Modulating APP Splicing to Reduce Aβ42 Production
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Solution Overview
Problem
Current therapies for Alzheimer's disease are inadequate in effectively reducing amyloid β (Aβ) production, particularly Aβ42, which is prone to aggregation and neurotoxicity, as they fail to target the underlying mechanism of APP cleavage effectively.
Innovation Solution
Modified oligonucleotides targeted to the APP transcript are used to modulate splicing, specifically blocking exon 17 splicing, which prevents the formation of Aβ42 by inducing an alternatively spliced APP mRNA isoform that lacks the γ-secretase cleavage sites, thereby reducing Aβ and Aβ42 production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used to treat Alzheimer's disease, then they are administered to patients, but they fail to effectively reduce Aβ production particularly Aβ42
Solution Approach 1:
The patent extracts and removes exon 17 from the APP transcript through antisense-mediated splicing blockade. By targeting the splice site of exon 17 with modified oligonucleotides, the invention prevents inclusion of this critical exon in the mature mRNA, thereby extracting the harmful Aβ42-generating sequence from the functional transcript while preserving other APP isoforms that do not contain exon 17
Solution Approach 2:
The invention changes the splicing parameter of APP mRNA by inducing alternative splicing patterns. The modified oligonucleotides alter the splicing machinery's behavior to produce APP isoforms lacking exon 17, thereby changing the molecular composition parameter of the APP protein and eliminating the γ-secretase cleavage sites that generate Aβ42
2Object-generated harmful factors
If modified oligonucleotides block exon 17 splicing, then Aβ42 formation is prevented, but this requires specific targeting of the APP transcript
Solution Approach 1:
The patent uses modified oligonucleotides as intermediary molecules that mediate between the therapeutic goal (reducing Aβ42) and the molecular target (APP transcript splice site). These oligonucleotides serve as intermediaries that specifically bind to the exon 17 flanking regions and recruit splicing regulatory proteins, thereby indirectly controlling the splicing outcome without directly modifying the spliceosome machinery
Solution Approach 2:
The invention applies local quality by designing oligonucleotides with specific sequences that match only the exon 17 flanking regions of the APP transcript. The modified oligonucleotides contain localized sequence complementarity to the target splice sites, ensuring that the splicing blockade effect is confined to exon 17 inclusion events while leaving other APP exons and transcripts unaffected
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
This approach effectively decreases Aβ and Aβ42 levels, potentially delaying or preventing the formation of senile plaques associated with Alzheimer's disease by altering the splicing pattern of APP, providing a novel therapeutic strategy for reducing amyloid aggregation.
Implementation Method 1
The principle behind antisense technology is that an antisense compound, which hybridizes to a target nucleic acid, modulates gene expression activities
Data Source
AI summary
Certain embodiments disclosed herein are directed to compounds and methods for modulating APP expression. In certain embodiments, modulating the splicing of amyloid precursor protein (APP) reduces amyloid β (Aβ) production.