FDA-approved Alzheimer’s drug could save lives by inducing a state of “suspended animation”

Researchers at Harvard University’s Wyss Institute for Biologically Inspired Engineering have discovered a potential life-saving use for donepezil (DNP), a drug already approved by the FDA for treating Alzheimer’s disease.

Their study, published in ACS Nano, demonstrates how DNP can induce a torpor-like state in Xenopus laevis frog tadpoles, mimicking a form of hibernation. This could one day help prevent irreversible organ damage during emergency medical situations, extending the critical “Golden Hour” after traumatic injury.

The idea of slowing the body’s metabolic processes to reduce injury is not new. Cooling patients to induce a similar state of biostasis has been used in hospitals for years, but it requires specialized equipment that is not always available in less-equipped medical settings.

According to Michael Super, Ph.D., Director of Immuno-Materials at the Wyss Institute, this new approach could offer a more accessible solution. “Achieving a similar state of ‘biostasis’ with an easily administered drug like DNP could potentially save millions of lives every year,” said Super.

This research builds on previous work by the Wyss Institute, which is part of the Defense Advanced Research Projects Agency (DARPA) Biostasis Program. The goal of the program is to extend the window for life-saving treatment after injury or infection.

Since joining the program in 2018, the Wyss Institute has made several strides toward this goal, using machine learning algorithms and animal models to identify drug compounds that might suspend biological processes.

Initially, the team had success with a drug called SNC80, which reduced metabolic activity in mammalian hearts and human organ chips. However, SNC80 can cause seizures, making it unsuitable for human use. Seeking alternatives, the researchers used their predictive machine learning tool, NeMoCad, to search for other compounds.

DNP emerged as a top candidate. Approved since 1996 to treat Alzheimer’s, it had shown side effects in clinical overdoses, such as drowsiness and a slower heart rate, which are similar to the signs of torpor. This hinted that DNP might be repurposed for biostasis.

“We know DNP can protect neurons from metabolic stress in models of Alzheimer’s disease,” explained María Plaza Oliver, Ph.D., the study’s first author. “But this is the first study to explore leveraging its torpor-like effects as the main clinical response, rather than a side effect.”

To test this hypothesis, the researchers administered DNP to X. laevis tadpoles and observed that it did, in fact, induce a reversible torpor-like state. However, they also noted a drawback—the drug was toxic at certain levels and accumulated throughout the animals’ tissues.

To address this issue, they encapsulated DNP inside lipid nanocarriers, which not only reduced toxicity but also caused the drug to accumulate in brain tissue, an encouraging result since the central nervous system plays a role in hibernation and torpor.

This advance in the encapsulation of DNP is key to making the drug a viable treatment for emergency biostasis. The lipid nanocarriers that the team used are already approved for clinical use in other medical applications, meaning the encapsulated version of DNP could be scaled up for use in larger animals and potentially humans with relative ease.

Donald Ingber, M.D., Ph.D., Founding Director of the Wyss Institute and senior author of the study, is optimistic about the potential future applications of DNP. “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,” Ingber said. “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.”

While the research is promising, more work remains. The team will need to further investigate exactly how DNP induces torpor, as well as scale up production of the encapsulated version for larger animal models and, eventually, human trials. Still, the prospect of using a well-established drug like DNP to significantly extend the window for lifesaving medical treatment offers a tantalizing possibility for emergency medicine in the future.

This breakthrough is the culmination of efforts by a large team of scientists. Among them are former Wyss members Erica Gardner, Takako Takeda, Shruti Kaushal, 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 collaborators Maria V. Lozano and Manuel J. Santander Ortega from the University of Castilla-La Mancha in Spain.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

Like these kind of feel good stories? Get The Brighter Side of News' newsletter.