ATXN3 Splicing Modulators for Reducing Toxic Protein Aggregates
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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 repeats in the ATXN3 gene leading to toxic Ataxin-3 protein aggregates, which progressively affects brain and spinal cord function and causes severe dysarthria, dysphagia, and ultimately leads to death.
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 treat, prevent, or delay progression of SCA3 symptoms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If small molecule splicing modulators are used to reduce full-length ATXN3 expression, then toxic protein aggregates are reduced, but the complexity of the treatment approach increases
Solution Approach 1:
The patent uses small molecule splicing modulators as intermediary compounds that bind to pre-mRNA to modulate splicing events. These small molecules act as mediators between the cellular splicing machinery and the ATXN3 gene, enabling precise control of toxic isoform production without directly targeting the protein aggregates themselves.
Solution Approach 2:
The invention changes the splicing parameters of the ATXN3 pre-mRNA by introducing small molecules that alter splice site selection. This modifies the splicing outcome to favor non-toxic isoforms over toxic full-length variants, changing the molecular composition parameter of the expressed protein products.
2Duration of action of stationary object
If splicing modulation is used to reduce full-length ATXN3, then disease progression is delayed, but the manufacturing precision of the therapeutic compound is challenging
Solution Approach 1:
The patent employs small molecule compounds with specific molecular parameters (size, functional groups, binding affinity) that can be optimized through medicinal chemistry. These parameter adjustments enable precise control over splicing modulation while maintaining manufacturability through conventional pharmaceutical synthesis methods.
Data Source
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.