Antisense Oligomers for SETD5 NMD Exon Skipping
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Solution Overview
Problem
Alternative splicing events in genes can lead to non-productive mRNA transcripts, affecting protein expression levels, and existing therapeutic agents are inadequate in modulating these events to treat conditions caused by protein deficiency.
Innovation Solution
The use of agents or vectors that modulate the splicing of non-sense mediated RNA decay-inducing exons (NMD exons) from pre-mRNA, specifically targeting the SETD5 gene, to increase the expression of functional proteins by promoting the exclusion of these exons from processed mRNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If alternative splicing events occur in genes, then mRNA transcripts are produced, but non-productive mRNA transcripts are generated that cannot be translated into functional proteins
Solution Approach 1:
The patent uses antisense oligomers as intermediary molecules that bind to specific sequences in pre-mRNA to modulate splicing events. These oligomers act as mediators between the splicing machinery and the target pre-mRNA, promoting the exclusion of NMD-inducing exons and thereby converting non-productive splicing events into productive ones that yield translatable mRNA
Solution Approach 2:
Instead of attempting to correct the splicing error after it occurs, the invention inverts the approach by preventing the inclusion of NMD-inducing exons in the first place through antisense-mediated exon skipping. This reverses the natural splicing outcome to produce the desired productive mRNA isoform
2Reliability
If existing therapeutic agents are used to modulate splicing events, then some splicing modulation occurs, but the agents are inadequate in achieving sufficient protein expression levels
Solution Approach 1:
The patent employs chemically modified oligomers with enhanced stability, affinity, and bioavailability parameters compared to unmodified nucleic acids. These parameter changes in the therapeutic agent structure enable more effective and sustained splicing modulation, leading to sufficient increases in functional protein expression levels that previous agents could not achieve
3Adaptability or versatility
If NMD exons are included in pre-mRNA, then alternative splicing diversity is achieved, but the processed mRNA becomes non-productive and is degraded by nonsense-mediated RNA decay
Solution Approach 1:
The invention selectively extracts or removes specific NMD-inducing exons from the pre-mRNA transcript through antisense oligomer-mediated exon skipping. This extraction of problematic exons allows the remaining mRNA to be productive and translatable, while preserving the ability of the system to maintain splicing diversity through selective rather than blanket exon exclusion
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 enhances the level of processed mRNA and increases the expression of target proteins, such as SETD5, addressing conditions associated with protein deficiency or loss-of-function mutations, including intellectual disabilities and autism spectrum disorders.
Implementation Method 1
contacting an agent or a vector encoding the agent to the cell, whereby the agent modulates splicing of the NMD exon from the pre-mRNA
Data Source
AI summary
Alternative splicing events in genes can lead to non-productive mRNA transcripts which in turn can affect protein expression level, and therapeutic agents which can target the alternative splicing events in 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.