New approaches to the molecular pathogenesis of CCHS: implications for therapeutic strategies

Congenital Central Hypoventilation Syndrome (CCHS), also known as Ondine's Curse, is a very rare neonatal neurological disorder. The main problem in CCHS is a defect in the automatic control of breathing due to a reduced capability to sense oxygen carbon dioxide increase and oxygen decrease in the blood. Affected children hypoventilate (under-breathe) and possibly stop breathing during sleep, with possible very severe neurological damages. CCHS may occur in association with Hirschsprung disease (gut disease) and tumors (neuroblastoma). CCHS is due to a genetic defect in a specific gene (PHOX2B) that affects the development of neurons that regulate the cardiovascular, respiratory and digestive organs early in fetal life. The PHOX2B gene encode for a transcription factor, a protein that is deputed to switch on or switch off the expression of various genes. CCHS is a lifelong disorder, but, as no pharmacological respiratory stimulants have turned out to be effective, assisted ventilation is always required, especially during sleep. The present project intends to define the molecular pathogenetic mechanisms underlying CCHS, with emphasis on the genes whose expression is regulated by PHOX2B, as they may represent potential therapeutic targets. To this aim we also intend to better understand the structure and the functions of PHOX2B. Finally, very recently it has been fortuitously observed that two females patients, using a progestin drug, Desogestrel, for contraceptive purposes, partially ameliorated the clinical symptoms of CCHS. One of the objectives of our project is to study this drug, to identify the molecular targets and the pharmacodynamic mechanisms of Desogestrel in order to develop alternative molecules without contraceptive effects.