UNC13A Antisense Oligonucleotides for Cryptic Exon 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 and develop therapeutic strategies to treat these conditions, as existing knowledge is limited and current treatments are inadequate.
Innovation Solution
The development of UNC13A antisense oligonucleotides (ASOs) that modulate splicing by preventing the inclusion of cryptic exons in UNC13A mRNA, thereby rescuing UNC13A protein function, using chemically modified ASOs, guide RNAs, and viral vectors to target splicing regulatory elements and prevent the recognition of cryptic exons.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TDP-43 is depleted in neurodegenerative disorders, then cryptic exons are included in mRNA due to loss of repressive action, but this leads to aberrant RNA degradation and reduced protein levels
Solution Approach 1:
The patent uses antisense oligonucleotides (ASOs) as intermediary molecules that bind to cryptic exons in pre-mRNA, preventing their inclusion in mature mRNA. This ASO-mediated intervention restores proper splicing patterns and protein production without directly replacing TDP-43 function, thereby resolving the contradiction between maintaining repressive control and ensuring adequate protein levels.
2Reliability
If splicing machinery recognizes cryptic exons in the disease state, then aberrant splicing occurs leading to disease progression, but preventing this recognition requires targeted therapeutic intervention
Solution Approach 1:
The patent extracts or removes the problematic cryptic exons from the splicing pathway by using ASOs to mask them, thereby preventing the splicing machinery from recognizing and incorporating these aberrant sequences. This extraction approach restores accurate splicing without requiring complex systemic interventions.
3Reliability
If UNC13A cryptic exon is included in mature mRNA, then UNC13A protein function is lost, but preventing inclusion requires specific ASO design and delivery
Solution Approach 1:
The patent employs ASOs that enable the splicing machinery to skip over the cryptic exon region and directly join flanking exons, thereby producing functional UNC13A mRNA without the detrimental cryptic sequence. This skipping mechanism restores protein function while using relatively straightforward ASO molecules for manufacture and delivery.
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 the inclusion of cryptic exons in UNC13A mRNA, restoring UNC13A protein function and potentially treating neurodegenerative disorders associated with TDP-43 depletion, such as ALS and FTD.
Implementation Method 1
an antisense oligonucleotide (ASO) comprising a nucleotide sequence of 13-30 nucleotides, wherein the nucleotide sequence has sequence complementarity with SEQ ID NO: 1
Data Source
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.