By Luigi Taranto Montemurro, MD, CSO of Apnimed and David P. White, MD, SVP Medical Affairs, Apnimed

In our first article, we discussed the pressing need for pharmaceutical treatment options to treat obstructive sleep apnea (OSA) and how the complex anatomy and neurobiology underlying OSA have made drug discovery challenging. In this second article in the series, we describe recent advances in understanding the neurobiological components of OSA, and how those advances have moved the needle on developing pharmaceutical treatment options for it.

As we mentioned previously, the anatomy and neurobiology of the upper airway involves about 20 muscles and the nerves that control them. One of these muscles, the genioglossus (tongue muscle), is arguably the most complicated muscle in the body because it plays a major role in how we use the upper airway to breath, swallow and talk.

Everyone can automatically keep their upper airway open while awake. In people with narrow upper airways, the neurobiological system works a bit harder than normal to keep the muscles active and the airway open, though the person has no conscious awareness of this extra effort.

This neurobiological system undergoes changes during sleep. For example, like most body muscles, upper airway dilator muscles such as the genioglossus relax. In people with narrow airways, this drop in dilator muscle activity further reduces the size of the airway, or even allows it to collapse, leading to OSA.

However, we know that not all people with narrow airways develop OSA. Research over the past 15 years has revealed why: three additional traits – upper airway response, arousal threshold, and ventilatory control stability (also called loop gain) – can contribute to the development of OSA when the airway is narrow.1

Let’s look at how each of these traits is involved in OSA.

Responses, arousals and cycles

The upper airway response works by boosting the activity of the pharyngeal dilator muscles after collapse of the upper airway leads to reduced breathing (hypoventilation) and gradually rising levels of carbon dioxide (CO2) in the bloodstream.

If CO2 levels rise beyond a certain point, they trigger a chemoreflex system that increases the effort to breathe (respiratory drive) and activates the dilator muscles in the pharynx to open the airway. The dilator muscles can also be activated by mechanoreceptors in the upper airway that sense the negative pressure in the pharynx caused by increasing ventilatory effort.

If the muscle response opens the airway enough, normal breathing is restored, preventing OSA and allowing stable sleep to continue. However, the upper airway response varies considerably between individuals: in some people, it can compensate for a narrow airway, and no or little OSA ensues; in other people, it is insufficient to compensate for a narrow airway, leading to more severe OSA.

Two other factors related to the upper airway response contribute to whether or not that response is sufficient to keep OSA at bay.

First, the person needs to remain asleep long enough for the dilator muscles to activate and open the airway. If the intensified effort to breathe wakes up the person before the dilator muscles are sufficiently activated – that is, if the individual has a low arousal threshold – the upper airway response does not re-establish adequate ventilation during stable sleep. Instead, the person briefly awakens and then falls back to sleep and starts the cycle of upper airway collapse and response anew.

A second factor is the size of the increased breathing effort induced by elevated blood levels of CO2. If that effort is too large, the resulting hyperventilation can overshoot the mark and drive blood levels of CO2 well below normal. When the chemoreflex system detects these very low levels of CO2, a period of hypoventilation follows, during which the airway can collapse again, triggering another cycle of hyperventilation, low blood levels CO2, and hypoventilation. This cyclic phenomenon is known as unstable ventilatory control or high loop gain – the latter term referring to a feedback loop that causes oscillating, rather than stable, behavior in a physiological system.

This understanding of how the muscle activation in the upper airway response, arousal threshold and loop gain contribute to OSA has opened the door to the possibility of treating the condition with medication that targets one or more of those three traits.

In our next article, we’ll delve into the research that identified two neurological pathways regulating activity in the upper airway muscles during sleep that Apnimed is targeting for the treatment of OSA.




[1] As reviewed in: Taranto-Montemurro L, et al. J Clin Med. 2019;8:1846. doi:10.3990/jcm8111846; and Whyte DP. Sleep Med Clin. 2016;11:203-212. doi:10.1016/j.jsmc.2016.01.007.