RNA-based downregulation of PHOX2B expression as a putative CCHS therapeutic

Congenital Central Hypoventilation Syndrome (CCHS) is a rare life-threatening neurological disorder that is characterized by compromised chemosensitivity and inadequate autonomic control of breathing. The cause is mainly attributed to de novo heterozygous polyalanine repeat expansion mutations (PARMs) in Paired-like homeobox 2b (PHOX2B). PHOX2B is a gene that plays a key role in regulating the development of the autonomic nervous system. So far, there are no therapies available for treating CCHS. A recent study, conducted on patient-derived autonomic neurons, revealed that PARMs induce a toxic gain of function, leading to cell death among PHOX2B-expressing cells. In addition, clinical observations have reported that two CCHS patients, utilizing the synthesized progestin as a contraceptive, exhibited amelioration of respiratory symptoms. Subsequent studies showed that this synthetic progestin downregulates PHOX2B expression both in cell and rat models. Together, these studies suggest that reducing PHOX2B expression could be clinically beneficial for CCHS patients. In this study, we are developing antisense oligonucleotides (ASOs) to downregulate PHOX2B expression that might alleviate the respiratory symptoms in CCHS patients. To further explore their clinical relevance, lead ASOs are being tested in disease iPSC-derived autonomic neurons that express PHOX2B endogenously and in mice models. Our research has the potential to advance the development of innovative therapeutic strategies for CCHS, effectively alleviate symptoms and improve disease management.

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Collaboration with Prof. Gad Vatine, BGU and Dr. Avital Adato, "Yad LaNeshima"

Funded by the Ministry of Innovation, Science & Technology (MOST)