Dual-Targeting Antisense Oligonucleotides for UNC13A Cryptic Splicing

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Solution Overview

Problem

There is currently no effective treatment for amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD), as single nucleotide polymorphisms in the UNC13A gene lead to cryptic splicing and reduced UNC13A protein expression due to aberrant RNA degradation or premature stop codons, contributing to these neurodegenerative diseases.

Innovation Solution

Dual targeting antisense oligonucleotides are used to modulate the splicing of UNC13A cryptic exons, inhibiting their inclusion in mature mRNA and restoring UNC13A expression, thereby addressing the underlying genetic cause of ALS and FTD.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If single-targeting antisense oligonucleotides are used to modulate splicing, then splicing modulation effect is achieved, but off-target risks increase

Engineering Contradiction:

Improvesplicing modulation efficacyVSAvoidoff-target risks

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The antisense oligonucleotide is divided into multiple distinct targeting sequences (first antisense sequence and second antisense sequence) that bind to different target regions on the UNC13A pre-mRNA. This segmentation allows the single oligonucleotide molecule to simultaneously engage multiple binding sites, thereby enhancing splicing modulation efficacy while reducing off-target effects through cooperative binding

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Multiple antisense sequences with different target specificities are merged into a single dual-targeting oligonucleotide molecule. The first antisense sequence targets one region of the UNC13A pre-mRNA while the second antisense sequence targets a different region, and both sequences are incorporated into the same oligonucleotide structure to achieve coordinated splicing modulation with reduced off-target risks

Inventive Principle:

Principle #5Merging (Combining)

2Adaptability or versatility

If cryptic exon inclusion occurs in UNC13A mature mRNA, then splicing variant is produced, but UNC13A protein expression is reduced

Engineering Contradiction:

Improvesplicing variant diversityVSAvoidUNC13A protein expression

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The dual-targeting antisense oligonucleotide is designed to bind to the UNC13A pre-mRNA before the cryptic exon can be incorrectly included during spontaneous splicing. By occupying the target regions with complementary binding, the oligonucleotide prevents the formation of aberrant splice sites and ensures proper exon skipping, thereby maintaining normal UNC13A protein expression levels

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The antisense oligonucleotide acts as an intermediary molecule that binds to both the UNC13A pre-mRNA and the splicing machinery components. Through this intermediary binding, it modulates the splicing process to prevent cryptic exon inclusion while allowing normal splicing of other exons, thus preserving UNC13A protein expression without completely blocking splicing activity

Inventive Principle:

Principle #24Intermediary (Mediator)

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 oligonucleotides effectively inhibit the inclusion of cryptic exons and restore UNC13A protein expression, providing a potential therapeutic approach for ALS and FTD by targeting specific sequences within the UNC13A pre-mRNA.

Implementation Method 1

antisense oligonucleotides comprising a first antisense sequence targeting a first target region and a second antisense sequence targeting a second target region... modulates splicing of an UNC13A cryptic exon

Methodology Applied

Scientific EffectComplementary base pairing:

Data Source

PatentUS12612630B2Compositions and methods for splicing modulation of UNC13A

Publication Date: 2026.04.28 TAKEDA PHARMA CO LTD

AI summary

Antisense oligonucleotides for splicing modulation of UNC13A (e.g., inhibiting inclusion of an UNC13A cryptic exon into an UNC13A mature mRNA), compositions including the antisense oligonucleotides, and methods of use are described. Also disclosed are pharmaceutical compositions including one or more antisense oligonucleotides and methods of treating an UNC13A-associated disease or a disease associated with TDP-43 dysfunction in a subject by administering the antisense oligonucleotides to the subject.