Identification of pharmacological inducers of a reversible hypometabolic state for whole organ preservation
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Published on: August 13, 2014
Megan M Sperry1,2, Berenice Charrez1, Haleh Fotowat1
1Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, United States.
Abstract:
Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially for organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening of metabolism, mobility, and development in Xenopus, we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability. Although SNC80 was developed as a delta opioid receptor activator, we discovered that its ability to slow metabolism is independent of its opioid modulating activity as a novel SNC80 analog (WB3) with almost 1000 times less delta opioid receptor binding activity is equally active. Metabolic suppression was also achieved using SNC80 in microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Pharmacological induction of physiological slowing in combination with organ perfusion transport systems may offer a new therapeutic approach for tissue and organ preservation for transplantation, trauma management, and enhancing patient survival in remote and low-resource locations.
Insights
Researchers discovered SNC80, a drug that reversibly slows metabolism, preserving organs for transplantation. This method shows promise for improving organ preservation and patient survival in various medical scenarios.
Area of Science:
- Biomedical Engineering
- Pharmacology
- Organ Transplantation
Background:
- Hypoxia-reperfusion injury poses a significant challenge in organ preservation, particularly for sensitive organs like the heart.
- Existing methods for organ preservation have limitations, driving the need for novel therapeutic strategies.
Purpose of the Study:
- To identify existing drugs capable of inducing reversible metabolic suppression for enhanced organ preservation.
- To investigate the mechanism of metabolic slowing induced by SNC80 and its potential clinical applications.
Main Methods:
- Whole-organism screening in *Xenopus* to identify compounds affecting metabolism, mobility, and development.
- Testing SNC80 and a novel analog (WB3) in human organs-on-chips and explanted porcine organs.
- Assessing metabolic suppression, cell viability, and tissue preservation.
Main Results:
- SNC80 was identified as a drug that rapidly and reversibly slows metabolic and physiological processes while maintaining cell and tissue viability.
- The metabolic slowing effect of SNC80 is independent of its delta opioid receptor activity.
- Successful metabolic suppression was demonstrated in human organs-on-chips and porcine organs, indicating cross-species relevance.
Conclusions:
- Pharmacological induction of physiological slowing using agents like SNC80 represents a novel therapeutic approach for organ preservation.
- This strategy holds potential for improving outcomes in organ transplantation, trauma management, and healthcare in resource-limited settings.
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