‘Suspended Animation’ Drug Could Aid Organ Transplantation, Survival After Traumatic Injury

Researchers have shown that a non-addictive painkiller could be used to preserve cells and organs quickly and safely for transplantation, eliminating the need for static cold storage.

The research, published in eLifeprovides strong evidence that the existing drug, SNC80, can rapidly and reversibly slow biochemical and metabolic activities while preserving cell and tissue viability.

Research suggests that SNC80 not only has the potential to ensure that donor organs can be safely preserved for longer before transplantation, but could also be used to slow the damaging effects of tissue and organ trauma across a broad spectrum. range of health emergencies.

The rapid and reversible slowing down of metabolic and other physiological processes (called biostasis) improves the survival of cells and organs intended for transplantation. The conventional approach to achieving this is to lower the temperature such that these processes slow down as they would during hibernation. However, prolonged cold storage can damage tissues, and the systems currently used to keep cells and tissues alive may be difficult to use at the point of care or when resources are limited.

“There remains a large unmet need for improved tissue and organ preservation approaches for multiple clinical applications,” says lead author Megan Sperry, a researcher at the Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, UNITED STATES.

“In this study, we sought to identify potential drugs that could slow metabolism and mimic the states normally induced by hypothermia or hibernation. We needed an approach that was inducible in less than an hour and safely reversible, with major tissue functions returning to normal. Within 24 hours.”

The team studied the scientific literature to identify drug candidates with unintended side effects, such as a drop in body temperature, and the drug SNC80, a compound developed as a non-addictive painkiller that works through the delta opioid pathway, caught their attention. It has been shown to induce hypothermia and protect against the effects of blocked blood flow in the spinal cord. This led them to test whether it had the potential to slow metabolism on demand by administering it to tadpoles.

Less than an hour after treatment, SNC80 reduced tadpoles’ swimming activity by 50% compared to untreated tadpoles, and this trend quickly reversed once the drug was withdrawn. SNC80 also reduced oxygen consumption (a measure of metabolism) and had extremely suppressive but reversible effects on heart rate.

Excited by these findings, the team’s next step was to test the potential clinical value of SNC80.

“Heart transplants are currently hampered by the shortage of donors, the limited length of time you can preserve heart tissue, and the lack of optimal storage conditions,” says Sperry. “This means that hearts can only be allocated to people within four hours of the donor. We wanted to see if SNC80 could induce biostasis in the heart, which could ultimately lengthen the time between donation organ and the recipient’s surgical intervention.”

In collaboration with Vascular Perfusion Solutions, Inc, they explored this by testing whether the SNC80 could preserve a donor pig’s heart over a six-hour period, during which the heart was preserved in a portable, oxygenated preservation device maintained at a temperature of 20 to 23°C. °C, i.e. below body temperature but not hypothermia.

Treatment with SNC80 caused a rapid decrease in the heart’s oxygen consumption, to less than 50% of that of untreated controls, over a six-hour period. However, once they restored blood flow and restarted the heart using a defibrillator, they observed a rapid return to normal oxygen consumption levels and pulse rates.

Encouraged by this, the team explored whether the drug also induced biostasis in human cells, using organ-on-a-chip intestinal models. They found that treatment with SNC80 resulted in a 6-fold decrease in oxygen consumption (i.e. metabolism) after 48 hours, which gradually returned to normal as the drug was cleared from the cells .

The authors caution that further validation is needed before the SNC80 can be used in a clinical setting. First, SNC80 is currently not approved for use in clinical settings: during preclinical trials of the drug, side effects, including seizures, were noted and its development was halted.

These seizures are hypothesized to be related to CNS delta opioid activity80. The team therefore also created a new non-opioid analogue called WB3, which will be used in future work. Additionally, in their study, the team characterized the function of the donor pig heart outside the body, and so their future work will seek to verify the function and quality of the hearts after they are transplanted.

“Our results demonstrate that SNC80 can be used to induce biostasis and produce a hypometabolic state which, in combination with an autonomous transport system, could potentially increase organ viability outside the body for prolonged periods,” the author concludes. principal Donald Ingber, founder. Director of the Wyss Institute for Biologically Inspired Engineering at Harvard University.

“Additionally, the ability to rapidly induce a reversible suspended animation-like state via point-of-care injection could enable new therapeutic approaches to slow the effects of trauma and acute infection, thereby increasing survival in some number of contexts, from military and military space exploration to civilian health emergencies such as road accidents or limiting damage from strokes.