Antisense Oligonucleotides Modulating LRP8 Splicing
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Solution Overview
Problem
Current therapies fail to effectively modulate the alternative splicing of the LRP8 transcript, particularly in regulating exon 19 inclusion, which is crucial for maintaining normal signaling pathways involved in memory and learning, and disruptions can lead to conditions like Alzheimer's Disease.
Innovation Solution
Development of modified oligonucleotides that are complementary to specific regions of the LRP8 transcript, including exon 19 and its flanking intronic sequences, to increase the ratio of mRNA with exon 19 inclusion, thereby modulating splicing and potentially treating neurodegenerative diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional antisense compounds are used to modulate LRP8 transcript splicing, then some level of splicing modulation is achieved, but the compounds fail to effectively increase exon 19 inclusion ratio
Solution Approach 1:
The patent modifies the chemical parameters of antisense compounds by incorporating specific chemical modifications (such as 2'-O-methyl, 2'-methoxyethyl, phosphorothioate linkages) and optimizing oligonucleotide length and composition to enhance binding affinity and selectivity for the LRP8 transcript, thereby achieving effective exon 19 inclusion
Solution Approach 2:
The invention designs antisense compounds that are complementary copies of specific regions of the LRP8 transcript (including exon 19 and flanking intronic sequences), allowing these synthetic oligonucleotides to bind to and modulate the endogenous transcript splicing pattern to increase exon 19 inclusion
2Adaptability or versatility
If current therapies are applied, then general treatment is provided, but they fail to specifically regulate alternative splicing of LRP8 transcript
Solution Approach 1:
The patent targets specific segments of the LRP8 transcript, particularly exon 19 and its flanking intronic sequences, with designed antisense oligonucleotides that selectively bind to these regions to modulate splicing without affecting other parts of the transcript or unrelated genes
Solution Approach 2:
The antisense compounds act as intermediary molecules that bridge the therapeutic need for splicing modulation and the molecular mechanism of RNA-protein interaction, facilitating specific regulation of LRP8 alternative splicing through controlled binding to the transcript
3Manufacturing precision
If modified oligonucleotides are designed to target specific regions, then splicing modulation is achieved, but complexity of compound design increases
Solution Approach 1:
The patent applies different chemical modifications at specific positions within the oligonucleotide sequence (such as modified sugar moieties at certain nucleosides, modified phosphodiester linkages at specific internucleoside bonds) to optimize local binding properties and overall molecular characteristics for enhanced splicing modulation
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 modified oligonucleotides specifically enhance the inclusion of exon 19 in LRP8 mRNA, thereby restoring or improving signaling pathways critical for memory and learning, offering a therapeutic approach for conditions such as Alzheimer's Disease.
Implementation Method 1
oligonucleotides are complementary to a target region of the LRP8 transcript comprising exon 19 or the intronic sequence upstream or downstream of exon 19
Data Source
AI summary
The present invention provides compounds comprising oligonucleotides complementary to an LRP8 transcript. Certain such compounds are useful for hybridizing to an LRP8 transcript, including but not limited, to an LRP8 transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the LRP8 transcript. In certain embodiments, such hybridization results in an increase in inclusion of exon 19 in the LRP8 mRNA transcript. In certain embodiments, such compounds are used to treat Alzheimer's Disease.