Antisense Nucleic Acid for TDP-43 Intron 6 Splicing Control
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Solution Overview
Problem
Current treatments for TDP-43 proteinopathies, such as ALS and FTLD, are ineffective and can cause adverse effects on both diseased and healthy cells due to the inability to selectively target cytoplasmic aggregate formation while maintaining nuclear TDP-43 protein function.
Innovation Solution
An antisense nucleic acid that enhances alternative splicing of intron 6 of TDP-43 mRNA, adjusting the expression ratio of mRNA isoforms to suppress cytoplasmic aggregation and restore nuclear TDP-43 protein function, using a sequence complementary to specific regions of TDP-43 mRNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If TDP-43 mRNA expression is reduced to suppress cytoplasmic aggregation, then cytoplasmic TDP-43 aggregation is reduced, but nuclear TDP-43 protein function is lost
Solution Approach 1:
The invention segments the TDP-43 mRNA into different isoforms through alternative splicing of intron 6. By reducing the full-length TDP-43 mRNA (which produces aggregation-prone protein) and increasing the TDP-43ΔIDR mRNA isoform (which produces protein lacking the intrinsically disordered region), the treatment selectively suppresses cytoplasmic aggregation while preserving nuclear function through the alternative isoform.
Solution Approach 2:
The invention applies local quality by creating a specific isoform distribution pattern: the TDP-43ΔIDR isoform is enriched to perform nuclear functions without the aggregation-prone IDR region. This localized modification of protein quality (lacking IDR) allows the protein to function in the nucleus while avoiding cytoplasmic aggregation.
2Reliability
If TDP-43 mRNA expression is enhanced to restore nuclear function, then nuclear TDP-43 protein function is improved, but cytoplasmic aggregation increases
Solution Approach 1:
Rather than simply enhancing total TDP-43 mRNA expression, the invention segments the expression into isoforms: it enhances the TDP-43ΔIDR mRNA isoform specifically while suppressing the full-length TDP-43 mRNA. This segmented approach allows nuclear function restoration without proportionally increasing the aggregation-prone full-length protein.
Solution Approach 2:
The invention modifies the quality of expressed TDP-43 protein by enriching for the ΔIDR isoform lacking the aggregation-prone intrinsically disordered region. This local quality enhancement allows the protein to perform nuclear functions with improved reliability while inherently resisting cytoplasmic aggregation.
3Quantity of substance
If antisense oligonucleotide targets TDP-43 mRNA to degrade it, then TDP-43 mRNA is reduced, but both diseased and healthy cells are affected
Solution Approach 1:
The antisense oligonucleotide is designed to target specific regions of TDP-43 mRNA that are unique to the full-length isoform or differ between isoforms. This allows selective degradation or splicing modulation of the aggregation-prone isoform while sparing the functional ΔIDR isoform, thereby affecting diseased cells preferentially while preserving healthy cell function.
Solution Approach 2:
The invention segments the antisense oligonucleotide's effect to act specifically on certain TDP-43 mRNA isoforms rather than all TDP-43 mRNA. By targeting sequences that distinguish the full-length isoform from the ΔIDR isoform, the treatment achieves isoform-specific modulation, reducing aggregation-prone protein while preserving functional protein in healthy cells.
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 antisense nucleic acid effectively enhances splicing of intron 6, reducing cytoplasmic aggregation and restoring nuclear TDP-43 protein function, providing a potential therapeutic approach for TDP-43 proteinopathies like ALS and FTLD.
Implementation Method 1
using a sequence complementary to specific regions of TDP-43 mRNA
Data Source
AI summary
An antisense nucleic acid targeting intron 6 of TDP-43 mRNA, and including a nucleotide sequence complementary to a sequence consisting of 10 or more consecutive bases in a target sequence, wherein the target sequence is the 96th to 330th or 400th to 530th positions of a nucleotide sequence represented by SEQ ID NO:1.