ATXN3 Splicing Modulators for Toxic Aggregate Reduction

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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 toxic Ataxin-3 protein aggregates, which progressively degenerate brain and spinal cord tissues.

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 toxic Ataxin-3 protein aggregates.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If expanded CAG repeats are present in the ATXN3 gene, then polyglutamine repeats are produced in the ataxin-3 protein, but toxic aggregates form leading to neurodegeneration

Engineering Contradiction:

Improvetoxic Ataxin-3 protein aggregatesVSAvoidneurodegeneration progression

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies preliminary action by using splicing modulators to prevent the formation of toxic full-length Ataxin-3 protein before it can form aggregates. The modulators act on the pre-mRNA splicing process to exclude exon 10 containing the expanded CAG repeats, thereby preventing the production of harmful polyglutamine repeats and aggregate formation in the first place

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent applies the extraction principle by removing the harmful exon 10 containing the expanded CAG repeats from the mature mRNA through modulated splicing. This excises the toxic genetic information from the final protein product, allowing the rest of the Ataxin-3 protein to be produced without the pathogenic polyglutamine expansion that leads to aggregate formation

Inventive Principle:

Principle #2Taking out (Extraction)

2Object-affected harmful factors

If splicing modulators are used to reduce full-length ATXN3 expression, then toxic aggregate formation is reduced, but complete elimination of ATXN3 function may occur

Engineering Contradiction:

Improvetoxic aggregate formationVSAvoidAtaxin-3 protein function

Core Design Contradiction:

Object-affected harmful factorsVSStability of the object's composition

Solution Approach 1:

The patent applies local quality by selectively targeting only the harmful portion of the gene (exon 10 with expanded CAG repeats) for exclusion through splicing modulation, while preserving the rest of the Ataxin-3 gene that encodes the functional deubiquitinase domain. This localized approach eliminates toxic aggregates while maintaining essential protein functions

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent converts the harmful expanded CAG repeats in exon 10 into a beneficial therapeutic target. By designing splicing modulators that specifically recognize and exclude this pathogenic exon, the treatment transforms the source of toxicity into the key for selective intervention, reducing aggregate formation while preserving normal protein function

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS20260027118A1Compositions useful for modulating splicing

Publication Date: 2026.01.29 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.