Scientists have been using noninvasive methods to selectively control cellular activity in medical research. Now a team led by scientists at the Howard Hughes Medical Institute has identified Pfizer’s nicotine-addiction drug Chantix as a chemical switch that can help control neurons, a system they believe could enable precision treatments for neurological disorders.
After searching through several FDA-approved drugs, the Howard Hughes-led team found that Chantix (varenicline) can bind to proteins expressed in certain groups of neurons. With that knowledge, the scientists successfully manipulated targeted neurons in live mice and monkeys and changed the animals’ behaviors, according to a study published in the journal Science.
The approach is based on a technique known as chemogenetics. It works by engineering macromolecules that can interact with particular foreign small molecules to affect the activity of cells. Usually, in neuroscience, viral vectors encoding those proteins are delivered into specific brain regions. Once expressed, they can be exclusively activated by small molecules and activate or inhibit neuronal activities.
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Chemogenetic tools have gained popularity in medical research, as they can help scientists non-invasively control and study cell signaling in live animals. Columbia University spinout Kallyope, which collected $66 million in series B last February, is using chemogenetics to help map out gut-brain interactions for clues of therapeutic targets in different diseases, including Parkinson’s. Recently launched Coda Biotherapeutics is using the technology in a more direct therapeutic way—to develop gene therapies that can be switched on and off.
One popular method involves G protein-couple receptors (GPCRs), which are cell-surface receptors that are responsible for signal transmission. But so far the small-molecule drugs that have been used to latch onto them have shown side effects that make them inappropriate for human use, according to the authors of the new Science paper.
Scott Sternson and colleagues at Howard Hughes designed a system based on ion channels, which are proteins that control electrical signals by gating the flow of ions across cell membranes. To find the best small-molecule partner that is both potent and safe, the team screened 44 clinically used drugs, and Chantix emerged as the best candidate.
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Then, the researchers improved the structure of two ion channel proteins to make them more sensitive to Chantix. They also designed Chantix analogs that are potent and that have improved selectivity.
In mice, the researchers used the platform to act on GABAergic neurons, which produce the neurotransmitter GABA and are often targeted by scientists to fight CNS disorders. The chemogenetic pair successfully induced behavioral changes in the animals, the team reported. And a similar effect was observed in rhesus monkeys.
“These are the most potent chemogenetic receptors described so far,” Sternson said in a statement.” Even low doses of varenicline—well below the level used for smoking cessation—can have a big effect on neural activity.”
Howard Hughes has licensed Sternson’s platform to a startup called Redpin Therapeutics, which is running preclinical studies. In the future, the researchers hope the technology’ ability to selectively turn cells on or off could lead to more targeted treatments. For example, in severe epilepsy patients, drugs that target problematic neurons could serve as a less invasive alternative to surgery. For pain management, drugs can be sent to an injured area rather than to the entire body, potentially reducing addiction to painkillers, Sternson said.