ATXN3 Pre-mRNA Splicing Modulators for SCA3 Aggregate Prevention

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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 results 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 its splicing to reduce full-length ATXN3 expression and potentially ameliorate symptoms by administering a therapeutically effective amount of the compound.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If expanded CAG repeats in the ATXN3 gene are translated into expanded polyglutamine repeats, then toxic Ataxin-3 protein aggregates are formed, but no effective treatment exists to prevent or treat the disease progression

Engineering Contradiction:

Improvedisease treatment effectivenessVSAvoidtoxic Ataxin-3 protein aggregates

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

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 translation of toxic polyglutamine repeats and aggregate formation upstream in the disease pathway

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent applies the extraction principle by selectively removing exon 10 from the ATXN3 pre-mRNA through modulated splicing. This excision of the harmful exon containing the expanded CAG repeats prevents its inclusion in the mature mRNA, thereby extracting the source of toxic protein production from the system

Inventive Principle:

Principle #2Taking out (Extraction)

2Productivity

If conventional splicing processes are used, then full-length ATXN3 protein is produced, but this leads to disease progression and severe symptoms

Engineering Contradiction:

ImproveATXN3 protein productionVSAvoidneurodegeneration and disease symptoms

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the splicing parameters of ATXN3 pre-mRNA through small molecule modulators. These compounds alter the splicing machinery's behavior to change exon inclusion/exclusion decisions, specifically promoting exon 10 exclusion to produce truncated, non-toxic protein variants instead of full-length toxic protein

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces splicing modulator compounds as intermediaries between the natural splicing process and the desired outcome. These small molecules bind to splicing factors or the pre-mRNA to mediate changes in splicing patterns, serving as chemical mediators that redirect the splicing pathway away from toxic full-length protein production

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20260001889A1Compositions useful for modulating splicing

Publication Date: 2026.01.01 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.