XGR-101 for Treatment of Rett syndrome

XGR-101 is an AAV9-delivered miREX X-reactivation therapy for the treatment of X-linked genetic disorders. In our lead program, we are developing the technology for the treatment of Rett syndrome.

Rett syndrome is a neurodevelopmental disorder affecting approximately 1 in 10,000 females. Clinical manifestations typically appear between 6 to 18 months of age and consist of deficits in areas including speech, purposeful hand movements, walking, eating, and breathing. Rett syndrome is often accompanied by repetitive hand movements such as hand wringing and clapping. There is currently no cure for Rett syndrome, and available therapeutics mainly manage symptoms and are not disease-modifying. Progressive decline in motor and cognitive functions continues after symptom onset, with breathing dysfunction as a leading cause of morbidity and premature mortality.

The underlying cause of Rett syndrome is a loss-of-function mutation of the MeCP2 gene. In females, XGR-101 partially reactivates the silenced X chromosome in each cell. This allows the production of fully functional MeCP2 protein from the previously silenced healthy X chromosome in cells with an active X chromosome carrying the mutated MeCP2. Importantly, XGR-101 does not cause MeCP2 overexpression in cells where a healthy copy of MeCP2 is active, as the silent chromosome will carry the non-functional gene. Reactivation leading to the expression of functional MeCP2 with XGR-101 significantly slowed the progression of phenotypic abnormalities, including cognitive and breathing-related symptoms, in a severe mouse model of the disease.