Harvard researchers discover new life-saving potential in Alzheimer's drug

New research on tadpoles shows that the FDA-approved drug donepezil induces a reversible, torpor-like state in the animals.

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University have succeeded in inducing a hibernation-like state of rest in Xenopus laevis Tadpoles with donepezil (DNP), an FDA-approved drug for the treatment Alzheimer Illness.

The team had previously used another drug, SNC80, to achieve similar results in tadpoles and improve the survival of whole mammalian hearts for transplant. However, 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 its metabolic processes has long been used in medicine to reduce injury and long-term problems in severe disease, but currently it is only possible in well-equipped hospitals,” said co-author Michael Super, Ph.D., director of immune materials at the Wyss Institute. “Achieving a similar state of 'biostasis' with an easily administered drug like DNP could potentially save millions of lives each year.”

Research supported by DARPA

This study published today ACS Nanowas supported within the framework of the DARPA The Biostasis program 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.

Through a combination of predictive machine learning Using 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 a known side effect of 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.

Clinical observations and new research

“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 around the world for decades, so its properties and manufacturing processes are well established. Lipid nanocarriers similar to the ones we used are now approved for clinical use in other applications as well. 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 lead author Donald Ingber, MD, Ph.D.

Reference: “Donepezil nanoemulsion induces a torpor-like state with reduced toxicity in non-hibernating Xenopus laevis tadpoles” by Maria Plaza Oliver, Erica Gardner, Tiffany Lin, Katherine Sheehan, Megan M. Sperry, Shanda Lightbown, Manuel Ramsés Martínez, Daniela del Campo, Haleh Fotowat, Michael Lewandowski, Takako Takeda, Alexander C. Pauer, Shruti Kaushal, Vaskar Gnyawali, Maria V. Lozano, Manuel J. Santander Ortega, Richard Novak, Michael Super, and Donald E. Ingber, August 21, 2024, ACS Nano.
DOI: 10.1021/acsnano.4c02012

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).