UNC13A Antisense Oligonucleotides for TDP-43 Splicing Rescue
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Solution Overview
Problem
There is a need to understand the mechanisms of TDP-43 depletion and its associated pathology in neurodegenerative disorders such as ALS and FTD, and to develop therapeutic strategies to treat these diseases.
Innovation Solution
The use of UNC13A antisense oligonucleotides (ASOs) that modulate splicing by preventing the inclusion of cryptic exons in UNC13A mRNA, thereby rescuing functional protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TDP-43 is depleted from the nucleus, then cryptic exons are included in mRNA through aberrant splicing, but this leads to reduced protein levels and disease pathology
Solution Approach 1:
Antisense oligonucleotides (ASOs) are introduced as intermediary molecules that bind to cryptic exons in pre-mRNA, blocking the splicing machinery from incorporating these aberrant sequences. The ASOs act as mediators between the depleted TDP-43 system and the splicing machinery, restoring faithful splicing and enabling production of functional UNC13A protein despite TDP-43 depletion
Solution Approach 2:
The ASOs perform preliminary blocking action by binding to cryptic exon sequences before the splicing machinery can recognize and incorporate them. This preemptive intervention prevents the formation of aberrant mRNA transcripts that would otherwise lead to nonsense-mediated decay and reduced functional protein levels
2Reliability
If antisense oligonucleotides are used to block cryptic exons, then splicing fidelity is restored, but the complexity of therapeutic intervention increases
Solution Approach 1:
The invention extracts and targets only the specific problematic element - the cryptic exon sequence - rather than attempting to restore TDP-43 itself. By designing ASOs that specifically bind to the aberrant splicing sites, the therapy isolates and corrects the splicing defect without requiring complex mechanisms to replenish the depleted RNA-binding protein
Solution Approach 2:
The ASOs serve as synthetic copies or mimics of the function normally performed by TDP-43 at cryptic exon sites. Rather than restoring the original protein, the therapy introduces oligonucleotide molecules that replicate the splicing-regulatory function, binding to RNA sequences with high specificity to prevent cryptic exon inclusion
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 UNC13A ASOs effectively prevent aberrant splicing and restore UNC13A protein levels, offering a therapeutic approach for neurodegenerative disorders associated with TDP-43 depletion.
Implementation Method 1
The UNC13A ASOs effectively prevent aberrant splicing and restore UNC13A protein levels
Data Source
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AI summary
Antisense oligonucleotides (ASOs) are provided which are capable of modulating splicing by preventing inclusion of an UNC13A cryptic exon into an UNC13A mature mRNA. Such ASOs may be used as a medicament, for example, to treat neurodegenerative disorders, particularly those associated with TDP-43 pathology.