Oligonucleotides Modulating ATP2A2 Expression

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Solution Overview

Problem

Current treatments for cardiac diseases such as congestive heart failure and muscular dystrophy are inadequate due to insufficient regulation of the contraction/relaxation cycle of muscle cells, primarily because of decreased ATP2A2 activity, which affects calcium ion transport and muscle function.

Innovation Solution

Development of single-stranded oligonucleotides that target the PRC2-associated regions of the ATP2A2 gene to upregulate its expression, thereby enhancing calcium ion transport and improving muscle contraction/relaxation cycles, using specific sequences and modifications to avoid off-target effects and ensure effective delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for cardiac diseases are used, then disease management is achieved, but the contraction/relaxation cycle of muscle cells cannot be adequately regulated due to insufficient ATP2A2 activity

Engineering Contradiction:

Improveregulation of contraction/relaxation cycleVSAvoidATP2A2 activity

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the expression level parameter of the ATP2A2 gene by delivering oligonucleotides that modulate gene expression. This increases ATP2A2 protein production, thereby improving calcium ion transport activity and enabling better regulation of the contraction/relaxation cycle in cardiac muscle cells.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If oligonucleotides are designed to target PRC2-associated regions of ATP2A2, then upregulation of ATP2A2 expression is achieved, but off-target effects may occur

Engineering Contradiction:

ImproveATP2A2 expressionVSAvoidoff-target effects

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing oligonucleotides with specific sequence characteristics and structural features tailored to bind only to PRC2-associated regions of the ATP2A2 gene. This specificity ensures upregulation of ATP2A2 expression while minimizing off-target effects through precise local targeting.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses PRC2-associated regions as intermediary elements. The oligonucleotides bind to these intermediate regions rather than directly to the gene promoter, serving as a mediator to achieve upregulation of ATP2A2 expression while controlling specificity and reducing off-target effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If single-stranded oligonucleotides are used to upregulate ATP2A2, then calcium ion transport is enhanced, but delivery efficiency and pharmacokinetics need optimization

Engineering Contradiction:

Improvecalcium ion transportVSAvoiddelivery and pharmacokinetics

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent modifies parameters of the oligonucleotide molecules through chemical modifications and conjugations. These changes improve delivery efficiency, enhance pharmacokinetic properties, and increase cellular uptake, thereby ensuring effective enhancement of calcium ion transport through upregulated ATP2A2 expression.

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 significantly increase ATP2A2 expression, leading to improved cardiac function and potential treatments for cardiac diseases, including congestive heart failure and muscular dystrophy, by enhancing calcium ion transport and muscle function.

Implementation Method 1

single stranded oligonucleotides that target a PRC2-associated region of an ATP2A2 gene

Methodology Applied

Scientific EffectHybridization:

Implementation Method 2

ATP2A2 maintains a low cytoplasmic concentration of Ca2+ ions through hydrolysis of ATP coupled with the translocation of calcium from the cytosol into the sarcoplasmic reticulum lumen

Methodology Applied

Scientific EffectActive transport:

Implementation Method 3

ATP2A2 maintains a low cytoplasmic concentration of Ca2+ ions through hydrolysis of ATP

Methodology Applied

Scientific EffectHydrolysis: Hydrolysis

Data Source

PatentUS10174323B2Compositions and methods for modulating ATP2A2 expression

Publication Date: 2019.01.08 THE GENERAL HOSPITAL CORP

AI summary

Aspects of the invention provide single stranded oligonucleotides for activating or enhancing expression of ATP2A2. Further aspects provide compositions and kits comprising single stranded oligonucleotides for activating or enhancing expression of ATP2A2. Methods for modulating expression of ATP2A2 using the single stranded oligonucleotides are also provided. Further aspects of the invention provide methods for selecting a candidate oligonucleotide for activating or enhancing expression of ATP2A2.