ATXN3 Pre-mRNA Splicing Modulator Composition for SCA3

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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 the formation of toxic Ataxin-3 protein aggregates that affect brain tissue and result in progressive neurological symptoms.

Innovation Solution

Development of a small molecule splicing modulator (SMSM) that binds to ATXN3 pre-mRNA, modulating its splicing to reduce full-length ATXN3 expression and potentially mitigate the effects of the toxic Ataxin-3 protein aggregates.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If no treatment is administered for SCA3, then the disease progresses relentlessly until death, but there are currently no available treatments to address the toxic Ataxin-3 protein aggregates

Engineering Contradiction:

Improvedisease progression controlVSAvoidtreatment availability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies preliminary action by using splicing modulators to prevent the formation of toxic full-length Ataxin-3 protein through alternative splicing of ATXN3 pre-mRNA. This upstream intervention occurs at the RNA splicing stage before protein translation, thereby preventing the generation of pathogenic protein aggregates that would otherwise lead to disease progression.

Inventive Principle:

Principle #10Preliminary action

2Object-affected harmful factors

If small molecule splicing modulators are used to reduce full-length ATXN3 expression, then toxic Ataxin-3 protein aggregates are mitigated, but the complexity of splicing modulation mechanisms increases

Engineering Contradiction:

Improvetoxic protein aggregatesVSAvoidsplicing modulation mechanism

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent employs small molecule splicing modulators as intermediaries that bind to specific RNA sequences or splicing factors to alter splicing outcomes. These small molecules act as mediators between the therapeutic goal (reducing toxic protein) and the molecular mechanism (splicing regulation), simplifying the overall approach compared to direct genetic manipulation while maintaining therapeutic efficacy.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-affected harmful factors

If alternative splicing is induced to reduce full-length ATXN3, then the amount of toxic protein is reduced, but the precision of splicing modulation must be maintained to avoid affecting other ATXN3 isoforms

Engineering Contradiction:

Improvefull-length ATXN3 proteinVSAvoidsplicing modulation specificity

Core Design Contradiction:

Object-affected harmful factorsVSManufacturing precision

Solution Approach 1:

The patent applies local quality by designing splicing modulators with high specificity for particular splice sites or RNA sequences within the ATXN3 pre-mRNA. This localized action ensures that only specific alternative splicing events are modulated, allowing reduction of toxic full-length protein while preserving other potentially functional ATXN3 isoforms through selective splice site targeting.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20250304593A1Compositions useful for modulating splicing

Publication Date: 2025.10.02 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.