Splicing Modulators Correct IKBKAP Abnormal Splicing
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Solution Overview
Problem
Familial dysautonomia, a congenital fatal disease caused by abnormal splicing due to a mutation in the IKBKAP gene, and other genetic diseases where abnormal splicing contributes to disease progression, lack effective treatments to inhibit or reverse the abnormal splicing process.
Innovation Solution
A pharmaceutical composition containing a compound expressed by specific formulas (I) and (II) or their pharmaceutically acceptable salts, which are used to alter abnormal splicing in mammalian cells, increasing the ratio of wild-type splicing to abnormal splicing, particularly for the mutant IKBKAP gene with the IVS20 +6T→C mutation, thereby inhibiting disease progression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for familial dysautonomia, then disease progression cannot be inhibited, but abnormal splicing continues to produce harmful effects
Solution Approach 1:
The patent applies this principle by using splicing modulators to convert the harmful abnormal splicing process into a beneficial outcome. The compounds induce a switch in splicing patterns that favors wild-type splicing, thereby converting the pathogenic splicing event into a therapeutic effect that produces normal IKBKAP protein and eliminates abnormal splicing products
Solution Approach 2:
The patent applies this principle by changing the splicing parameters through administration of splicing modulators. These compounds alter the splicing regulatory parameters (such as splicing factor binding affinity or splice site recognition efficiency) to shift the splicing equilibrium from abnormal to wild-type patterns, thereby improving the ratio of functional to non-functional mRNA
2Quantity of substance
If abnormal splicing is not inhibited, then IKBKAP protein production is interfered with, but no effective treatment exists to alter the splicing pattern
Solution Approach 1:
The patent applies this principle by introducing splicing modulators as intermediary compounds that mediate between the mutant IKBKAP pre-mRNA and the splicing machinery. These small molecule intermediaries bind to specific splicing regulatory elements and modulate the splicing process to favor inclusion of exon 20, thereby increasing normal protein production without directly altering the genetic sequence
Solution Approach 2:
The patent applies this principle by changing the biochemical parameters of splicing through drug administration. The splicing modulators alter key splicing parameters such as the affinity of splicing factors for regulatory sequences or the kinetic rates of splice site selection, thereby shifting the splicing outcome toward the wild-type pattern and increasing functional protein yield
3Manufacturing precision
If exon 20 is excluded from mRNA, then abnormal splicing occurs, but the abnormal splicing process cannot be reversed without specific compounds
Solution Approach 1:
The patent applies this principle by converting the harmful exon skipping event into a beneficial inclusion event through splicing modulators. The compounds induce a reverse switch in splicing regulation that promotes exon 20 inclusion, thereby converting the pathogenic splicing pattern into a functional one and eliminating the harmful effect of exon skipping
Solution Approach 2:
The patent applies this principle by using splicing modulators as intermediary agents that bridge the gap between the mutant pre-mRNA and correct splicing outcome. These small molecules act as mediators that bind to splicing regulatory elements and facilitate the inclusion of exon 20 by the splicing machinery, thereby restoring accurate splicing without direct genetic modification
Data Source
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AI summary
A compound and a pharmaceutical composition for disease associated with an abnormal splice variant, use of the compound and the pharmaceutical composition, or a screening method of the compound and the pharmaceutical composition are provided. One or more embodiments disclose a compound expressed by the following formula (I) or (I') or prodrugs or pharmaceutically acceptable salts thereof. Another one or more embodiments disclose a screening method using a DNA construct that is fused, arranged, or constructed so as to express different reporter genes for a wild-type splice variant and an abnormal splice variant that contributes to the development or progression of disease;