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

Abstract

Geleophysic dysplasia (GD) is a rare genetic disorder characterized by severe cardiorespiratory dysfunction and poor prognosis. With no cure available, current treatments focus on symptomatic management. Using a cellular model of ADAMTSL2 p.A165T variant, our screening of 2,321 FDA-approved drugs identified several glucocorticoids, particularly betamethasone dipropionate (BMD), which significantly enhance secretion of two crucial proteins for GD, ADAMTSL2 and FBN1 while improving 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 only 60% 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 significantly improved survival rates to 80% and 69%, respectively. These findings suggest that BMD offers a promising therapeutic approach to prevent early mortality in GD patients.