The regulation of central respiratory drive by progestins alone or in combination with serotoninergic and orexinergic drugs, a therapeutic perspective for the treatment of central hypoventilations? – ProgestVentil

Central hypoventilations encompass several neuro-respiratory diseases that result from neurologic disorders. The cause of central hypoventilations may be congenital or acquired. Hypercapnia, acidosis and hypoxemia which result from central hypoventilations have deleterious effects on cardiovascular and neurocognitive functions, neurocognitive outcome and long-term quality of life. Hypoventilation expose patients on high risk of death. Patients suffering from central hypoventilations do not respond to conventional respiratory stimulants. There is no effective pharmacotherapy, artificial ventilation is the only available treatment all the lifelong of these patients. It can be delivered either as positive pressure ventilation via a tracheotomy or a mask, as phrenic nerve pacing, or as negative pressure ventilation via a cuirass shell. Therefore, new approaches to provide pharmacological treatments are needed.

The general aim of the present proposal is to examine whether the pharmacological manipulation of progesteronergic systems with drugs of the gonane family alone or in combination with drugs targeting the serotoninergic and orexinergic systems could constitute a pharmacological therapeutic perspective for congenital or acquired central hypoventilation syndromes. The proposal is based mainly on recent data of the project’s participants which have now paved the way for exploring an original hypothesis in collaborative investigations. We have already published data that highlight the interest to work on the specific family of progestin, the gonanes. Indeed, while progesterone, known to have some hyperventilatory effects, does not correct the central hypoventilations, the desogestrel, a progestin, could unveil latent chemosensitive neural circuits in patient suffering of central alveolar hypoventilation syndrome. However, another clinical report, also in central alveolar hypoventilation syndrome patient, does not report any recovery of the CO2/H+ chemosensitivity. These contrasting findings may be due to either the complexity of the progestin action or idiosyncrasies of patients or both. To better understand the action mechanisms of the progestin of the gonane family, it is thus fundamental to evaluate the conditions under which patients suffering of central hypoventilation may benefit from these progestins. In such a context, our proposal is multiple with a major feature: by acting on progesteronergic systems, we aim at activating respiratory pathways able to compensate the functions that are defective in central hypoventilation syndromes. By multiple tracts, notably in a translational way by comparative links between human and rodent investigations, we will work on progesteronergic systems and also on serotoninergic and orexinergic systems. Serotoninergic and orexinergic systems are chosen on the basis of preliminary results we recently obtained in rodents. The project will be conducted along basic and clinical studies structured around fours Tasks, i) an epidemiologic study of respiratory impact of the progestins of the gonane family consumption in central hypoventilation syndrome patients, ii) a characterization of the mechanisms by which progestins of the gonane family facilitate the respiratory drive in rodent, iii) an evaluation of the ability of progestins of the gonane family alone or combined with drugs targeting the serotoninergic and orexinergic systems to reverse hypoventilation in congenital central alveolar hypoventilation syndrome mouse models, and iv) evaluation of the ability of progestins of the gonane family alone or combined with serotoninergic drugs to reverse hypoventilation in CHS patients.

As a whole, the expected data should provide the necessary knowledge to evaluate the conditions under which progestins of the gonane family could be used as a pharmacological treatment of central hypoventilation syndromes.