Therapeutical approaches in Congenital Central Hypoventilation Syndrome (CCHS): the case of the progestin Desogestrel

Congenital Central Hypoventilation Syndrome (CCHS, MIM 209880) is a rare neonatal disease characterized by abnormal ventilatory response to hypoxia and hypercapnia, owing to failure of autonomic respiratory control. Frameshift mutations (5%) and polyalanine triplet expansions (95%) have been detected in the coding region of the transcription factor PHOX2B, responsible for the proper development and function of the autonomic nervous system. Consistent with its role as transcriptional regulator, it is reasonable to suppose that transcriptional dysregulation might be an important mechanism of CCHS pathogenesis. Current research on treatments of CCHS is focused on counteracting the toxic effects of the mutated PHOX2B protein. In particular, drugs promoting the refolding and/or the clearance of mutant protein aggregates have been turned out to be effective in vitro in rescuing the nuclear localisation and transactivation activity of mutants. Another strategy currently under investigation regards the use of progestinic drugs, stemming from the fortuitous observation that progestin can relief some symptoms of the disease. The molecular mechanism of this unexpected pharmacological effect is completely unknown. The importance to understand the molecular mechanisms underlying the chemosensitivity recovery observed after desogestrel assumption relies on the necessity to identify potential pharmacological targets for alternative molecules without contraceptive effects. To this purpose, we have identified, by ChIP-Seq analysis in IMR32, new PHOX2B target gene candidates and show that Desogestrel enhanced the expression of some relevant PHOX2B target genes in a promoter specific manner, by acting on the activity of the wild type as well as mutant protein.