FDA-approved Alzheimer's drug causes torpor-like condition in tadpoles

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University report that they have succeeded in educating tadpoles of Xenopus laevis to put 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 transplant, but SNC80 is not approved for clinical use in humans because it can trigger seizures. In contrast, DNP is already used in the clinic, meaning it could potentially be quickly repurposed for use in emergency situations to prevent irreversible organ damage while a person is being transported to a hospital.

“Cooling a patient's body to slow down their metabolic processes has long been used in the medical setting to reduce injuries and long-term problems due to serious illness. However, this is currently only possible in well-equipped hospitals,” said co-author Dr. Michael Super, head of the Immunomaterials Department at the Wyss Institute.

Achieving a similar state of 'biostasis' with an easily administered drug such as DNP could potentially save millions of lives each year.”

Michael Super, Ph.D., Director of Immunomaterials, Wyss Institute

This study published today ACS Nanowas supported under the DARPA Biostasis program, which funds projects aimed at extending the time for life-saving medical treatments, 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's Biostasis team has identified and tested existing drug compounds that have the potential to put living tissue into a state of suspended animation. Their first successful candidate, SNC80, significantly reduced oxygen consumption (an indicator of metabolism) in both a beating pig heart and human organ chips, but has the well-known side effect of causing seizures when injected systemically.

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

“Interestingly, clinical overdoses of DNP in patients with Alzheimer's disease have been associated with drowsiness and reduced heart rate – symptoms reminiscent of freezing. However, to our knowledge, this is the first study to focus on using these effects as the main clinical response rather than as side effects,” said the study's lead author, Dr. María Plaza Oliver, who was a postdoctoral fellow at the Wyss Institute at the time the study was conducted.

The team used X. laevis Tadpoles to study the effect of DNP on a whole living organism and found that it successfully induced a torpor-like state that could be reversed after the drug was removed. However, the drug seemed to cause some toxicity and accumulated throughout the animals' tissues. To overcome this problem, the researchers encapsulated DNP in lipid nanocarriers and found that this both 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 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 freezing, and to scale up production of the encapsulated DNP for use in larger animals and potentially humans.

“Donepezil has been used by patients worldwide for decades, so its properties and manufacturing processes are well established. Lipid nanocarriers similar to the ones we used are now 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 diseases, and it could be easily formulated and produced at scale in a much shorter time frame than a new drug,” said senior author Donald Ingber, MD, Ph.D. Ingber is founding director of the Wyss Institute, which Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital and the Hansjörg Wyss Professor for Bioinspired Engineering at the John A. Paulson School of Engineering and Applied Sciences at Harvard.

Other authors of the paper include former Wyss members Erica Gardner, Takako Takeda, Shruti Kaushal, Vaskar Gnyawali, and Richard Novak; current Wyss members Tiffany Lin, Katherine Sheehan, Megan Sperry, Shanda Lightbown, Ramsés Martínez, Daniela del Campo, Haleh Fotowat, Michael Lewandowski, and Alexander Pauer; and Maria V. Lozano and Manuel J. Santander Ortega of the University of Castilla-La Mancha, Spain.

This research was supported by DARPA under the collaboration agreement no. W911NF-19-2-0027, the Margarita Salas Postdoctoral Fellowship co-funded by the Spanish Ministry of Universities and the University of Castilla-La Mancha (NextGeneration EU UNI/551/2021).