860. Long-Term Correction of Lysosomal Storage in CNS and Somatic Tissue in Adult MPS II Mice by Intravenous Administration of AAV

A major obstacle in developing therapies for the central nervous system (CNS) disease in mucopolysaccharidoses (MPS) is the presence of the blood-brain barrier (BBB). Therapeutic effects of AAV gene delivery on both somatic and the CNS features in adult MPS II mice were studied using IV injection after pretreatment with mannitol, to disrupt the BBB and facilitate the CNS entry of the vector. An AAV serotype 2 vector, AAV2-CMV-hIdS, was used, containing a human iduronate sulfatase cDNA (hIdS) driven by a human cytomegalovirus promoter (CMV). A single dose of AAV2-CMV-hIdS viral vector (2-4×1011 viral particles in 200 μl) was delivered into adult (4-6 week old) MPS II mice (n=20) by tail vein injection 10 minutes after an IV infusion of mannitol (1-2 mg/gm of body weight). Our results demonstrated correction of GAG storage in multiple organs/tissues. A complete correction of GAG accumulation in liver was achieved (P < 0.01) and partial correction in kidney, heart, intestine and muscles was observed (P < 0.05) at 3, 6, 9 and up to 17 months in one animal. No obvious decrease of GAG content was observed in the spleens of the mice after AAV injection. Iduronate sulfatase enzyme activity was detected in the injected mouse liver samples with complete correction of lysosomal storage, at a level of 10-50% of that in the liver of normal mice. Transmission electron microscopy and histopathology study demonstrated clearance of lysosomal storage in liver. In the brain of injected MPS II mice, a decrease of lysosomal storage was shown by histopathology in Purkinje cells and also in the neurons of the hippocampus, thalamus and cerebral cortex. In addition, physical appearances of IV injected MPS II mice, such as facial feature and spinal curvature, were clearly improved, and the life span of IV injected mice was prolonged, compared to that of non-treated MPS II mice. Our results suggest that IV administration of AAV vector following mannitol pretreatment may be a promising approach for treating both somatic and CNS disease in lysosomal storage disorders.