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Barry J. Byrne M.D., Ph.D. - "Gene Therapy Strategies for Inherited Myopathies"

Child Health Research Institute, UF Powell Gene Therapy Center, University of Florida, College of Medicine, USA
When May 02, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
Pompe disease results from a deficiency or absence of the lysosomal enzyme acid alpha glucosidase (GAA), resulting in lysosomal accumulation of glycogen which impacts striated muscle and motorneurons.  The weakness observed in patients is a manifestation of the cellular changes which include alterations in the neuromuscular junction (NMJ).  Cardiorespiratory failure is the leading cause of morbidity and mortality in Pompe patients.  We have investigated the utility of AAV vectors expressing GAA to restore lysosomal function in several non-clinical studies a phase I/II study in ventilator-dependent and independent pediatric Pompe patients. In a series of preclinical studies, we have found that restoration of GAA activity in muscle and neural tissue is able to reverse ventilatory insufficiency by reversing motor neuron dysfunction and restoring the integrity of the NMJ.  The principle defect in the motor unit is related to deficiency of NMJ structure and function.  
New evidence also indicates the need for early intervention related to neural dysfunction since motor neurons show evidence of apoptosis in the murine and canine model of Pompe disease.  These deficits are present early in the mouse model and restoration of GAA activity in the muscle and neurons before 6 months of age leads to restoration of in situ force production.  After 18 months of age, the loss in motor neurons leads to permanent deficits in force production of the tibialis anterior.  
Nine children were studied in the first Pompe gene therapy trial and all subjects have undergone one year of follow up.  All children had improvement in spontaneous ventilatory endurance from baseline to the one-year study endpoint.  Additionally, findings related to immune management pave the way to the current clinical studies in adults and younger subjects who are candidates for systemic admiration of a next-generation AAV vector delivered systemically.  The loss of neuromuscular junction formation is a major contributor of weakness and ventilatory failure and these deficits can be prevented by early administration of AAV-GAA which leads to rescue of the CNS deficits.  Current studies utilizing AAV9-GAA are expected to lead to more efficient targeting of muscle and motor neurons following systemic and CNS vector delivery

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