DREADD receptors have reached clinical trials: a gene marks neurons, and clozapine changes their activity
DREADD receptors have reached clinical trials: a gene marks neurons, and clozapine changes their activity
On August 14, Chemical & Engineering News reported at least seven Chinese clinical trials of therapies based on engineered receptors. The indications include epilepsy, Parkinson's disease, and neuropathic pain. Two public registries show the same approach being applied to different brain circuits.
“Stunned silence” was how pharmacologist Bryan Roth described his colleagues' reaction when he told them about the human trials. Twenty years ago, Roth developed DREADDs, engineered receptors that neuroscientists used in experiments to alter the activity of selected nerve cells. The same method is now being tested in the first patient protocols.
A genetic address provides the selectivity. A viral vector delivers a gene to a small group of neurons, instructing the cells to produce the engineered inhibitory receptor hM4Di. This receptor is particularly sensitive to clozapine. When the patient takes the drug, the receptor reduces signaling in the marked cells. The gene therefore determines which cells respond to clozapine.
The same combination underlies a protocol for Parkinson's disease. Six participants are scheduled to receive an AAV-vector, a type of viral vector, carrying hM4Di into both subthalamic nuclei, which are deep brain structures. Investigators will then determine an individual clozapine dose for each participant. The registry lists this early phase 1 study as not yet recruiting. In a neuropathic pain study that is already recruiting participants, the hM4Di gene is delivered to the anterior cingulate cortex, a brain region involved in pain processing. Investigators then determine and maintain a fixed oral dose of clozapine.
This is how DREADDs are moving from the laboratory into clinical research. Previously, an engineered receptor helped researchers test the role of a specific neural circuit. Now, the genetic address, the receptor, and clozapine are being used together to alter the function of a selected circuit in a patient. These early trials are assessing the safety and tolerability of this approach.