Neonatal retroviral vector-mediated hepatic gene therapy reduces bone, joint, and cartilage disease in mucopolysaccharidosis VII mice and dogs

Robert L. Mango, Lingfei Xu, Mark S. Sands, Carole Vogler, Gabriela Seiler, Tobias Schwarz, Mark E. Haskins, Katherine Parker Ponder

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient β-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.

Original languageEnglish
Pages (from-to)4-19
Number of pages16
JournalMolecular genetics and metabolism
Volume82
Issue number1
DOIs
StatePublished - May 1 2004

Keywords

  • Gene therapy
  • Glycosaminoglycans
  • Lysosomal storage disease
  • Mucopolysaccharidosis VII
  • Retroviral vector
  • β-Glucuronidase

Fingerprint Dive into the research topics of 'Neonatal retroviral vector-mediated hepatic gene therapy reduces bone, joint, and cartilage disease in mucopolysaccharidosis VII mice and dogs'. Together they form a unique fingerprint.

  • Cite this