Neonatal Gene Therapy Attenuates Chondrocyte Maturation in Craniofacial Dysplasia

Objectives: To characterize the cellular and molecular mechanisms underlying craniofacial dysplasia in vivo, with particular emphasis on the developmental window during which a genetic anomaly can impair skeletogenesis. Methods: The Sandhoff disease mouse, harboring a targeted deletion of the HexB locus, was employed as a model of craniofacial dysplasia. Results: HexB deficiency impaired chondrocyte maturation and differentiation ultimately affecting the craniofacial skeleton. Moreover, neonatal restitution of the attendant genetic anomaly at postnatal day P4 ameliorated chondrocytic maturation and restored craniofacial morphology in vivo. PTHrP and COX-2 were also implicated as important factors in craniofacial skeletogenesis and as possible factors underlying the development of observed defects. Conclusion: HexB deficiency impairs skeletogenesis during postnatal development by accelerating chondrocyte maturation in the cranial base synchondroses, an anomalies that can be treated by the neonatal administration of a therapeutic vector.