Antisense Oligonucleotides Modulating ATXN2 Expression

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Solution Overview

Problem

Current treatments for neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), Alzheimer's frontotemporal dementia (FTD), and parkinsonism are inadequate in effectively reducing the expression of ataxin 2 (ATXN2) protein, which is linked to these conditions.

Innovation Solution

Development of antisense oligonucleotides specifically targeting the ATXN2 transcript, particularly focusing on the sequence within intron 9, to inhibit ATXN2 expression, using beta-D-oxy LNA nucleosides and phosphorothioate internucleoside linkages, and their formulation as pharmaceutical compositions for administration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antisense oligonucleotides are used to target ATXN2, then some reduction in ATXN2 expression is achieved, but the reduction is insufficient to effectively treat neurodegenerative diseases

Engineering Contradiction:

Improveeffectiveness of ATXN2 expression reductionVSAvoidcurrent treatment efficacy

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of oligonucleotides through the use of LNA (locked nucleic acid) modifications and phosphorothioate linkages. These structural parameter changes enhance the binding affinity and stability of the oligonucleotides to ATXN2 mRNA, resulting in significantly improved efficacy in reducing ATXN2 expression compared to conventional oligonucleotides

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by creating chimeric oligonucleotide structures that combine different nucleic acid components (LNA-modified nucleotides, phosphorothioate linkages, and DNA/RNA segments). This composite approach optimizes both the binding affinity to the target and the resistance to nucleases, achieving superior therapeutic effect in reducing ATXN2 expression

Inventive Principle:

Principle #40Composite materials

2Reliability

If antisense oligonucleotides with modified nucleosides and phosphorothioate linkages are used, then ATXN2 expression reduction is significantly improved, but the molecular complexity of the oligonucleotide increases

Engineering Contradiction:

ImproveATXN2 expression inhibition efficacyVSAvoidoligonucleotide molecular structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent systematically modifies specific parameters of the oligonucleotide structure (incorporating LNA at specific positions, using phosphorothioate linkages at defined locations) rather than uniformly complexing the entire molecule. This targeted parameter change approach achieves high efficacy while controlling the degree of molecular complexity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by introducing modified nucleosides (LNA) and phosphorothioate linkages at specific positions within the oligonucleotide sequence rather than uniformly throughout. This localized modification strategy optimizes binding affinity and stability at critical regions while minimizing overall molecular complexity

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 antisense oligonucleotides effectively reduce ATXN2 expression in both in vitro and in vivo models, showing potential therapeutic benefits for the mentioned neurodegenerative diseases by inhibiting ATXN2 protein production.

Implementation Method 1

antisense oligonucleotides which target the Homo sapiens Ataxin 2 (ATXN2) transcript and are capable of inhibiting the expression of ATXN2

Methodology Applied

Scientific EffectHybridization:

Implementation Method 2

all internucleoside linkages are phosphorothioate internucleoside linkages

Methodology Applied

Scientific EffectPhosphorothioate linkage:

Data Source

PatentUS11286485B2Oligonucleotides for modulating ATXN2 expression

Publication Date: 2022.03.29 F HOFFMANN LA ROCHE INC

AI summary

The present invention relates to antisense oligonucleotides that are capable of modulating expression of ATXN2 in a target cell. The oligonucleotides hybridize to ATXN2 mRNA. The present invention further relates to conjugates of the oligonucleotide and pharmaceutical compositions and methods for treatment of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), Alzheimer's frontotemporal dementia (FTD), parkinsonism and conditions with TDP-43 proteinopathies using the oligonucleotide.