Glucocorticoid treatment rescues early lethality in a mouse model of geleophysic dysplasia

Abstract

Geleophysic dysplasia (GD) is a rare genetic disorder characterized by severe cardiorespiratorydysfunction and poor prognosis. With no cure available, current treatments focus on symptomaticmanagement. Using a cellular model of ADAMTSL2 p.A165T variant, our screening of 2,321 FDAapproved drugs identified several glucocorticoids, particularly betamethasone dipropionate (BMD),which significantly enhance secretion of two crucial proteins for GD, ADAMTSL2 and FBN1 whileimproving extracellular matrix organization. In a mouse model carrying the Adamtsl2 p.A165T variant,we observed a high early mortality rate, mirroring the short lifespan seen in GD patients. Around only60% of homozygous p.A165T mice survived beyond two days after birth, while hemizygous p.A165T/-mice had an even lower survival rate of 40%. Notably, BMD administration at birth significantlyimproved survival rates to 80% and 69%, respectively. These findings suggest that BMD offers apromising therapeutic approach to prevent early mortality in GD patients.