ATXN3 Splicing Compounds for Exon 4 Skipping in SCA3
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Solution Overview
Problem
There are no disease-modifying therapies available for spinocerebellar ataxia type 3 (SCA3), and there is a need for improved methods and compositions to treat the symptoms associated with this rare autosomal dominantly inherited disease.
Innovation Solution
The use of substituted heteroaryl compounds that induce exon 4 skipping in the ATXN3 pre-mRNA during the splicing process, leading to premature termination codons and subsequent mRNA degradation, thereby reducing ATXN3 protein levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If exon skipping compounds are used to reduce ATXN3 protein levels, then disease pathology is ameliorated, but no disease-modifying therapies are currently available for SCA3
Solution Approach 1:
The invention segments the ATXN3 pre-mRNA by inducing exon 4 skipping, creating a spliced mRNA variant that lacks exon 4. This segmentation approach allows the therapeutic compound to specifically target and remove the pathogenic segment containing the expanded CAG repeats, thereby reducing mutant protein production while preserving normal ATXN3 function from other exons.
Solution Approach 2:
Instead of directly targeting and degrading the mutant ATXN3 protein or mRNA, the invention inverts the approach by targeting the splicing process itself. The compound induces premature exon skipping during pre-mRNA processing, which indirectly leads to reduced mutant protein levels. This inverted strategy of targeting splicing rather than the final protein or mature mRNA represents a novel therapeutic mechanism for SCA3.
2Quantity of substance
If exon 4 skipping is induced in ATXN3 pre-mRNA, then ATXN3 protein levels are reduced, but the mechanism requires creation of premature termination codons
Solution Approach 1:
The compound performs preliminary action by inducing exon skipping during the pre-mRNA splicing process, before the mRNA is translated into protein. By acting at this early stage in gene expression, the compound prevents the production of mutant ATXN3 protein rather than attempting to degrade it afterward. The premature termination codons created by exon skipping serve as a signal for mRNA degradation, further reducing protein levels through a preliminary protective mechanism.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach effectively decreases ATXN3 mRNA levels, potentially ameliorating SCA3 pathology by reducing the production of mutant ataxin-3 protein, which is associated with neurodegeneration.
Implementation Method 1
Exon 4 skipping of ATXN3 mRNA changes the open reading frame (ORF) and creates premature termination codons (PTCs) in the ATXN3 exon 4-skipped mRNA (ΔE4 mRNA). It has been shown that such exon skipping splicing events could serve to reduce gene expression by creating mRNAs with premature termination codons, thus signaling the mRNAs to be degraded rather than translated into proteins.
Data Source
AI summary
An aspect of the present description relates to compounds useful for improving pre-mRNA splicing in a cell. In particular, another aspect of the present description relates to substituted heteroaryl compounds, forms, and pharmaceutical compositions thereof and methods of use for treating or ameliorating spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD).