dATP-Generating Cells for Heart Function Recovery

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Solution Overview

Problem

Current positive inotropic agents used to enhance cardiac contractility in treating heart diseases do not improve patient survival and are associated with increased myocardial oxygen consumption, arrhythmias, and adverse signaling pathways.

Innovation Solution

The use of genetically modified cells expressing elevated ribonucleotide reductase activity to increase deoxyATP (dATP) levels in cardiomyocytes, which can be delivered to a graft site in the heart to enhance cardiac function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Force

If traditional positive inotropic agents are used to increase cardiac contractility, then the force of contraction is improved, but myocardial oxygen consumption increases and arrhythmias occur

Engineering Contradiction:

Improvecardiac contractilityVSAvoidmyocardial oxygen consumption

Core Design Contradiction:

ForceVSUse of energy by moving object

Solution Approach 1:

The invention changes the biochemical parameters within cardiomyocytes by increasing intracellular dATP levels through RNR overexpression. This alters the energy state and nucleotide composition of the cell, enabling improved contractility through a different biochemical pathway than traditional inotropic agents, thereby avoiding the associated increase in myocardial oxygen consumption

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention uses genetically modified cells as intermediaries that produce and release dATP into the extracellular space. This dATP then acts as a signaling molecule or energy source for neighboring cardiomyocytes, providing a mediated approach to enhancing contractility that bypasses the direct pharmacological stimulation causing increased oxygen consumption

Inventive Principle:

Principle #24Intermediary (Mediator)

2Force

If traditional positive inotropic agents are used to increase cardiac contractility, then the force of contraction is improved, but arrhythmia burden increases

Engineering Contradiction:

Improvecardiac contractilityVSAvoidarrhythmia burden

Core Design Contradiction:

ForceVSReliability

Solution Approach 1:

The invention alters the intracellular nucleotide profile by increasing dATP levels through RNR overexpression. This biochemical parameter change provides a different mechanism for enhancing contractility that does not activate the same adverse signaling pathways as traditional inotropic agents, thereby maintaining reliability and reducing arrhythmia burden

Inventive Principle:

Principle #35Parameter changes

3Force

If ribonucleotide reductase is overexpressed to increase dATP levels, then cardiac contractility is improved, but the complexity of the treatment approach increases

Engineering Contradiction:

Improvecardiac contractilityVSAvoidtreatment complexity

Core Design Contradiction:

ForceVSDevice complexity

Solution Approach 1:

The invention employs genetically modified cells that autonomously produce and secrete dATP without requiring external administration or complex delivery systems. The modified cells serve themselves by continuously generating the therapeutic molecule (dATP) and releasing it to affect surrounding tissue, simplifying the overall treatment approach despite the genetic modification

Inventive Principle:

Principle #25Self-service

Data Source

PatentUS20250145957A1Generation of deoxyadenosine triphosphate donor cells and uses thereof

Publication Date: 2025.05.08 UNIV OF WASHINGTON

AI summary

Provided herein are compositions and methods directed toward the discovery of improved methods for generating deoxyATP (dATP) in cells that can be delivered to a graft site in the heart to enhance cardiac function.