PBRM1 Splicing-Switch Oligonucleotide Composition for Exon 27 Skipping

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Solution Overview

Problem

Current therapies fail to effectively target the alternative splicing of the Polybromo 1 (PBRM1) gene, leading to immune evasion and cancer progression, particularly in cancers like clear cell renal cell carcinoma, despite the known impact of exon 27 inclusion in cancer tissues.

Innovation Solution

A splicing-switch oligonucleotide (SSO) is designed to selectively skip exon 27 of PBRM1 pre-mRNA, enhancing immune cell activation and inducing cancer cell death by regulating PBRM1 gene splicing.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional therapies are used to treat cancer, then general cancer treatment is provided, but they fail to effectively target the alternative splicing of the PBRM1 gene, leading to immune evasion and cancer progression

Engineering Contradiction:

Improveeffectiveness of cancer treatmentVSAvoidability to target alternative splicing

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces splicing-switch oligonucleotides (SSOs) as intermediary molecules that specifically bind to PBRM1 pre-mRNA to regulate alternative splicing. These SSOs act as mediators between the therapeutic agent and the target gene splicing process, enabling precise modulation of exon 27 inclusion without affecting other cellular processes. This resolves the contradiction by providing a mechanism that is both specific to alternative splicing (improving adaptability) and effective in preventing immune evasion (improving reliability).

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the splicing parameter of PBRM1 pre-mRNA by using SSOs to alter exon 27 inclusion levels. By modulating this specific splicing parameter, the therapy achieves effective cancer treatment outcomes while specifically targeting the alternative splicing mechanism that conventional therapies cannot address. This resolves the technical contradiction by demonstrating that changing the splicing parameter enables both effectiveness and specificity simultaneously.

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If exon 27 is included in PBRM1 mRNA as found in most cancer tissues, then cancer progression and immune evasion are promoted, but conventional therapies cannot target this splicing pattern

Engineering Contradiction:

Improveimmune evasion and cancer progressionVSAvoidavailability of splicing-targeting therapy

Core Design Contradiction:

Object-affected harmful factorsVSEase of manufacture

Solution Approach 1:

The patent extracts and targets the specific harmful splicing pattern (exon 27 inclusion) from the complex cellular environment. By designing SSOs that specifically recognize and bind to sequences flanking exon 27, the therapy isolates and corrects this particular splicing defect without needing to address the entire cancer genome or protein machinery. This resolves the contradiction by making the therapy specifically manufacturable for targeting exon 27 inclusion while effectively addressing the harmful effects of immune evasion.

Inventive Principle:

Principle #2Taking out (Extraction)

3Reliability

If splicing-switch oligonucleotide is used to skip exon 27, then anti-cancer effects of immune cells are enhanced, but requires specific complementary binding to PBRM1 pre-mRNA

Engineering Contradiction:

Improveanti-cancer effectVSAvoidcomplementary binding requirement

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the PBRM1 pre-mRNA target into specific binding regions flanking exon 27, and designs SSOs with complementary sequences that match these segmented regions. This segmentation allows the SSOs to achieve reliable anti-cancer effects through precise local binding, rather than requiring complex interactions across the entire pre-mRNA molecule. The segmentation principle resolves the contradiction by simplifying the binding requirement into manageable sequence-specific interactions while maintaining high reliability of the anti-cancer effect.

Inventive Principle:

Principle #1Segmentation

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 SSO induces exon 27 skipping, boosting the anti-cancer effects of immune cells, including natural killer cells and T cells, thereby reducing tumor size and promoting cancer cell death.

Implementation Method 1

induce splicing that selectively skips exon 27 of PBRM1 (Polybromo 1) pre-mRNA through complementary binding between the SSO and PBRM1 (Polybromo 1) pre-mRNA

Methodology Applied

Scientific EffectComplementary binding:

Data Source

PatentUS20250333739A1Composition for regulating splicing of polybromo 1 gene comprising splicing-switch oligonucleotide as effective component

Publication Date: 2025.10.30 THE IND & ACADEMIC COOP IN CHUNGNAM NAT UNIV (IAC)

AI summary

A composition for regulating splicing of Polybromo 1 (PBRM1) gene includes a splicing-switch oligonucleotide as an effective component. The splicing-switch oligonucleotide exhibits the effect of regulating the splicing of PBRM1 (Polybromo 1) gene and also, when exon 27 is skipped in cancer cells through the splicing regulation, enhancing cancer cell death through activation of NK92 cells.