Antisense Oligonucleotides Induce Exon Skipping in SLC7A11 Pre-mRNA
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Solution Overview
Problem
Current methods for targeting and downregulating the human gene SLC7A11, a cystine/glutamate antiporter, are limited in effectively treating various diseases including cancer, as they lack specificity and efficiency in modulating gene expression at the pre-mRNA level.
Innovation Solution
The use of antisense oligonucleotides that induce exon skipping during the splicing of SLC7A11 pre-mRNA, specifically targeting exons 7 and 9 to form mRNA lacking these exons, thereby reducing the expression of the cystine/glutamate antiporter protein in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional methods are used to target SLC7A11, then gene expression can be downregulated, but the methods lack specificity and efficiency at the pre-mRNA level
Solution Approach 1:
The antisense oligonucleotide binds to the SLC7A11 pre-mRNA transcript before splicing occurs, preventing the formation of the mature mRNA that would encode the functional antiporter protein. This preliminary intervention at the pre-mRNA level ensures both high specificity for the target gene and efficient downregulation of protein expression, resolving the contradiction between precision and productivity.
2Reliability
If exon skipping is induced to reduce SLC7A11 expression, then protein levels decrease, but the mechanism requires precise targeting of pre-mRNA splicing elements
Solution Approach 1:
The antisense oligonucleotide acts as an intermediary molecule that bridges the gap between external treatment and the internal splicing machinery. By binding to specific sequences in the SLC7A11 pre-mRNA, it recruits or blocks splicing factors, thereby modulating exon inclusion/exclusion with high precision. This intermediary mechanism ensures reliable protein downregulation while maintaining precise control over the splicing process.
3Object-affected harmful factors
If SLC7A11 activity is reduced in cancer cells, then cell proliferation decreases and ROS accumulates, but the therapeutic effect must be sufficient to induce senescence
Solution Approach 1:
The invention exploits the harmful effect of reactive oxygen species (ROS) accumulation as a beneficial therapeutic outcome. By downregulating SLC7A11, which normally protects cells from oxidative stress, the treatment intentionally allows ROS to accumulate to toxic levels in cancer cells. This converts what would normally be a harmful byproduct into a therapeutic mechanism that induces cancer cell senescence and death, while the antisense oligonucleotide provides specific targeting to ensure this effect occurs primarily in cancer cells expressing SLC7A11.
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 effectively decreases the expression and activity of the cystine/glutamate antiporter in cancer cells, leading to reduced cancer cell proliferation and increased accumulation of reactive oxygen species, resulting in cell senescence, thereby providing a therapeutic option for treating cancers.
Implementation Method 1
contacting the SLC7A11 pre-mRNA transcript with an antisense oligonucleotide
Data Source
AI summary
Described are methods for enhancing exon skipping in a pre-mRNA of interest, comprising contacting the pre-mRNA with interfering oligonucleotides such as antisense, siRNA, and miRNA. The exon skipping methods are associated with methods of treating a variety of diseases and conditions, including cancer.