Splice Modulating Oligonucleotides for Prolactin Receptor Splicing
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Solution Overview
Problem
Current cancer therapies, particularly those targeting the estrogen receptor, have limitations in efficacy and specificity, as they do not effectively address cancers with elevated prolactin levels or those that are estrogen receptor negative, and there is a need for targeted approaches that can modulate splicing of specific genes to inhibit cancer cell survival and proliferation.
Innovation Solution
Administration of splice modulating oligonucleotides (SMOs) that target specific pre-mRNAs, such as those encoding the prolactin receptor, to alter splicing patterns, thereby reducing expression of oncogenic forms or increasing expression of tumor-suppressive forms, thereby inhibiting cancer cell survival, proliferation, and metastasis, or promoting apoptosis and anti-tumor immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cancer therapies target the estrogen receptor, then treatment efficacy is improved for estrogen receptor positive cancers, but treatment effectiveness deteriorates for estrogen receptor negative cancers or cancers with elevated prolactin levels
Solution Approach 1:
The patent changes the target parameter from estrogen receptor to prolactin receptor splicing patterns. By using splice modulating oligonucleotides to alter the splicing of prolactin receptor pre-mRNA, the therapy can effectively target cancers that are estrogen receptor negative or have elevated prolactin levels, thereby expanding therapy applicability while maintaining efficacy through molecular targeting
Solution Approach 2:
The patent introduces splice modulating oligonucleotides as intermediary molecules that bind to specific splice sites or splice enhancers/silencers in the prolactin receptor pre-mRNA. These oligonucleotides act as mediators to alter splicing patterns, promoting inclusion of exon 10 or exclusion of exon 11, thereby enabling targeted therapy against diverse cancer types through a common molecular mechanism
2Productivity
If alternative splicing is used to create different prolactin receptor forms, then cancer cell survival and growth are promoted by the long form, but the short form decreases cell survival and cancer growth
Solution Approach 1:
The patent extracts and targets specific splice sites or regulatory elements within the prolactin receptor pre-mRNA. By using splice modulating oligonucleotides that bind to specific locations (such as exon 10 or exon 11), the therapy selectively removes or excludes specific exons from the mature mRNA, thereby extracting the oncogenic potential from the protein product and generating tumor-suppressive forms
Solution Approach 2:
Instead of allowing the default splicing pattern to produce the oncogenic long form, the patent applies oligonucleotides that force alternative splicing outcomes. The therapy inverts the normal splicing tendency by targeting splice enhancers that promote cancer-promoting splicing and splice silencers that prevent them, thereby inverting the splicing outcome to produce tumor-suppressive short forms
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 use of SMOs effectively reduces cancer cell survival and metastasis, enhances anti-tumor immune responses, and decreases cancer stem cell numbers, demonstrating therapeutic benefits in breast, prostate, and ovarian cancers by specifically modulating splicing to inhibit oncogenic proteins and promote tumor suppression.
Implementation Method 1
a splice modulating oligonucleotide that modifies splicing of a pre-mRNA
Data Source
AI summary
A method of treating cancer in a subject is provided. The method includes administering a splice modulating oligonucleotide to the subject in an amount effective to provide a therapeutic benefit to the subject. In the method, the oligonucleotide modifies splicing of a pre-mRNA encoding a polypeptide, and either: reduces expression of the polypeptide if the polypeptide promotes cancer cell survival, proliferation, and/or metastasis, or promotes angiogenesis, or a combination thereof; or increases expression of the polypeptide if the polypeptide inhibits cancer cell survival, proliferation and/or metastasis, or inhibits angiogenesis, or a combination thereof. Similar methods of treating diseases involving prolactin or the prolactin receptor are also provided.