Antisense Oligomers for ASCE Inclusion in Protein Deficiency
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Solution Overview
Problem
Alternative splicing events in genes lead to non-productive mRNA transcripts, resulting in aberrant protein expression and disease conditions such as protein deficiency, which current therapeutic agents fail to effectively modulate or inhibit, thereby causing diseases like Polycystic Kidney Disease, Age-related macular degeneration, and other diseases.
Innovation Solution
Therapeutic agents or vectors that promote the inclusion of alternatively spliced coding exons (ASCE) during pre-mRNA processing, thereby increasing the level of processed mRNA containing the ASCE and enhancing target protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If alternative splicing events occur in genes, then mRNA processing is enhanced, but non-productive mRNA transcripts are produced leading to protein deficiency
Solution Approach 1:
The patent converts the harmful effect of alternative splicing (which produces non-productive mRNA and leads to protein deficiency) into a beneficial therapeutic approach by using antisense oligomers to selectively promote inclusion of alternatively-spliced coding exons. This transforms the aberrant splicing event from a harmful process into a controllable therapeutic mechanism that increases functional protein expression.
Solution Approach 2:
The patent changes the splicing parameters by using antisense oligomers to modulate the splicing process, specifically promoting the inclusion of alternatively-spliced coding exons. This parameter change shifts the splicing outcome from producing non-productive transcripts to producing functional mRNA that encodes therapeutic proteins.
2Adaptability or versatility
If current therapeutic agents are used to modulate alternative splicing, then some protein expression can be influenced, but they fail to effectively modulate or inhibit the splicing events
Solution Approach 1:
The patent employs antisense oligomers that undergo parameter changes through chemical modifications (such as phosphorothioate backbones, 2'-O-methyl groups, or locked nucleic acids) to enhance their binding affinity and stability. This allows the therapeutic agents to effectively modulate splicing events by changing their molecular parameters to achieve reliable interaction with pre-mRNA.
Solution Approach 2:
The antisense oligomers serve as intermediary molecules that mediate between the splicing machinery and the pre-mRNA. These oligomers bind to specific sequences in the pre-mRNA and recruit splicing factors to promote inclusion of alternatively-spliced coding exons, thereby effectively modulating the splicing process.
3Speed
If alternatively-spliced coding exons are excluded during pre-mRNA processing, then processing speed is increased, but target protein expression is reduced
Solution Approach 1:
The patent converts the trade-off between processing speed and protein quantity by using antisense oligomers to selectively promote inclusion of alternatively-spliced coding exons. This allows the cell to maintain efficient processing while ensuring that the included exons encode functional proteins, thereby increasing target protein expression without sacrificing processing efficiency.
Data Source
AI summary
Alternative splicing events in genes can lead to non-productive mRNA transcripts which in turn can lead to aberrant or reduced protein expression, and therapeutic agents which can target the alternative splicing events in the genes can modulate the expression level of functional proteins in patients and/or inhibit aberrant protein expression. Such therapeutic agents can be used to treat a condition or disease caused by protein deficiency.