FDA-approved drug could revolutionize organ transplantation

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

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

Michael Super, Ph.D., Co-author and Study Director, 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 treatment, often referred to 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 identified and tested previously existing pharmaceutical compounds that had the potential to put living tissues into a state of suspended animation. The first successful candidate, SNC80, significantly reduced oxygen consumption (a proxy for metabolism) in both a beating pig heart and a human organ chip, but has a known side effect of inducing seizures when administered systemically.

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

“Interestingly, clinical overdoses of DNP in patients suffering from Alzheimer’s disease have been associated with somnolence and decreased heart rate—symptoms resembling agitation. However, this is the first study, to our knowledge, that focuses on leveraging these effects the primary clinical response and not as side effects,” said study first author Maria 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 assess the effects of DNP in a whole living organism and found that it successfully induced a panic-like state that was reversible when the drug was removed. The drug, however, appeared to cause some toxicity and accumulate in all tissues of the animals. To solve this problem, the researchers encapsulated DNP inside lipid nanocarriers and found that this reduced toxicity and caused the drug to accumulate in the animals’ brain tissue. This is a promising result, as the central nervous system is known to mediate hibernation and agitation 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 propagates, as well as to scale up production of encapsulated DNP for use in larger animals and , possibly people.

“Donepezil has been used worldwide by patients for decades, so its properties and manufacturing methods are well established. Lipid nanocarriers, similar to the ones we used, are also approved for clinical use in other applications. This study shows that an encapsulated version of The drug could potentially be used in the future to buy patients critical time to survive devastating injuries and illnesses, and could easily be formulated and produced at scale on a much shorter time scale than a new drug,” said senior author Donald Ingber, MD, Ph.D., is the founding director of the Wyss Institute 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.