APP Antisense Oligonucleotides for Exon Skipping in Alzheimer's
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Solution Overview
Problem
Current therapies for neurodegenerative disorders, such as Alzheimer's disease, are inadequate in addressing the shift in APP mRNA isoform expression that contributes to the progression of the disease, leading to increased levels of toxic Aβ peptides.
Innovation Solution
Development of phosphorodiamidate morpholino oligomers (PMOs) that target specific regions of APP mRNA to promote exon skipping, specifically exons 7 and 8, thereby increasing the expression of the APP695 isoform and reducing APP751 and APP770 isoforms, using antisense oligonucleotides (AONs) to alter gene expression and protein production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for neurodegenerative disorders, then treatment is provided, but they are inadequate in addressing the shift in APP mRNA isoforms which contributes to disease progression
Solution Approach 1:
The invention changes the splicing parameters of APP mRNA by using antisense oligonucleotides to block specific splice sites, thereby shifting the isoform expression profile from pathological (APP751/APP770 dominant) to therapeutic (APP695 dominant). This directly addresses the inadequacy of current therapies by specifically targeting the isoform shift mechanism.
Solution Approach 2:
The antisense oligonucleotides act as intermediary molecules that bind to APP mRNA and modulate splicing. These oligonucleotides serve as the missing link between current therapies and the pathological mechanism, enabling targeted intervention at the mRNA splicing level which previous therapies could not achieve.
2Reliability
If exon skipping is promoted to increase APP695 expression, then therapeutic benefit is achieved, but the complexity of the treatment approach increases
Solution Approach 1:
The invention extracts and targets specific splice sites (exons 7 and 8) that are responsible for generating pathological isoforms. By focusing on these specific sequences with antisense oligonucleotides, the complex splicing regulation is simplified into a targeted blockage mechanism that promotes APP695 expression without requiring complex multi-component systems.
3Object-affected harmful factors
If the splicing pattern is altered to reduce amyloid beta production, then disease progression is countered, but the mechanism involves complex molecular interactions
Solution Approach 1:
Instead of directly targeting amyloid beta production or neuronal damage, the invention inverts the approach by targeting the upstream splicing mechanism. By altering splicing to favor APP695, the pathway leading to amyloid beta generation is indirectly blocked, simplifying the therapeutic strategy from direct toxicology to upstream regulatory control.
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 AONs effectively achieve 100% skipping of targeted exons, increasing APP695 levels at both mRNA and protein levels, providing a feasible therapeutic approach to treat neurodegenerative disorders by modulating APP mRNA splicing.
Implementation Method 1
phosphorodiamidate morpholino antisense oligomers (PMOs) that target exons 7 and 8 of the APP mRNA to promote exon skipping
Data Source
AI summary
The invention relates to neurodegenerative disorders, and in particular to novel oligonucleotides for treating such conditions, for example Alzheimer's disease. The invention provides novel antisense oligonucleotides, and compositions comprising such oligos, and therapies and methods for treating neurodegenerative disorders. The invention includes genome editing techniques for achieving similar results as using the novel antisense oligonucleotides.