title: Neonatal retroviral vector-mediated hepatic gene therapy reduces bone, joint, and cartilage disease in mucopolysaccharidosis VII mice and dogs.
abstract: Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient beta-glucuronidase (GUSB) activity. Accumulation of glycosaminoglycans (GAGs) in bone, cartilage, and synovium likely contributes to reduced mobility in untreated MPS VII individuals. We previously reported that neonatal intravenous injection of a retroviral vector (RV) expressing canine GUSB resulted in hepatocyte transduction in mice and dogs, and secreted GUSB was taken up from blood by other organs. Here we report the effect of this therapy on bone, cartilage, and joint disease. Osteocytes and bone-lining cells from RV-treated MPS VII mice had GUSB activity, resulting in a marked reduction, as compared with untreated MPS VII mice, in lysosomal storage in bone and at the bone:growth plate interface where bone elongation occurs. Although chondrocytes did not have detectable GUSB activity and had little reduction in lysosomal storage, the thickness of the growth plate was reduced toward normal. These pathological changes were likely responsible for improvements in facial morphology and long bone lengths. The synovium had reduced hyperplasia and lysosomal storage, and the thickness of the articular cartilage was reduced. Similarly, RV-treated MPS VII dogs had improved facial morphology and reduced lysosomal storage in osteocytes and synovium, but not chondrocytes. Nevertheless, the internal area of the trachea was increased, and erosions of the femoral head were reduced. We conclude that neonatal gene therapy can improve bone and joint disease in MPS VII mice and dogs. However, better delivery of GUSB to chondrocytes will be necessary to achieve more profound effects in cartilage.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Mango
authors.forename: Lingfei
authors.initials: L
authors.lastname: Xu
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
authors.forename: Carole
authors.initials: C
authors.lastname: Vogler
authors.forename: Gabriela
authors.initials: G
authors.lastname: Seiler
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwarz
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.forename: Katherine Parker
authors.initials: KP
authors.lastname: Ponder
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001847:Bone Diseases / Q000628:therapy; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D002357:Cartilage Diseases / Q000628:therapy; D004285:Dogs; D005145:Face / Q000002:abnormalities; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D005966:Glucuronidase / Q000235:genetics*; D022781:Hepatocytes / Q000821:virology; D007592:Joint Diseases / Q000628:therapy; D007596:Joints / Q000473:pathology; D008297:Male; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics*; D016538:Mucopolysaccharidosis VII / Q000473:pathology / Q000628:therapy*; D009140:Musculoskeletal Diseases / Q000473:pathology / Q000628:therapy*; D011859:Radiography; D014132:Trachea / Q000473:pathology
chemical_list: D005966:Glucuronidase