices.

Innovation Solution

Development of oligomeric compounds with specific modifications in the 5′-, 3′-, and central regions, including 2′-modified furanosyl sugar moieties, altered internucleoside linkages, and modified nucleobases, which enhance nuclease resistance and target affinity, thereby increasing maximum tolerated dose and therapeutic index.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemically modified nucleosides are incorporated into antisense compounds to enhance nuclease resistance and pharmacokinetics, then stability and therapeutic index are improved, but device complexity and manufacturing complexity increase

Engineering Contradiction:

Improvenuclease resistanceVSAvoidcompound structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The oligonucleotide is divided into distinct functional regions (5′-region with 2-4 modified nucleosides, central region with 7-10 unmodified or minimally modified nucleosides, and 3′-region with 1-5 modified nucleosides). This segmentation allows each region to perform its specific function: the modified regions provide nuclease resistance and stability, while the central unmodified region maintains target affinity and enables RNase H recruitment, thus resolving the contradiction between stability and structural simplicity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Different regions of the oligonucleotide are assigned different chemical properties: the 5′ and 3′ regions have high modification density for nuclease resistance, while the central region has low or no modification for target binding. This local differentiation optimizes both stability and simplicity by placing complexity only where necessary for the intended function.

Inventive Principle:

Principle #3Local quality

2Duration of action of stationary object

If modified nucleosides with 2′-modified furanosyl sugar moieties are used in the 5′ and 3′ regions to enhance stability, then pharmacokinetics improve, but manufacturing precision requirements increase

Engineering Contradiction:

Improvepharmacokinetic profileVSAvoidsynthesis precision

Core Design Contradiction:

Duration of action of stationary objectVSManufacturing precision

Solution Approach 1:

The oligonucleotide is divided into distinct functional regions (5′-region with 2-4 modified nucleosides, central region with 7-10 unmodified or minimally modified nucleosides, and 3′-region with 1-5 modified nucleosides). This segmentation allows each region to perform its specific function: the modified regions provide nuclease resistance and stability, while the central unmodified region maintains target affinity and enables RNase H recruitment, thus resolving the contradiction between stability and structural simplicity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Different regions of the oligonucleotide are assigned different chemical properties: the 5′ and 3′ regions have high modification density for nuclease resistance, while the central region has low or no modification for target binding. This local differentiation optimizes both stability and simplicity by placing complexity only where necessary for the intended function.

Inventive Principle:

Principle #3Local quality

3Measurement precision

If the central region comprises at least one altered nucleotide with modified internucleoside linkage or modified nucleobase, then target affinity and efficacy are enhanced, but manufacturing complexity increases

Engineering Contradiction:

Improvetarget affinityVSAvoidsynthesis ease

Core Design Contradiction:

Measurement precisionVSEase of manufacture

Solution Approach 1:

Instead of modifying all nucleotides in the central region, only specific positions (at least one, up to ten) are altered with modified internucleoside linkages or nucleobases. This partial modification approach provides sufficient target affinity enhancement and efficacy improvement while avoiding the manufacturing complexity of comprehensive modification across the entire central region.

Inventive Principle:

Principle #16Partial or excessive action

4Quantity of substance

If oligomeric compounds are designed with specific gapmer structures and regional modifications to increase maximum tolerated dose, then therapeutic index improves, but device complexity increases

Engineering Contradiction:

Improvemaximum tolerated doseVSAvoidmolecular structure complexity

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The oligonucleotide is divided into distinct functional regions (5′-region with 2-4 modified nucleosides, central region with 7-10 unmodified or minimally modified nucleosides, and 3′-region with 1-5 modified nucleosides). This segmentation allows each region to perform its specific function: the modified regions provide nuclease resistance and stability, while the central unmodified region maintains target affinity and enables RNase H recruitment, thus resolving the contradiction between stability and structural simplicity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent systematically varies parameters including the number of modified nucleosides in 5′ and 3′ regions (1-5 each), the length of the central region (7-10 nucleosides), and the specific types of modifications (2′-MOE, 2′-OMe, phosphorothioate linkages). These parameter optimizations enable titration of the maximum tolerated dose while maintaining the fundamental gapmer architecture, thus improving therapeutic index without excessive complexity.

Inventive Principle:

Principle #35Parameter changes

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 oligomeric compounds demonstrate improved stability and efficacy in inhibiting target RNA function, with enhanced safety profiles and increased maximum tolerated doses compared to unmodified counterparts.

Implementation Method 1

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 2

Chemically modified nucleosides may be incorporated into antisense compounds to enhance one or more properties, such as nuclease resistance

Methodology Applied

Scientific EffectNuclease resistance:

Implementation Method 3

at least one altered nucleotide, comprising a modified internucleoside linkage other than phosphorothioate and/or a modified nucleobase other than 5-methylcytosine

Methodology Applied

Scientific EffectBase stacking:

Data Source

PatentUS20250354135A1Modified Compounds and Uses Thereof

Publication Date: 2025.11.20 IONIS PHARMACEUTICALS INC

AI summary

The present disclosure provides oligomeric compound comprising a modified oligonucleotide having a central region comprising one or more modifications. In certain embodiments, the present disclosure provides oligomeric compounds having an improved therapeutic index or an increased maximum tolerated dose.