Mutant p53 siRNA Targeting for Allele-Specific Cancer Silencing
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Solution Overview
Problem
Current cancer treatments targeting mutant proteins are not specific enough, often affecting both mutant and wild-type forms, leading to undesirable side effects.
Innovation Solution
Development of mutant-p53-specific siRNAs that selectively target single point mutations in the p53 gene, silencing mutant p53 expression without affecting wild-type p53, thereby inducing cell death and retarding tumor growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If inhibitors or blocking antibodies are used to target mutant proteins, then cancer treatment effectiveness is improved, but side effects on wild-type protein expressing cells increase
Solution Approach 1:
The patent applies local quality by designing siRNAs with specific nucleotide sequences that are complementary to mutant p53 mRNA but not to wild-type p53 mRNA. The siRNA sequences are designed to match specific mutation sites (R175H, R248W, R249S, R273H) so that they selectively silence only the mutant allele, leaving the wild-type allele unaffected. This achieves mutant-specific targeting at the molecular level, resolving the contradiction between treatment effectiveness and side effects.
Solution Approach 2:
The patent changes the parameter of nucleotide sequence specificity by designing siRNAs with precise sequence modifications that correspond to the mutant p53 sequences. The siRNA sequences are engineered with specific nucleotide changes at positions corresponding to the mutant residues, enabling discrimination between mutant and wild-type p53 mRNA. This parameter change allows selective targeting without affecting wild-type protein expressing cells.
2Reliability
If drugs are generated against mutant protein forms, then mutant protein activity is reduced, but cross-reactivity with wild-type form increases
Solution Approach 1:
The patent applies local quality by designing siRNAs with specific nucleotide sequences that are complementary to mutant p53 mRNA but not to wild-type p53 mRNA. The siRNA sequences are designed to match specific mutation sites (R175H, R248W, R249S, R273H) so that they selectively silence only the mutant allele, leaving the wild-type allele unaffected. This achieves mutant-specific targeting at the molecular level, resolving the contradiction between treatment effectiveness and side effects.
Solution Approach 2:
The patent uses copying by creating complementary RNA sequences (siRNAs) that mirror the mutant p53 mRNA sequence. The siRNA sequences are designed as complementary copies of the mutant mRNA, enabling specific binding and silencing of the mutant transcript. This copying approach allows precise targeting of the mutant form without affecting the wild-type form, as the siRNAs are designed to be incompatible with wild-type sequences.
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 siRNAs effectively silence mutant p53, abrogating its dominant-negative effects and addiction to survival, enhancing chemotherapy sensitivity and retarding tumor growth without side effects.
Implementation Method 1
Development of mutant-p53-specific siRNAs that selectively target single point mutations in the p53 gene, silencing mutant p53 expression without affecting wild-type p53
Data Source
AI summary
Provided herein are nucleic acid sequences for targeting one or more single point mutations within a target gene, wherein the target gene is one or more tumour suppressor genes; wherein the tumour suppressor gene is p53; and methods of treating cancer in a subject comprising administering the same.