Treatment of Sleep Disordered Breathing With Leptin Loaded Exosomes

Abstract

RationaleSevere obesity leads to two types of sleep disordered breathing, including more prevalent obstructive sleep apnea (OSA), recurrent obstruction of the upper airway during sleep, and obesity hypoventilation syndrome (OHS) caused by impaired central nervous system responses to CO2. Adipokine leptin suppresses food intake, increases metabolic rate, stimulates breathing and ventilatory responses to CO2, and activates pharyngeal muscles improving upper airway patency during sleep. However, diet‐induced obesity (DIO) causes leptin resistance due to reduced permeability of the blood‐brain barrier (BBB) for leptin. Recent work with exosomes as nanocarriers for drug delivery vehicles have shown the possibility of overcoming the BBB to deliver therapeutic agents. We hypothesize that leptin loaded exosomes overcome BBB and treat OSA and OHS in DIO mice.MethodsMale DIO mice (n=6) were head mounted with EEG and EMG leads. Polysomnogram in the barometric plethysmography chamber was performed with IV administration of saline, free leptin, empty exosomes, and leptin loaded exosomes one week apart in a randomized cross‐over manner. Minute ventilation (VE) was measured through sleep/wake states and normalized to body weight. Upper airway obstruction was defined by the presence of inspiratory airflow limitation (IFL), as characterized by an early inspiratory plateau in airflow at a maximum level (VImax) while effort continued to increase.ResultsAs we have shown previously, DIO mice treated with placebo demonstrated upper airway obstruction, especially during REM sleep, and hypoventilation throughout both NREM and REM sleep. Leptin loaded exosomes nearly doubled VImax (p<0.05) and induced an approximately 1.8 increase in VE in REM IFL (p<0.05) compared to the IV saline, IV leptin, and empty exosome groups (Figure 1), suggesting that upper airway obstruction was relieved. In addition, leptin loaded exosomes significantly increased VE during non‐flow limited breathing (p<0.05) compared to all other groups.ConclusionExosomal leptin delivery increased ventilation during both non‐flow limited breathing and flow limited breathing, suggesting a stimulatory effect on control of breathing and upper airway patency. Our results indicate that exosomal leptin can be considered for OSA and OHS pharmacotherapy in obesity.Leptin loaded exosomes presented increased ventilation in diet‐induced obese mice. Maximal inspiratory flow (VImax; mL/s). Minute ventilation normalized to body weight (nVE; mL/min/g).Figure 1