Gene Therapy Improves OSA in Mice

Floppy, untoned muscles in a person’s tongue and airway can block airflow and result in obstructive sleep apnea (OSA). Now, Johns Hopkins Medicine researchers have shown in mice that they can treat the sleep disorder and keep the airway open by using gene therapy to stimulate the nerve that contracts muscles in the tongue.

The researchers say their findings, published online on July 16, 2020, by the American Journal for Respiratory and Critical Care Medicine, ultimately may be translated into therapy for people at greatest risk of death from OSA’s impact, such as those with conditions like stroke or severe atherosclerotic heart disease.

“The tongue muscles that are partly responsible for obstructive sleep apnea have a direct line via a nerve to the area of the brain that controls them,” says senior author Vsevolod Polotsky, MD, PhD, director of sleep basic research and professor of medicine at the Johns Hopkins University School of Medicine, in a release. “Knowing this, we looked for a way to use this pathway in two directions: first, to travel to the control area with gene therapy to make it receptive to drug stimulation, and then once it’s been activated, send a signal back to the tongue to make the problem muscles contract.”

The gold standard for treating the condition is a continuous positive airway pressure (CPAP) machine that provides a steady flow of air to the user during sleep. “However,” Polotsky adds, “only 50% of people adhere to the treatment, so our team has been investigating alternative therapies.”

The tongue has eight pairs of muscles. One of these sets, the genioglossus, is stimulated by the hypoglossal nerve, which runs to it from the medulla, the lowest part of the brainstem. The medulla is connected to the spinal cord and controls involuntary functions, such as breathing and heartbeat. By implanting a pacemaker in the tongue, other researchers have shown that electrical pulses can make the hypoglossal nerve contract the genioglossus and prevent sleep apnea. The problem with this procedure, Polotsky says, is that it requires invasive surgery.

In their study, Polotsky and his team turned to a non-invasive method—an innocuous virus —to deliver laboratory-developed chemical receptors to the brains of obese mice. Once in place within the medulla, these receptors—known as DREADDs (designer receptors exclusively activated by designer drugs)—enable the brain cells in the medulla to accept a synthetic (“designer”) drug. The artificial DREADD receptors remain in the medulla for months after a single tongue injection.

After Polotsky and his colleagues injected the drug under the skin of the obese mice, it traveled up the hypoglossal nerve to the waiting DREADDs and stimulated the brain cells, which in turn activated the nerve to send a return signal to contract the tongue’s genioglossus muscles.

The researchers used magnetic resonance imaging on the sleeping mice to show that their airways opened after delivering the drug, but not in other mice injected with only saline. The researchers also measured six-fold higher electrical activity in the tongue muscles of the drug-treated mice, which indicated the tongue was contracting.

In upcoming mouse studies, the researchers plan to refine the virus delivery system to ensure it only gets designer receptors exclusively activated by designer drugs into the type of brain cells that control the hypoglossal nerve, rather than other nearby neurons. They also will look at the role that other tongue muscles may play in obstructive sleep apnea.

Based on these studies, human trials of DREADDs may follow.

“We believe that if this treatment works in humans, the drug to activate the receptors could be given orally every night and its effects will last about five to six hours,” says research associate Thomaz Fleury Curado, PhD, who led the study, in a release. “Therefore, by the time a person gets up, talking and eating won’t be a problem.”

from Sleep Review https://ift.tt/2WYYXVk