Alzheimer’s drug could save lives by creating ‘apparent death’ – Harvard Gazette

Donepezil, an FDA-approved drug to treat Alzheimer's disease, could also be repurposed for use in emergency situations to prevent irreversible organ damage, according to researchers at Harvard University's Wyss Institute for Biologically Inspired Engineering.

Using donepezil (DPN), researchers were able to put tadpoles of the species Xenopus laevis into a hibernation-like state.

“Cooling a patient's body to slow down their metabolic processes has long been used in medicine to reduce injury and long-term problems in severe disease, but currently this is only possible in well-equipped hospitals,” said co-author Michael Super, director of immune materials 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.”

This research, published today in ACS Nano, was funded through 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 participated 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 is known to cause seizures when injected systemically.

In the new study, they used their algorithm again 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, María Plaza Oliver, who was a postdoctoral fellow at the Wyss Institute at the time the work was conducted.

The team studied the effect of DNP on a whole living organism using X. laevis tadpoles and found that it successfully induced a torpor-like state that could be reversed after the drug was removed. However, the drug appeared 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 leads to torpor 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 timeframe than a new drug,” said senior author Donald Ingber, Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital and 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 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).