Researchers have discovered that an Alzheimer’s medication called donepezil can trigger a safe and reversible state similar to hibernation in tadpoles of the Xenopus laevis species at room temperature. This breakthrough in ‘biostasis’ could provide a method to slow down bodily functions, potentially giving patients more time in emergencies and critical health conditions, especially when they are far from medical facilities.
Scientists from the Wyss Institute for Biologically Inspired Engineering at Harvard University have successfully induced a hibernation-like state in Xenopus laevis tadpoles using donepezil (DNP), which is an FDA-approved drug for treating Alzheimer’s disease. Previously, the team used another drug, SNC80, to achieve similar outcomes in tadpoles and to improve the viability of mammalian hearts for transplant, but SNC80 isn’t approved for human use due to its potential to cause seizures. In contrast, DNP is already utilized in clinical settings, making it a feasible option for repurposing in emergency scenarios to avert irreversible organ damage while transferring a patient to a hospital.
“Lowering a patient’s body temperature to decelerate metabolic functions has been a common practice in medical settings to minimize injuries and long-term complications from severe conditions, but this can currently only happen in well-equipped hospitals,” explained co-author Michael Super, Ph.D., Director of Immuno-Materials at the Wyss Institute. “By achieving a similar ‘biostasis’ state with a readily administered drug like DNP, we could potentially save millions of lives annually.”
This research, published today in ACS Nano, was part of the DARPA Biostasis Program, which funds initiatives aiming to prolong the time available for lifesaving medical care, often referred to as “the Golden Hour,” following traumatic incidents or acute infections. The Wyss Institute has been involved in this program since 2018 and has reached several key objectives over the years.
Leveraging a combination of predictive machine learning algorithms and animal models, the Wyss Biostasis team had previously identified and tested existing drug compounds capable of inducing a suspended animation state in living tissues. Their initial successful candidate, SNC80, showed a notable reduction in oxygen consumption (indicating lower metabolism) in both a beating pig heart and human organ chips, but it has been associated with the side effect of seizures when injected into the bloodstream.
For this latest study, the team employed their algorithm, NeMoCad, again to identify other drugs with structures similar to that of SNC80. Their top selection was DNP, which has been approved for Alzheimer’s treatment since 1996.
“Interestingly, clinical overdoses of DNP in Alzheimer’s patients have shown symptoms akin to drowsiness and a slower heart rate, both of which resemble a torpor state. However, this research appears to be the first focused on using these effects as the primary clinical goal, not merely as side effects,” noted the study’s lead author, María Plaza Oliver, Ph.D., who conducted this work as a Postdoctoral Fellow at the Wyss Institute.
The researchers tested the effects of DNP on X. laevis tadpoles and confirmed that the drug indeed induced a reversible torpor-like state upon its removal. However, it did show some toxicity and tended to accumulate in various tissues of the tadpoles. To address this issue, the researchers encapsulated DNP within lipid nanocarriers, which reduced the drug’s toxicity and resulted in its accumulation in the brain tissue of the animals. This outcome is promising since the central nervous system is known to regulate hibernation and torpor in other species.
Even though DNP has been shown to help protect neurons from metabolic stress in more extensive models of Alzheimer’s disease, the researchers emphasize that additional studies are required to fully comprehend how it induces torpor and to increase the production of the encapsulated DNP for testing in larger animal models and, potentially, humans.
“Donepezil has been used globally by patients for many years, so its characteristics and manufacturing processes are well established. Lipid nanocarriers like those we used have also received clinical approval for various applications. This study provides evidence that an encapsulated formulation of the drug could potentially be developed in the future to give patients critical time to survive severe injuries and illnesses. Moreover, it could be produced on a much shorter timeline than developing a new drug,” stated senior author Donald Ingber, M.D., Ph.D., who serves as the Founding 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.
Other contributors to 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; along with Maria V. Lozano and Manuel J. Santander Ortega from the University of Castilla-La Mancha, Spain.
This research received funding from DARPA under Cooperative Agreement Number W911NF-19-2-0027, along with 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).
