Scientists at the Howard Hughes Medical Institute are using an FDA-approved anti-smoking drug as a chemical switch that allowed them to turn specific populations of neurons on and off in live rodents and a primate. The chemogenetics technology involves inserting engineered ion channel proteins into targeted neurons, and then administering the drug, varenicline, which binds to the channels to control neuronal signaling.
Chemogenetics is being used to help study brain circuitry, but therapeutically relevant systems could one day lead to the development of targeted treatments for pain and diseases including epilepsy. Initial tests by the HHMI team provided proof of principle that their system can both silence and activate neurons and have a behavioral impact. “It’s still many steps to the clinic, but we’re trying to shorten that route,” commented research lead Scott Sternson, PhD, a group leader at the Howard Hughes Medical Institute’s Janelia Research Campus. Sternson and colleagues report on their development in Science, in a paper titled, “Ultrapotent chemogenetics for research and potential clinical applications.”
Scientists have been working on chemogenetics approaches to controlling cellular activity for the last 20 years or so. The general strategy targets exogenous receptors to specific cell populations. The receptors can then control the functioning of that cell type, but only when activated by a selective compound or drug. Current methods tested in live animals have demonstrated drawbacks, however, including the lack of effective activating compounds. “… existing small molecule agonists show insufficient potency or selectivity,” the authors wrote. Current systems would also not be suitable for clinical use. “There is also need for chemogenetic systems compatible with both research and human therapeutic applications … human therapies would be facilitated by chemogenetic receptors that are potently activated by existing clinically approved drugs.”
For their reported chemogenetics technology the researchers turned to ion channel proteins, which directly influence neuronal activity, and so would be less likely to lead to side effects. Searching through dozens of already-approved drugs to find potential agonists of the ion channels, they identified varenicline, which was both selective and highly active at very low concentrations.
Varenicline was an ideal agonist candidate for chemogenetic applications in the central nervous system, as an already approved drug it is also well tolerated by patients at low doses, can easily penetrate the brain, and doesn’t easily bind to plasma proteins, the researchers pointed out. They slightly modified the structure of the varenicline compound to generate what they called ultrapotent pharmacologically selective effector molecules (uPSEMs) and tweaked the structures of the two selected ion channel proteins to improve the modified varenicline binding. One was triggered to fire when the varenicline uPSEMs bound. The other ion channel switched off neuronal signaling in the presence of varenicline. “These are the most potent chemogenetic receptors described so far,” Sternson said.
The researchers then used techniques including in vivo electrophysiology, calcium imaging, positron emission tomography, and behavioral efficacy testing to demonstrate that their chemogenetics platform actively modulated the activity of target neurons in rodent models and in a rhesus monkey.
The effectiveness, ease of use, and targeted nature of chemogenetics have made the approach attractive for clinical applications, the authors pointed out. The technology uses only a limited repertoire of drug/receptor pairs, but can achieve different therapeutic effects by targeting receptors to different regions. “This offers a model for therapy that circumvents the pharmacological complexity of protein target identification followed by drug development for each new target.” And as part of their experimental set the team demonstrated chemogenetic activity in two regions of the brain that are already the targets of invasive deep brain stimulation therapies for Parkinson’s disease.
Another potential benefit of the new chemogenetic system for therapeutics is that uses a well-tolerated, approved drug, which could potentially be applied at even lower doses than those for which it is currently sanctioned.
The authors acknowledged that more research will be needed to confirm the long-term safety and effectiveness of chemogenetic receptors for therapeutic applications, but conclude that their system using the described receptors and varenicline uPSEMs offer “opportunities in basic research and the capability for extending findings to potential therapeutic applications.”
Sternson is one of the co-founders of Redpin Therapeutics, which has an exclusive global license from HHMI to the therapeutic applications of the platform, and is continuing preclinical research.