ATXN3 Splicing Modulators to Reduce Toxic Ataxin-3 Expression

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 results in progressive brain and spinal cord degeneration and severe symptoms.

Innovation Solution

Development of small molecule splicing modulators (SMSMs) that bind to ATXN3 pre-mRNA, modulating splicing to reduce full-length ATXN3 expression and potentially ameliorate disease symptoms by targeting the Ataxin-3 protein aggregates.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecule splicing modulators are developed to target ATXN3 pre-mRNA, then full-length ATXN3 expression is reduced, but the complexity of drug development and clinical translation increases

Engineering Contradiction:

Improvedisease treatment efficacyVSAvoiddrug development complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent uses small molecule splicing modulators as intermediaries that bind to ATXN3 pre-mRNA to modulate splicing, thereby reducing full-length ATXN3 expression. This intermediary approach allows indirect targeting of the disease mechanism without directly interacting with the toxic protein aggregates, thus improving treatment efficacy while managing development complexity through a defined molecular mechanism

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the splicing parameters of ATXN3 pre-mRNA by introducing small molecules that alter splice site selection. This parameter change approach enables reduction of full-length ATXN3 expression through modulation of RNA processing rather than direct protein inhibition, providing a novel therapeutic strategy with potentially lower off-target effects

Inventive Principle:

Principle #35Parameter changes

2Object-generated harmful factors

If splicing modulation is used to reduce ATXN3 expression, then toxic protein aggregates may be reduced, but off-target effects on other pre-mRNA splicing could occur

Engineering Contradiction:

Improvetoxic protein aggregatesVSAvoidoff-target splicing effects

Core Design Contradiction:

Object-generated harmful factorsVSObject-affected harmful factors

Solution Approach 1:

The small molecule splicing modulators are designed to act locally on specific splice sites of ATXN3 pre-mRNA through sequence-specific or structural recognition. This local action at defined splice junctions allows selective modulation of ATXN3 splicing while minimizing widespread effects on other pre-mRNA molecules, thereby reducing off-target splicing effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent converts the natural splicing process, which normally produces the toxic full-length ATXN3 protein, into a beneficial outcome by modulating splice site selection to generate alternative spliced products. This approach uses the cell's own splicing machinery to produce therapeutic effects, reducing toxic aggregates while potentially avoiding the need for external protein degradation systems

Inventive Principle:

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

Data Source

PatentUS20250340572A1Compositions useful for modulating splicing

Publication Date: 2025.11.06 SKYHAWK THERAPEUTICS INC

AI summary

Described herein are compounds of Formula (I) 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, such a disease being, e.g. Spinocerebellar Ataxia 3.