The natural antisense lncRNA PHOX2B-AS1 in the pathogenesis and as potential drug target in Congenital Central Hypoventilation Syndrome (CCHS)

Congenital Central Hypoventilation Syndrome (CCHS) is a rare and devastating neonatal neurological disease characterized by a breathing defect control of the autonomic nervous system, essential during sleep, in association with symptoms of a more generalized autonomic dysfunction. Generally, children with the disease have near-normal breathing when awake, while they hypoventilate during sleep. Since no pharmacological treatment has been found to be effective, mechanical ventilation supports are the only options available for children with this disease. In patients, heterozygous mutations have been identified in the PHOX2B gene, which encodes a transcription factor essential for the development of the autonomic nervous system, which cause the expression of mutated proteins with toxic activity. Bioinformatics analyses and preliminary data allowed us to identify a long non-coding RNA (PHOX2B-AS1), transcribed in the opposite direction and partially complementary to the PHOX2B gene transcript, capable of promoting the production of the PHOX2B protein. Our project aims to evaluate the role of PHOX2B-AS1 in the pathogenesis of CCHS and the effects of its modulation on the expression of normal and mutated proteins. To pursue this goal, we will use human neuronal cultures differentiated from stem cells obtained by reprogramming fibroblasts from CCHS patients. The results of this research will allow us to evaluate whether PHOX2B-AS1 can be identified as a new therapeutic target for the treatment of CCHS.