Smoking-cessation drug controls neurons for research

Chemical Switch

Scientists at the Howard Hughes Medical Institute are using Pfizer’s nicotine-addiction drug Chantix as a chemical switch to control neurons. The researchers hope to utilize the drug for precision treatments for neurological disorders, reported Angus Liu in Fierce Biotech.

The team discovered that Chantix (varenicline) is capable of binding to proteins expressed in certain groups of neurons. Then the scientists manipulated targeted neurons in live mice and monkeys and changed the animals’ behaviors, according to a study published in the journal Science. Based on a technique known as chemogenetics, the procedure works by “engineering macromolecules that can interact with particular foreign small molecules to affect the activity of cells,” Liu reported. Typically, in neuroscience, viral vectors that encode those proteins are delivered into specific brain regions. Once they are expressed, they can be exclusively activated by small molecules. They can activate or inhibit neuronal activities.

Because they enable scientists to non-invasively control and study cell signaling in live animals, chemogenetic tools become popular in medical research. Kallyope, a Columbia University spinout company, is using chemogenetics to help map out gut-brain interactions to decipher therapeutic targets in diseases such as Parkinson’s. Coda Biotherapeutics is attempting to develop gene therapies that can be switched on and off as needed.

Some scientists are using G protein-couple receptors (GPCRs), cell-surface receptors responsible for signal transmission, but the small-molecule drugs used to attach to them have shown side effects that raise concerns about human use, according to the authors of the new Science article.

Scott Sternson and other researchers at Howard Hughes created a system based on ion channels. These proteins control electrical signals by gating the flow of ions across cell membranes. In order to determine the best small-molecule partner that is both effective and safe, the Hughes team screened 44 clinically used drugs. Chantix was found to be the best candidate.

Subsequently, the Hughes researchers improved the structure of two ion channel proteins to render them more sensitive to Chantix. The scientists also developed Chantix analogs that are potent and that have improved selectivity. They used the platform in mice to act on GABAergic neurons, which produce the neurotransmitter GABA and are often targeted by scientists to control CNS disorders. The chemogenetic coupling brought about behavioral changes in the mice, as well as in rhesus monkeys.

According to Sternson, “These are the most potent chemogenetic receptors described so far. 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 company, Redpin Therapeutics, which is conducting preclinical studies. The researchers hope the technology’ ability to selectively turn cells on or off could result in more targeted treatments.

Sternson cited some examples. In severe epilepsy patients, drugs targeting problematic neurons could be used as a less invasive alternative to surgery. For pain management, drugs can target an injured area rather than covering the entire body, hopefully reducing addiction to painkillers.

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