Splice-Switching Oligonucleotide for TAU Pre-mRNA Splicing Control
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Solution Overview
Problem
There is no marketed agent that effectively addresses the need to address the abnormal expression of TAU protein by regulating splicing to treat or prevent TAU-related diseases.
Innovation Solution
A splice-switching oligonucleotide that binds to intron 1B of TAU pre-mRNA, modulating splicing to increase TAU mRNA including exon 1B and reduce TAU protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gapmer antisense oligonucleotides are used to reduce TAU expression by inducing RNA cleavage, then TAU protein expression is reduced, but the mechanism relies on DNA/RNA double-strand formation and RNase H activation which may have limitations in efficacy and specificity
Solution Approach 1:
The invention extracts and targets a specific functional element (exon 10) of the TAU gene that is critical for producing pathogenic TAU isoforms. By designing oligonucleotides that specifically bind to exon 10 sequences, the patent selectively induces exon skipping without requiring complex DNA/RNA double-strand formation mechanisms, thereby simplifying the mechanism while maintaining reliable TAU expression reduction.
Solution Approach 2:
The patent applies local quality by targeting a specific local region (exon 10) of the TAU pre-mRNA rather than acting on the entire TAU transcript. The oligonucleotides are designed with sequences complementary to specific regions within exon 10, enabling localized splicing modulation that selectively affects pathogenic isoform production while preserving normal TAU function.
2Adaptability or versatility
If splicing modulators are used to restore functional protein, then functional protein is restored, but no marketed agent currently reduces TAU expression by regulating splicing
Solution Approach 1:
Instead of using splicing modulators to restore functional protein (the conventional approach), the invention inverts the strategy by using splicing regulation to exclude a critical exon (exon 10) and thereby reduce the production of pathogenic TAU isoforms. This inverse approach leverages the same splicing modulation technology but applies it to achieve TAU expression reduction rather than restoration.
Solution Approach 2:
The invention takes preliminary action by interfering with splicing at the pre-mRNA level before translation occurs. The oligonucleotides bind to exon 10 sequences in the TAU pre-mRNA and prevent its inclusion in the mature mRNA, thereby preventing the synthesis of pathogenic TAU proteins from the outset rather than attempting to address them after protein synthesis.
3Reliability
If oligonucleotides bind to intron 1B of TAU pre-mRNA to modulate splicing, then TAU mRNA including exon 1B increases and TAU protein expression reduces, but the binding specificity and splicing modulation efficiency must be optimized
Solution Approach 1:
The invention applies local quality by designing oligonucleotides with sequences that are highly specific to particular regions within exon 10 of the TAU pre-mRNA. Rather than requiring perfect complementarity across the entire target sequence, the oligonucleotides are engineered to bind to specific local sequences (such as 5'-TGCAGG-3' or 5'-TGCAGC-3' motifs), which provides sufficient binding specificity while allowing for some sequence variation and improving manufacturing feasibility.
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
The oligonucleotide effectively treats or prevents TAU-related diseases by enhancing mRNA splicing to reduce TAU protein expression.
Implementation Method 1
A splice-switching oligonucleotide that binds to intron 1B of TAU pre-mRNA
Data Source
Figure 1A
Figure 1B
Figure 2A
AI summary
The present disclosure includes a splice-switching oligonucleotide that binds to intron 1B of TAU pre-mRNA, and a pharmaceutical composition comprising the splice-switching oligonucleotide for treating or preventing a TAU-related disease.