FDA-approved drug could revolutionize organ transplantation

Researchers at Harvard University’s Wyss Institute for Biologically Inspired Engineering report that they have successfully released tadpoles Xenopus laevis putting frogs into a hibernation-like state of torpor using donepezil (DNP), a drug approved by the FDA to treat Alzheimer’s disease. The team had previously used another drug, SNC80, to achieve similar results in tadpoles and improve the survival of whole mammalian hearts for transplants, but SNC80 is not approved for clinical use in humans because it can cause seizures. In contrast, DNP is already in use in the clinic, meaning it has the potential to be quickly repurposed for emergency use to prevent irreversible organ injury while a person is transported to a hospital.

Cooling a patient’s body to slow metabolic processes has long been used in medical settings to reduce injuries and long-term problems from serious conditions, but this can currently only be done in a well-equipped hospital. Achieving a similar state of ‘biostasis’ with an easy-to-administer drug like DNP could potentially save millions of lives every year.”

Michael Super, Ph.D., co-author and director of research, Immuno-Materials, Wyss Institute

This research, published today in ACS Nanowas supported as part of the DARPA Biostasis Program, which funds projects aimed at extending the time for life-saving medical treatments, known as “the Golden Hour,” following traumatic injury or acute infection. The Wyss Institute has been participating in the Biostasis Program since 2018 and has achieved several important milestones in recent years.

Using a combination of predictive machine learning algorithms and animal models, Wyss’ Biostasis team previously identified and tested existing drug compounds that had the potential to put living tissue into a state of suspended animation. Their first successful candidate, SNC80, significantly reduced oxygen consumption (a proxy for metabolism) in both a beating pig heart and human organ chips, but has a known side effect of causing seizures when injected systemically.

In the new study, they turned again to their algorithm, NeMoCad, to identify other compounds whose structures are similar to SNC80. Their top candidate was DNP, which has been approved for the treatment of Alzheimer’s disease since 1996.

“Interestingly, clinical overdoses of DNP in patients suffering from Alzheimer’s disease have been associated with drowsiness and decreased heart rate – symptoms similar to sedation. However, this is, to our knowledge, the first study that focuses on exploiting those effects as the main clinical response, and not as side effects,” said the study’s first author, María Plaza Oliver, Ph.D., who was a postdoctoral fellow at the Wyss Institute when the work was conducted.

The team used X. laevis tadpoles to evaluate the effects of DNP on an entire living organism and found that it successfully induced a torpor-like condition that could be reversed if the drug was removed. However, the drug appeared to cause some toxicity and accumulated in all tissues of the animals. To solve that problem, the researchers encapsulated DNP in lipid nanocarriers and found that this both reduced toxicity and allowed the drug to accumulate in the animals’ brain tissue. This is a promising result, because the central nervous system is known to mediate hibernation and torpor in other animals as well.

Although DNP has been shown to protect neurons from metabolic stress in models of Alzheimer’s disease, the team cautions that more work is needed to understand exactly how it anesthetizes, and to scale up production of the encapsulated DNP for use in larger animals and, possibly, people.

“Donepezil has been used by patients worldwide for decades, so its properties and manufacturing methods are well established. Lipid nanocarriers, similar to the one we used, have now also been approved for clinical use in other applications. This study shows that an encapsulated version of the The drug could potentially be used in the future to buy patients critical time to survive devastating injuries and diseases, and it could easily be formulated and produced at scale on a much shorter time scale than a new drug,” said senior author Donald Ingber, MD. Ingber is the founder and director of the Wyss Institute, the Judah Folkman professor of vascular biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences.