HMGCS2 Gene Delivery for Cardiomyocyte Regeneration

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Solution Overview

Problem

Adult mammalian cardiomyocytes have limited proliferative capacity, hindering effective cardiac regeneration after injury, as they fail to undergo substantial dedifferentiation and metabolic switches necessary for repair.

Innovation Solution

A gene delivery composition comprising a recombinant adeno-associated virus (rAAV) encoding human 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) is used to upregulate HMGCS2 expression in cardiomyocytes, inducing a metabolic switch from fatty acid to ketone utilization, promoting dedifferentiation and proliferation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If adult cardiomyocytes are used for heart repair, then the heart can maintain its structural integrity and function, but the limited proliferative capacity of adult cardiomyocytes hinders effective cardiac regeneration

Engineering Contradiction:

Improvecardiac functionVSAvoidproliferative capacity

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the metabolic parameters of adult cardiomyocytes by upregulating HMGCS2 expression, inducing a metabolic switch from fatty acid oxidation to ketone body utilization. This parameter change triggers dedifferentiation and restores proliferative capacity while maintaining cardiac function, resolving the contradiction between reliability and productivity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent performs preliminary metabolic reprogramming of adult cardiomyocytes before injury occurs or early after injury, by delivering HMGCS2 gene via AAV vector. This preliminary action prepares the cells for enhanced regenerative response, allowing them to proliferate effectively when needed while maintaining their functional reliability

Inventive Principle:

Principle #10Preliminary action

2Productivity

If cardiomyocytes undergo dedifferentiation and metabolic switch to promote proliferation, then cardiac regeneration is enhanced, but the adaptive response in adult mammals is not strong enough for complete or adequate cardiac regeneration after injury

Engineering Contradiction:

Improvecardiac regenerationVSAvoidadequacy of regeneration

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies preliminary action by pre-treating adult cardiomyocytes with HMGCS2 gene delivery via AAV before or early after cardiac injury. This preliminary metabolic reprogramming primers the cells for enhanced dedifferentiation and proliferation responses, making the adaptive response strong enough to achieve adequate cardiac regeneration that would not occur with natural injury response alone

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent implements significant parameter changes by forcibly upregulating HMGCS2 expression levels in adult cardiomyocytes, inducing a profound metabolic switch from fatty acid oxidation to ketone body utilization. This dramatic metabolic parameter change triggers substantial dedifferentiation and proliferation, achieving adequate cardiac regeneration that exceeds the weak natural adaptive response in adult mammals

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 upregulation of HMGCS2 in cardiomyocytes enhances dedifferentiation and proliferation, facilitating cardiac regeneration by inducing a metabolic switch that supports heart function improvement after myocardial infarction or hypoxic stress.

Implementation Method 1

Methodology Applied

Scientific EffectGene delivery:

Implementation Method 2

HMGCS2 enzyme or any of its functionally homologous forms

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Data Source

PatentUS20230151372A1Composition and Method of Treatment for Heart Protection and Regeneration

Publication Date: 2023.05.18 ACAD SINICA

AI summary

The present invention provides a gene delivery vehicle comprising a heterologous genome capable of upregulating the expression of HMGCS2 in human heart and, in particular, in the cardiomyocyte (CM). Upregulating the expression of HMBCS2 causes a metabolic switch that facilitates CM dedifferentiation and regeneration under myocardial infarction or hypoxic conditions. The present invention also provides a method of therapy for protection and/or regeneration of the human heart and, in particular, in the CM by administration of the composition of the present invention to the patient.