Oligonucleotide SRp30c Binding Inhibition Glucocorticoid Sensitivity

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Solution Overview

Problem

Current methods struggle to selectively inhibit the activity of serine/arginine-rich protein 30c (SRp30c) involved in glucocorticoid receptor splicing, leading to potential disruptions in body homeostasis and limited effectiveness in enhancing glucocorticoid sensitivity of cells.

Innovation Solution

Development of oligonucleotides that specifically inhibit the binding of SRp30c to glucocorticoid receptor pre-mRNA, increasing the expression of GRα relative to GRβ by binding to a continuous sequence of 15 to 50 bases with a high adenine and guanine content, thereby enhancing glucocorticoid sensitivity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current methods are used to inhibit SRp30c activity, then glucocorticoid sensitivity may be enhanced, but body homeostasis is disrupted and effectiveness is limited

Engineering Contradiction:

Improveglucocorticoid sensitivityVSAvoiddisruption of body homeostasis

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention segments the SRp30c protein into specific functional domains by using antisense oligonucleotides that target specific regions of the SRp30c mRNA. This allows selective inhibition of SRp30c's splicing activity on glucocorticoid receptor pre-mRNA without completely abolishing SRp30c function, thereby maintaining body homeostasis while enhancing glucocorticoid sensitivity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention applies local quality by designing oligonucleotides that specifically target the SRp30c binding site on glucocorticoid receptor pre-mRNA. The antisense oligonucleotides are complementary to a specific sequence (SEQ ID NO: 22) in the pre-mRNA, allowing selective interference only at the desired location without affecting other cellular processes.

Inventive Principle:

Principle #3Local quality

2Manufacturing precision

If SRp30c binding to pre-mRNA is inhibited, then GRα expression increases relative to GRβ, but non-specific inhibition of all SR proteins may occur

Engineering Contradiction:

Improveselectivity of SRp30c inhibitionVSAvoidspecificity for SRp30c over other SR proteins

Core Design Contradiction:

Manufacturing precisionVSAdaptability or versatility

Solution Approach 1:

The invention makes different parts of the SRp30c protein have different functions by targeting a specific region of SRp30c mRNA with antisense oligonucleotides. The oligonucleotides are designed to be complementary to a specific sequence (SEQ ID NO: 22) that is unique to SRp30c's binding site on glucocorticoid receptor pre-mRNA, allowing selective inhibition without affecting other SR proteins.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention uses antisense oligonucleotides as molecular copies that are complementary to the SRp30c mRNA sequence. These copies bind to the target mRNA through base pairing, forming a double-stranded structure that prevents SRp30c from binding to its target site, thereby achieving selective inhibition.

Inventive Principle:

Principle #26Copying

3Reliability

If glucocorticoid resistance is overcome by increasing GRα expression, then treatment effectiveness improves, but side effects may increase

Engineering Contradiction:

Improveglucocorticoid treatment effectivenessVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention applies partial action by using antisense oligonucleotides that partially inhibit SRp30c activity rather than completely abolishing it. This partial inhibition is sufficient to shift the splicing balance toward GRα production without causing excessive GRα accumulation that would lead to severe side effects.

Inventive Principle:

Principle #16Partial or excessive action

Solution Approach 2:

The invention changes the parameter of splicing regulation by using antisense oligonucleotides to alter the balance between GRα and GRβ expression. The oligonucleotides modify the splicing process to increase GRα relative to GRβ, thereby changing the functional parameters of glucocorticoid signaling to improve effectiveness while controlling side effects.

Inventive Principle:

Principle #35Parameter changes

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 oligonucleotides effectively increase glucocorticoid sensitivity of cells by selectively regulating GR splicing, potentially overcoming glucocorticoid resistance in diseases such as asthma, rheumatic diseases, and lymphocytic leukemia, with reduced side effects.

Implementation Method 1

binding to a continuous sequence of 15 to 50 bases with a high adenine and guanine content

Methodology Applied

Scientific EffectComplementary base pairing:

Data Source

PatentUS9234200B2Oligonucleotide, glucocorticoid sensitivity enhancer, pharmaceutical composition, and expression vector

Publication Date: 2016.01.12 NAT UNIV CORP TOKYO UNIV OF AGRI & TECH

AI summary

An oligonucleotide that inhibits the binding of a serine/arginine-rich protein 30c (SRp30c) to a pre-mRNA of a glucocorticoid receptor gene in vivo.