First Human Trials of Chemogenetic DREADD Therapies in China Stun US Neuroscientists
核心洞察
At least seven clinical trials in China are testing chemogenetic DREADD therapies in humans for the first time, targeting intractable epilepsy (搜索), Parkinson's disease (搜索), and trigeminal neuropathic pain (搜索).
The trials use an AAV-delivered inhibitory receptor (hM4Di (搜索)) activated by low-dose clozapine, offering a reversible, drug-titratable alternative to surgical brain resection.
Inventor Bryan Roth disclosed the findings at an NIH BRAIN Initiative meeting, where the reaction was described as "stunned silence."
At least seven clinical trials in China are now testing chemogenetic therapies in humans for the first time, a development that left US neuroscientists in "stunned silence" when it was disclosed this week at a US National Institutes of Health Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative meeting in Bethesda, Maryland.
The disclosure came from Bryan Roth of the University of North Carolina School of Medicine (搜索), who developed the chemogenetic technology twenty years ago. The approach is based on "designer receptors activated by designer drugs," or DREADDs — engineered proteins that respond to a small-molecule drug with extraordinary sensitivity. Roth told attendees about at least seven registered trials in China investigating intractable epilepsy (搜索), Parkinson's disease (搜索), and neuropathic pain.
How DREADDs Work
DREADDs are a family of chemogenetic tools — engineered versions of human G protein-coupled receptors (GPCRs) that no longer respond to their natural neurotransmitter but instead bind with picomolar affinity to an otherwise inert synthetic drug. The concept was pioneered in 2007 by Roth, who mutated human muscarinic acetylcholine receptors so they lost affinity for acetylcholine and gained picomolar affinity for synthetic ligands.
The therapy has two essential parts: a gene delivery step and a drug activation step. Researchers package the gene encoding the inhibitory DREADD hM4Di (搜索) into an adeno-associated virus (AAV) vector, which is injected directly into the disease-relevant brain region using stereotactic neurosurgery. Once infected, those neurons manufacture the designer receptor and insert it into their membranes, where it remains inert until the drug arrives.
The Chinese trials use the original pairing: hM4Di (搜索) activated by clozapine, an atypical antipsychotic normally dosed at 300 to 600 mg per day for schizophrenia. For DREADDs, effective doses are orders of magnitude lower because hM4Di binds clozapine with approximately 10,000-fold greater selectivity than native receptors. When clozapine binds hM4Di, the Gi signaling cascade hyperpolarizes the neuron via GIRK channels and suppresses presynaptic neurotransmitter release, dropping firing in that circuit for several hours after a single oral dose.
A More Precise Knife
Dirk Trauner, a biochemist at the University of Pennsylvania who works on optogenetics, a related technology, says DREADDs offer "a more precise knife" that could theoretically have reduced side effects compared with other approaches. Small molecules targeting endogenous receptors can have off-target effects when those receptors are expressed elsewhere in the brain or when the molecules trigger closely related receptors; in contrast, DREADDs appear only where they are introduced.
Unlike optogenetics, which requires a permanent intracranial implant, laser, and tether, chemogenetics uses an oral drug with no light hardware needed. The viral transgene can express for years, potentially a decade, but the silencing effect lasts hours per dose and is reversible — stop the drug and neuronal signaling normalizes. That reversibility is a key advantage over irreversible surgical lesions.
The Seven Chinese Trials
About two months ago, a rumor that designer proteins were being used to treat brain disease prompted Roth and a postdoctoral scholar to search clinical trial registries in the United States and China. They found seven studies. Three of the DREADD trials use an adeno-associated virus as a vector to deliver the chemogenetic therapy.
The trials target three indications. Intractable epilepsy (搜索) trials aim to target the epileptogenic focus as an alternative to surgical resection of brain tissue. Parkinson's disease (搜索) trials use AAV via stereotactic surgery to the subthalamic nucleus (STN), aiming to suppress pathological STN hyperactivity without deep brain stimulation hardware. Trigeminal neuropathic pain (搜索) trials target the trigeminal pain circuit.
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.
Safety Considerations
Gene therapies using viruses 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.
Clozapine's own pharmacology presents additional considerations. At antipsychotic doses, clozapine blocks dopamine D4, serotonin 5-HT2A, histamine H1 and muscarinic receptors, causing sedation, hypotension, and, rarely, agranulocytosis. The chemogenetic strategy depends on using 100- to 1,000-fold lower doses to stay below these thresholds.
The irreversibility of gene expression is another concern. Unlike a pill that washes out, AAV-delivered DREADDs persist. If unwanted silencing causes adverse circuit effects, clinicians cannot simply remove the receptor — they can stop the drug, but the protein remains.
Clinical Significance
Roth identifies the study with the greatest potential as the one focusing on trigeminal neuropathic pain (搜索), 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.
Jacques Carolan, a neuroscientist at University College London who was at the BRAIN Initiative meeting, posted on X: "If we needed more evidence that China is ahead in neuro, this is it."
Investigators listed in the registries have not yet responded to requests for comment, and no efficacy or safety results have been published as of August 2026. Roth noted that over the years, people approached him to commercialize the technology, but "there were all these barriers. I think nobody wanted to take the risk."