33. AAV-Mediated Gene Therapy in Pompe Disease with Dr. Barry Byrnes скачать в хорошем качестве

33. AAV-Mediated Gene Therapy in Pompe Disease with Dr. Barry Byrnes

Title: AAV-Mediated Gene Therapy in Pompe Disease: Clinical Immunology Considerations Speaker: Barry Byrne, MD, PhD - Powell Gene Therapy Center, University of Florida-Gainesville, USA Abstract: Early onset neuromuscular disease (NMD) is often associated with severe or null mutations that lead to greater disease burden. The success of gene replacement strategies in this setting may be influenced by limited endogenous protein expression leading to anti-transgene immune response and loss of effective copy number in skeletal muscle due to somatic growth. In one example, Pompe disease is due to a deficiency of absence of the lysosomal enzyme acid alpha glucosidase (GAA), resulting in lysosomal glycogen accumulation that impacts striated muscle and the CNS, including defects of the neuromuscular junction (NMJ). Respiratory failure is the leading cause of morbidity and mortality in Pompe patients. AAV vectors expressing GAA have been evaluated in a phase I/II study in ventilator-dependent and spontaneous breathing pediatric Pompe patients. These studies are based on the finding that accumulation of glycogen in spinal motor neurons contributes to weakness and diaphragmatic dysfunction observed in Pompe disease. In a number of preclinical studies, we have found that restoration of GAA activity in muscle and neural tissue is able to reverse ventilatory insufficiency by reversing moto 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 model of Pompe. 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 the situ force production. After 18 months of age, the loss in motor neurons leads to permanent deficits in force production of the tibialis anterior. Clinical studies of AAV-mediated gene therapy have been pursued to address the fundamental aspects of gene therapy in a neuromuscular disease where patients are identified by severe early onset or newborn screening. Findings in non-clinical and clinical studies related to immune management in conjunction with AAV systemic delivery have paved the way for clinical studies in adults and younger subjects who are candidates for therapeutic AAV administration. The loss of neuromuscular junction formation is a major contributor to weakness and ventilatory failure and these deficits can be prevented by early administration of AAV-GAA. Studies which utilize next generation AAV vectors for systemic administration have led to efficient targeting of muscle and motor neurons for the early treatment of Pompe disease. Related studies in Duchenne muscular dystrophy also highlight the importance of identification and management of pre-existing anti-AAV antibodies which are able to reduce the efficacy of systemic AAV vectors. Practical considerations for the implementation of systemic AAV administration will be discussed for early onset neuromuscular disease. All Rights reserved. No part of this video may be reproduced or transmitted in any form or by any means, electronic or mechanical, without the written permission of the copyright holder. Website: https://amda-pompe.org/ We Need Your Help! https://amda-pompe.org/donate/