Identification of new therapeutic candidates for Congenital Central Hypoventilation Syndrome

Congenital central hypoventilation syndrome (CCHS), a rare genetic disease caused by heterozygous PHOX2B mutations, is characterized by life-threatening breathing deficiencies. PHOX2B is a transcription factor required for the specification of the autonomous nervous system that contains respiratory centers. To date, the only treatment offered to patients is mechanical ventilatory support. Therefore, identifying molecules with potential alleviating effects is of prime importance. A transcriptomic dataset from cells transiently expressing both wild type and variant PHOX2B allowed to run the CMap online tool and to identify, using in vitro models, drug compounds capable of relocating PHOX2B mutated proteins in the nucleus and restoring proper regulation of PHOX2B target gene expression. Subsequently, we tested the most efficient molecule ex vivo on hindbrain preparations isolating the principal components of the central respiratory command. Our results provide evidence that the HDAC inhibitor Vorinostat, also known as SAHA, is a promising molecule for the treatment of CCHS Overall design: To identify drugs of interest for CCHS, SK-N-BE cells were plated in triplicate, transfected with constructs expressing wild-type or mutant PHOX2B proteins, and treated with vehicle (DMSO) or 17-AAG.