The role of the nervous system in craniofacial development remains controversial. An interesting body of evidence suggests that the nervous system is important in craniofacial development. Clinically, patients suffering from inherited lysosomal storage diseases often exhibit growth impairment, skeletal abnormalities, craniofacial malformations, and mental retardation. Histopathologically, neurons of the brain, trigeminal and spinal root ganglia display swollen vacuolated perikarya stored with excessive amounts of complex macromolecules. The associated formation of meganeurites and collateral synapses appears responsible for the onset and progression of neuronal dysfunction in neuronal storage disorders by altering electrical properties and modifying integrative operations of somatodendritic synaptic inputs. Based on these observations, the applicant hypothesizes that normal neuronal function is required for craniofacial development, and the neuronal dysfunction or loss seen in lysosomal storage diseases is responsible for aberrant craniofacial development. To address this hypothesis, the applicants will employ an animal model with severe craniofacial dysostosis, growth retardation and facial dysmorphism, associated with excessive neuronal storage of mucopolysaccharides and GM2 gangliosides due to lack of B-hexosaminidase (hexA / lhexB double knockout mice). The investigator proposes that restitution of B-hexosaminidase in the neurons of these mice will avert neuronal dysfunction and prevent the development of craniofacial malformations. The investigators propose to determine whether neuronal function is required for normal craniofacial development in these mice by conditionally restoring B-hexosaminidase activity in neurons during critical development periods. These results would also establish the critical developmental window during which gene therapy can effectively be employed in the treatment of inherited lysosomal storage disorders.
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