Seed-Directed Oligonucleotide RNAi Against AR Coregulators in CRPC
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Solution Overview
Problem
Current therapies for prostate cancer, particularly castration-resistant prostate cancer (CRPC), are ineffective due to the development of resistance in PCa cells that retain AR expression and activity, necessitating the need for novel therapeutic agents that target AR coregulators to overcome resistance.
Innovation Solution
A novel therapeutic strategy, Androgen Network-DISE (AN-DISE), utilizes RNA interference (RNAi) to target androgen receptor (AR) coregulators through off-target seed region complementarity to the 3′ UTR, specifically inhibiting essential survival genes and disrupting androgen signaling, leading to cell death in PCa cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies target androgen receptor (AR) in prostate cancer, then initial therapeutic benefit is achieved, but resistance develops leading to castration-resistant prostate cancer (CRPC)
Solution Approach 1:
The patent segments the therapeutic approach by using multiple independent RNAi target sequences against different AR coregulators (such as BCL2, BCLXL, MCL1, SURVIVIN) rather than targeting a single gene. This segmentation allows the therapy to remain effective even when cancer cells develop resistance to one target, as multiple pathways are simultaneously disrupted
Solution Approach 2:
The patent employs oligonucleotides with seed sequences that can target multiple AR coregulators simultaneously through off-target seed region complementarity to the 3' UTR. This multi-functionality allows a single therapeutic agent to disrupt multiple survival pathways, preventing resistance development and extending therapeutic duration
2Measurement precision
If RNAi uses seed sequence complementarity to target transcripts, then targeted gene knockdown is achieved, but off-target effects occur on non-target transcripts
Solution Approach 1:
The patent converts the harmful off-target effect of seed sequence complementarity into a beneficial mechanism by deliberately designing oligonucleotides with seed sequences that target multiple AR coregulators simultaneously. The off-target binding to 3' UTR regions of multiple survival genes becomes the therapeutic mechanism, allowing broad disruption of cancer cell survival pathways while maintaining selectivity for cancer versus normal cells
Solution Approach 2:
The patent changes the binding parameters by using imperfect complementarity and seed region matching rather than exact sequence matching. This allows the oligonucleotides to bind to multiple transcripts with similar seed sequences in the 3' UTR, expanding targeting capability while reducing the risk of affecting transcripts with critical functional regions
3Object-generated harmful factors
If multiple independent RNAi target sequences are used to determine phenotypic specificity, then off-target effects are reduced, but therapeutic complexity increases
Solution Approach 1:
The patent merges multiple targeting capabilities into a single oligonucleotide design by using seed sequences that naturally complement multiple AR coregulator 3' UTR regions. This combining approach achieves the specificity of multiple targets while simplifying delivery and reducing the complexity of using separate agents for each target
Solution Approach 2:
The patent uses the seed sequence region as an intermediary mechanism that mediates binding to multiple different transcripts. Rather than requiring separate oligonucleotides for each target, the seed sequence acts as a universal mediator that recognizes and binds to conserved regions across multiple AR coregulators, simplifying the therapeutic strategy
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
AN-DISE effectively kills CRPC cells by reducing AR signaling and essential survival genes, offering a potential treatment for prostate cancer that is resistant to conventional therapies and does not affect normal cells.
Implementation Method 1
Ribonucleic acid interference (RNAi) via small interfering ribonucleic acids (siRNA) and short hairpin RNAs (shRNA) is a useful tool for knocking-down messenger RNA (mRNA) expression and studying gene function.
Implementation Method 2
The loaded RNA guides RISC to target transcripts via sequence complementarity, resulting in subsequent transcript degradation and/or translation inhibition.
Data Source
AI summary
Interfering nucleic acids and methods of their use in treat prostate cancers, such as aggressive prostate cancers. The nucleic acids may be, for example, short interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA, DNA, antisense DNA, Chimeric Antisense DNA/RNA, and microRNA (miRNA) oligonucleotides. The oligonucleotide has a seed sequence that is complementary to a sequence of either a gene or an mRNA encoding an androgen receptor (AR) coregulator or a fragment having AR coregulator activity. The nucleic acid compound may have a non-natural modification in the oligonucleotide, and/or an organic moiety conjugated to the oligonucleotide. The oligonucleotide has inhibitory activity against the expression or biological activity of the AR coregulator.