339 Preservation of Renal Function in Murine Glycogen Storage Disease Type I with a Double Stranded Adeno Associated Virus Vector Molecular Therapy Volume 19, Supplement 1, May 2011 Copyright © The Am[.]
GENETIC AND METABOLIC DISEASES GENE & CELL THERAPY II 337 Correction of Neurological Disease of Mucopolysaccharidosis IIIB in Adult Mice by rAAV9 Trans-Blood-Brain-Barrier Gene Delivery Haiyan Fu,1,2 Juliann DiRosario,1 Smruti Killedar,1,2 Kimberly Zaraspe,1 Douglas M McCarty.1,2 Center for Gene Therapy, Research Institute at Nationwide Children’s Hospital, Columbus, OH; 2Department of Pediatrics, The Ohio State University, Columbus The greatest challenge in developing therapies for Mucopolysaccharidosis (MPS) IIIB is to achieve efficient CNS delivery across the blood-brain barrier (BBB) In this study, we used the novel ability of AAV9 to cross the BBB from the vasculature to achieve long-term global CNS, and widespread somatic restoration of α-N-acetylglucosaminidase (NAGLU) activity A single intravenous (IV) injection of rAAV9-CMV-hNAGLU, without extraneous treatment to disrupt the BBB, restored NAGLU activity to normal or above normal levels in adult MPS IIIB mice, leading to complete, or near complete, correction of lysosomal storage pathology in the CNS and periphery, and correction of astrocytosis and neurodegeneration The IV-delivered rAAV9 vector also transduced abundant neurons in the myenteric and submucosal plexus, suggesting peripheral nervous system targeting While CNS entry did not depend on osmotic disruption of the BBB, it was significantly enhanced (≥2 fold) by pretreatment with an IV infusion of mannitol Most important, we demonstrate that a single systemic rAAV9-NAGLU gene delivery provides long-term neurological benefits in MPS IIIB mice, resulting in significant improvement in cognitive and motor function, and extension of survival (18.8-20 months, ongoing) In addition, much less vector is required to achieve functional benefits by IV AAV9 delivery, in comparison to IV-mannitol-AAV2 regimen These data suggest promising clinical potential using the transBBB neurotropic rAAV9 vector for treating MPS IIIB and other neurogenetic diseases 338 Enhancement of Gene Therapy in Pompe Disease by Increased Mannose-6-Phosphate Receptor Expression in Target Tissues Dwight D Koeberl,1 Baodong Sun,1 Jian Dai,1 Andrew Bird,1 Deeksha S Bali.1 Pediatrics, Duke University Medical Center, Durham, NC The underlying deficiency of acid α-glucosidase (GAA) in Pompe disease has been partially corrected by enzyme replacement (ERT) However, skeletal muscle weakness persists in many patients on ERT, and poor uptake of GAA by skeletal muscle has been linked to low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) To further understand the role of CI-MPR in Pompe disease, we crossed muscle-specific CI-MPR knockout (KO) mice with GAA-KO (Pompe disease) mice We evaluated adenoassociated virus (AAV) vector-mediated gene therapy in CI-MPRKO/GAA-KO (double KO) mice The essential role of CI-MPR was emphasized by the lack of efficacy from AAV vector administration, as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with administration of the same AAV vector in GAA-KO mice We next attempted to increase CI-MPR expression in skeletal muscle to demonstrate the dependence of biochemical correction upon receptor-mediated uptake of GAA Therefore, the AAV vector-transduced liver depot was enhanced by the addition of a drug, clenbuterol, which was previously demonstrated to increase the expression of CI-MPR in muscle The liver was transduced by administering AAV-LSPhGAApA (2x1010 vector particles) to two groups of month-old male GAA-KO mice, and clenbuterol was administered to one group of vector-treated mice The effect of clenbuterol was evident, when Rotarod latency was increased by Molecular Therapy Volume 19, Supplement 1, May 2011 Copyright © The American Society of Gene & Cell Therapy 75% following vector administration and clenbuterol treatment, in comparison with vector administration alone (p