Nucleic Acid Modulation of RAS Splicing for Cancer Treatment

Solution Overview

Problem

Current treatments for cancer associated with RAS family genes, particularly KRAS, NRAS, and HRAS, are limited in effectively targeting mutations like Q61K and G60G silent mutations, which confer resistance to therapies and lead to oncogenic splicing patterns.

Innovation Solution

Development of nucleic acids that hybridize to precursor-mRNA of RAS family genes, specifically targeting exon splicing enhancer binding motifs with mutations, to modulate splicing patterns, such as promoting alternative splicing that excludes exon 3, thereby inhibiting oncogenic protein production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current cancer therapies are used to treat RAS family gene mutations, then general cancer treatment is provided, but the treatments fail to effectively target specific mutations like Q61K and G60G silent mutations, leading to treatment resistance

Engineering Contradiction:

Improvetreatment efficacyVSAvoidmutation-specific targeting

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by designing nucleic acid sequences that specifically target mutated regions (Q61K and G60G silent mutations) within the RAS family genes. The composition distinguishes between mutated and wild-type sequences by targeting specific local regions, thereby achieving mutation-specific treatment efficacy while preserving normal cellular function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent segments the treatment approach by creating distinct nucleic acid sequences tailored to different RAS mutations (KRAS, NRAS, HRAS variants). Each composition is designed to address specific mutation types, allowing for precise, segmented targeting of various oncogenic variants rather than a generalized approach.

Inventive Principle:

Principle #1Segmentation

2Measurement precision

If nucleic acid sequences are designed to target mutated RAS pre-mRNA, then specific modulation of oncogenic splicing is achieved, but the sequences must be highly specific to avoid affecting wild-type RAS genes in normal cells

Engineering Contradiction:

Improvesplicing modulation specificityVSAvoidsequence design complexity

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent applies local quality by designing nucleic acid sequences that specifically target mutated regions (Q61K and G60G silent mutations) within the RAS family genes. The composition distinguishes between mutated and wild-type sequences by targeting specific local regions, thereby achieving mutation-specific treatment efficacy while preserving normal cellular function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying nucleic acid sequences to match specific mutation variants. The compositions are designed with altered parameters (nucleotide sequences) that correspond to specific mutations, enabling precise discrimination between mutated and wild-type RAS genes through sequence parameter matching.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If existing therapies are used, then general cancer treatment is provided, but they cannot overcome resistance conferred by silent mutations like G60G

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidtreatment resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful effect of silent mutations (which previously conferred treatment resistance) into a beneficial targeting opportunity. By designing nucleic acid sequences that specifically recognize and bind to mutated regions including silent mutations, the invention transforms these previously undetectable resistance-conferring variants into specific targets for therapeutic intervention.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent applies local quality by designing nucleic acid sequences that specifically target mutated regions (Q61K and G60G silent mutations) within the RAS family genes. The composition distinguishes between mutated and wild-type sequences by targeting specific local regions, thereby achieving mutation-specific treatment efficacy while preserving normal cellular function.

Inventive Principle:

Principle #3Local quality

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 modulates splicing in tumor cells to produce non-functional proteins, overcoming resistance and enhancing the efficacy of existing cancer therapies by specifically targeting mutated RAS genes without affecting normal cells.

Implementation Method 1

nucleic acid comprising a sequence that hybridizes to a target, wherein the target comprises a precursor-mRNA (pre-mRNA) of a RAS family gene

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentUS20240209371A1Compositions and methods for treating cancer

Publication Date: 2024.06.27 DANA FARBER CANCER INSTITUTE INC

AI summary

This invention comprises compositions and methods for treating cancer. For example, this invention comprises compositions and methods for treating cancer by modulating splicing.