Itaconate-Based Preservation Solutions for Donor Heart Ischemia
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Solution Overview
Problem
Current methods for preserving donor hearts for transplantation are limited by the 4-hour ischemia time during cold storage, leading to primary graft dysfunction and increased mortality, as well as geographic restrictions due to transport time limitations, with existing solutions failing to effectively address ischemic injury and reperfusion damage.
Innovation Solution
The development of pharmaceutical compositions and tissue/organ preservation solutions containing itaconate and its derivatives, which are used to improve cardiac preservation by increasing Irg1 expression and itaconate levels, thereby reducing oxidative stress, inflammation, and harmful metabolite accumulation, and enhancing cardiac function during storage and transplantation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If cold storage preservation is used for donor hearts, then the heart can be stored for transplantation, but the ischemia time is limited to 4 hours which restricts geographic distribution and increases mortality
Solution Approach 1:
The patent changes the chemical parameters of the preservation solution by adding itaconate and its derivatives, which modify the metabolic environment to reduce ischemic injury and allow extended preservation times while maintaining graft function
Solution Approach 2:
Itaconate acts as an intermediary substance that mediates between the ischemic stress and cardiac tissue, reducing oxidative stress and inflammation to protect the heart during extended storage
2Ease of operation
If cold storage with mechanical arrest is used, then the heart can be preserved for transport, but primary graft dysfunction occurs in 10-20% of transplants due to prolonged ischemic time
Solution Approach 1:
The preservation solution parameters are modified by incorporating itaconate, which changes the metabolic state of the heart tissue to resist ischemic damage, enabling reliable transport and transplantation
3Speed
If ex vivo normothermic perfusion is used, then transport time is reduced, but obligate ischemic time remains due to arrest for placement and disengagement
Solution Approach 1:
The heart is pre-treated with itaconate-containing preservation solution before perfusion, providing preliminary protection against ischemic injury during the unavoidable arrest periods for device attachment and disengagement
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 use of itaconate-based preservation solutions significantly improves donor heart function, reduces ischemic damage, and extends the preservation time, leading to better post-transplant outcomes and reduced mortality by enhancing antioxidant activities and limiting succinate accumulation, thus addressing the limitations of current preservation methods.
Implementation Method 1
reducing oxidative stress, inflammation, and harmful metabolite accumulation
Implementation Method 2
limiting succinate accumulation
Data Source
AI summary
Provided herein are pharmaceutical compositions and tissue/organ preservation solutions comprising itaconate and/or derivatives thereof and methods of use thereof. In particular, provided herein are compositions comprising itaconate and methods of use thereof for the preservation of tissues/organs for transplantation and treatment/prevention/reduction of conditions such as myocardial infarction, sudden cardiac arrest, stroke, senescence, cardiomyopathies, and cardiotoxicity.