Китайские ученые впервые провели клинические испытания терапии на основе химогенетических рецепторов для лечения заболеваний мозга

News The latest chemistry news, including important research advances, business and policy trends, chemical safety practices, career guidance, and more. Read More “Stunned silence.” That’s how Bryan Roth of the University of North Carolina School of Medicine described the mood at a US National Institutes of Health Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative meeting in Bethesda, Maryland, this week when he told fellow attendees about at least seven clinical trials in China that are testing chemogenetic therapies in humans. Twenty years ago, Roth developed the chemogenetic technology the trials are using, which is based on a group of proteins called “designer receptors activated by designer drugs,” or DREADDs. Designer drug is a bit of a misnomer in this case; the receptor being used in the Chinese trials responds to a small-molecule drug, clozapine, used to treat schizophrenia. But the designer receptor is much more sensitive to the drug than any human receptor, binding to it with picomolar affinity. A researcher can introduce the gene encoding the receptor protein to a small group of neurons using a viral vector. Then, when the receptor is expressed and binds to the drug, it suppresses neuronal signaling in those cells and any brain circuits they belong to. Dirk Trauner, a biochemist at the University of Pennsylvania who works on optogenetics, a related technology, says that DREADDs offer “a more precise knife” that, theoretically, could have reduced side effects compared with other approaches. Small molecules targeting endogenous receptors can have off-target effects when those receptors are expressed in other parts of the brain or when the molecules trigger closely related receptors; in contrast, DREADDs appear only where they are introduced. The designer receptors have become a widespread research tool in neuroscience, where they have enabled researchers to alter brain circuits’ activity. But until now, they have not been used in the clinic. “Over the years, folks have approached me to commercialize the technology, but there were all these barriers,” Roth says. “I think nobody wanted to take the risk.” About 2 months ago, a rumor about designer proteins being introduced to treat brain diseases sent Roth and a postdoctoral scholar looking in clinical trial databases in the US and China. They found seven studies, which investigate intractable epilepsy, Parkinson’s disease, and neuropathic pain. For several of the diseases in question, the therapy of last resort is to remove a portion of the brain, Roth points out. Chemogenetic treatment might avoid that, though if the treatment ended up having unwanted side effects, trial patients might seek relief through surgery after all. Three of the DREADD trials use an adeno-associated virus as a vector to deliver the chemogenetic therapy. Gene therapies using viruses, such as these, carry the risk of serious, sometimes fatal immune reaction. Several people died recently in early-stage gene therapy trials in China. But Roth points out that six of the studies appear to have begun some months after the first epilepsy trial began, suggesting that investigators might have started after getting some indication that the gene therapy may be safe. Jacques Carolan, a neuroscientist at University College London who was at the BRAIN Initiative meeting, posted on X on Friday, “If we needed more evidence that China is ahead in neuro, this is it.” C&EN has reached out for comment to the investigators of record on the clinical trials. According to Roth, the study with the greatest potential focuses on trigeminal neuropathic pain, which can be debilitating enough that it is a risk factor for suicide. “If that trial is successful, then it opens the way basically to circuit-based therapeutics for virtually all neuropsychiatric diseases,” he says.