Antisense Oligonucleotide MSH3 Knockdown for Repeat Expansion Disorders

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Solution Overview

Problem

Nucleotide repeat expansion disorders, such as trinucleotide repeat expansion disorders, are challenging to treat due to the dynamic nature of repeat expansions and their impact on gene function and protein toxicity.

Innovation Solution

The method involves intracerebroventricular administration of a single-stranded oligonucleotide that targets MSH3, a DNA mismatch repair protein, to specifically reduce MSH3 mRNA and protein levels in the brain, thereby mitigating the progression of nucleotide repeat expansion disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If MSH3 activity is reduced to treat nucleotide repeat expansion disorders, then disease progression is delayed, but MSH3 is a DNA mismatch repair protein whose function is not fully understood

Engineering Contradiction:

Improvedisease progression delayVSAvoiduncertainty of MSH3 function

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary action by administering antisense oligonucleotides to reduce MSH3 mRNA and protein levels before nucleotide repeat expansions fully manifest their toxic effects. The treatment is initiated in subjects with constitutive expansions or at-risk individuals, aiming to prevent or delay disease progression by suppressing MSH3 activity prior to severe pathology development.

Inventive Principle:

Principle #10Preliminary action

2Quantity of substance

If antisense oligonucleotides are administered to reduce MSH3 mRNA levels, then MSH3 protein levels decrease, but the mechanism of action and long-term efficacy require further investigation

Engineering Contradiction:

ImproveMSH3 protein levelVSAvoidmechanism understanding

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent incorporates feedback mechanisms through monitoring of MSH3 mRNA and protein levels in response to antisense oligonucleotide administration. The reduction in MSH3 mRNA translates to decreased protein levels, and this feedback loop is used to assess treatment efficacy and adjust dosing regimens. Non-human primate models provide preliminary feedback data on sustainability of mRNA knockdown over several weeks to months.

Inventive Principle:

Principle #23Feedback

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

This approach effectively delays the onset and progression of nucleotide repeat expansion disorders by reducing MSH3 activity, which is associated with the expansion and toxicity of nucleotide repeats, as demonstrated by sustained mRNA knockdown in non-human primates over several weeks to months.

Implementation Method 1

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentUS20250197856A1Methods for the treatment of nucleotide repeat expansion disorders associated with MSH3 activity

Publication Date: 2025.06.19 TAKEDA PHARMACEUTICALS USA INC

AI summary

The present disclosure features useful compositions and methods to treat nucleotide repeat expansion disorders, e.g., in a subject in need thereof. In some aspects, the compositions and methods described herein are useful in the treatment of disorders associated with MSH3 activity.