Generation Of Suitable For Beta-Sarcoglycan Delivery and Targeting Of Cardiac And Skeletal Muscle As Alternative Therapy Of LGMD2E

Gene replacement therapies using adeno-associated virus (AAV) is a promising treatment of LGMD2E. Limitations of this approach are due to the immune response and production capacity for clinical trials. Nevertheless, the use of lentiviral vector delivering full-length gene into patient has been validated for a gene therapy approach in several diseases. As a gene therapy vehicle, lentiviral vector leads to stable transduction of genes into both dividing and non-dividing cells, including cardiac and skeletal muscle fibers. However, lentiviral vector administration requires to address the off-target non-muscle/cardiac tissues, resulting in unnecessary viral integration which might elicit unexpected toxicity within the treated individual. Moreover, the transduction efficacy should be taken into consideration, and we seek to address this problem by pseudotyping the full length β-sarcoglycan-expressing lentiviral vector with an optimal VSV-G viral envelope protein which increase the transduction efficiency and testing several muscle/cardiac promoters to restrict the entry and expression of the lentiviral vector into cardiac and skeletal muscles. This novel lentiviral vector will be tested for its ability to restore full-length β-sarcoglycan in cardiac and skeletal muscle fibres following systemic delivery in an β-sarcoglycan null mouse model of LGMD2E.