Donepezil, an FDA-approved drug to treat Alzheimer’s, has the potential to be repurposed for use in emergency situations to prevent irreversible organ injury, according to researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University.
Using donepezil (DPN), researchers report that they were able to put tadpoles of Xenopus laevis frogs into a hibernation-like torpor.
“Cooling a patient’s body down to slow its metabolic processes has long been used in medical settings to reduce injuries and long-term problems from severe conditions, but it can only currently be done in a well-resourced hospital,” said co-author Michael Super, director of immuno-materials at the Wyss Institute. “Achieving a similar state of ‘biostasis’ with an easily administered drug like DNP could potentially save millions of lives every year.”
This research, published Thursday in ACS Nano, was supported as part of the DARPA Biostasis Program, which funds projects that aim to extend the time for lifesaving medical treatment, often referred to as “the Golden Hour,” following traumatic injury or acute infection. The Wyss Institute has been a participant in the Biostasis Program since 2018, and has achieved several important milestones over the last few years.
Using a combination of predictive machine learning algorithms and animal models, the Wyss’ Biostasis team previously identified and tested existing drug compounds that had the potential to put living tissues 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 in human organ chips, but is known to cause seizures when injected systemically.
In the new study, they once again turned to their algorithm to identify other compounds whose structures are similar to SNC80. Their top candidate was DNP, which has been approved since 1996 to treat Alzheimer’s.
“Achieving a similar state of ‘biostasis’ with an easily administered drug like DNP could potentially save millions of lives every year.”
Michael Super
“Interestingly, clinical overdoses of DNP in patients suffering from Alzheimer’s disease have been associated with drowsiness and a reduced heart rate — symptoms that are torpor-like. However, this is the first study, to our knowledge, that focuses on leveraging those effects as the main clinical response, and not as side effects,” said the study’s first author, María Plaza Oliver, who was a postdoctoral fellow at the Wyss Institute when the work was conducted.
The team used X. laevis tadpoles to evaluate DNP’s effects on a whole living organism, and found that it successfully induced a torpor-like state that could be reversed when the drug was removed. The drug, however, did seem to cause some toxicity, and accumulated in all of the animals’ tissues. To solve that problem, the researchers encapsulated DNP inside lipid nanocarriers, and found that this both reduced toxicity and caused the drug to accumulate in the animals’ brain tissues. This is a promising result, as 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 causes torpor, as well as scale up production of the encapsulated DNP for use in larger animals and, potentially, humans.
“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 now approved for clinical use in other applications. This study demonstrates that an encapsulated version of the drug could potentially be used in the future to buy patients critical time to survive devastating injuries and diseases, and it could be easily formulated and produced at scale on a much shorter time scale than a new drug,” said senior author Donald Ingber, 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.
This research was supported by DARPA under Cooperative Agreement Number W911NF-19-2-0027, the Margarita Salas postdoctoral grant co-funded by the Spanish Ministry of Universities, and the University of Castilla-La Mancha (NextGeneration EU UNI/551/2021).
