ATXN3 Splicing Modulator Compounds for Spinocerebellar Ataxia 3

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There are currently no treatments for Spinocerebellar Ataxia 3 (SCA3), a rare, inherited neurodegenerative disease caused by expanded CAG tri-nucleotide repeats in the ATXN3 gene leading to toxic Ataxin-3 protein aggregates, which result in progressive brain and spinal cord degeneration and severe symptoms.

Innovation Solution

Development of a small molecule splicing modulator (SMSM) that binds to ATXN3 pre-mRNA, modulating splicing to reduce full-length ATXN3 expression and potentially ameliorate disease symptoms by administering a therapeutically effective amount of the compound.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If no treatment is available for SCA3, then the disease progresses relentlessly until death, but developing a treatment requires identifying a mechanism to reduce toxic ataxin-3 protein production

Engineering Contradiction:

Improvedisease treatment efficacyVSAvoidtreatment mechanism complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent extracts and removes the harmful full-length ataxin-3 protein from the system by modulating splicing to produce only truncated isoforms that lack the toxic polyglutamine repeats, thereby treating the disease without requiring complex external intervention mechanisms

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes the splicing parameters of the ATXN3 pre-mRNA to alter the protein production outcome, shifting from producing full-length toxic protein to producing truncated non-toxic isoforms through small molecule modulation of splicing machinery

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If expanded CAG repeats are translated into polyglutamine repeats causing toxic aggregates, then neurodegeneration occurs, but reducing full-length ATXN3 expression requires modulating splicing of pre-mRNA

Engineering Contradiction:

Improvetoxic ataxin-3 aggregatesVSAvoidsplicing modulation measurement

Core Design Contradiction:

Object-affected harmful factorsVSDifficulty of detecting and measuring

Solution Approach 1:

The patent replaces direct intervention with the complex splicing machinery with small molecule compounds that indirectly modulate splicing, simplifying the approach to reducing toxic protein production while avoiding direct manipulation of the complex spliceosome system

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Quantity of substance

If small molecule splicing modulator binds to ATXN3 pre-mRNA, then full-length ATXN3 is reduced, but the compound must specifically target the pre-mRNA without affecting other cellular processes

Engineering Contradiction:

Improvefull-length ATXN3 levelsVSAvoidcompound specificity

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The small molecule compound acts as an intermediary that binds to the ATXN3 pre-mRNA and modulates splicing through intermediate mechanisms, allowing reduction of full-length protein while maintaining specificity through the intermediary binding action rather than direct interference with multiple cellular processes

Inventive Principle:

Principle #24Intermediary (Mediator)

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 SMSM modulates splicing of ATXN3 pre-mRNA, reducing full-length ATXN3 levels, offering a potential therapeutic approach to treat, prevent, or delay the progression of SCA3 symptoms.

Implementation Method 1

the SMSM binds to the ATXN3 pre-mRNA and modulates splicing of the ATXN3 pre-mRNA in a cell of a subject to produce a spliced product of the ATXN3 pre-mRNA

Methodology Applied

Scientific EffectSplicing modulation:

Data Source

PatentUS20250340564A1Compositions useful for modulating splicing

Publication Date: 2025.11.06 SKYHAWK THERAPEUTICS INC

AI summary

Described herein are compounds that modulate splicing of a pre-mRNA, encoded by genes, and methods of treating diseases and conditions associated with gene expression or activity of proteins encoded by genes.