Expression in blood cells may contribute to biochemical and pathological improvements after neonatal intravenous gene therapy for mucopolysaccharidosis VII in dogs

Bin Wang, Thomas M. O'Malley, Lingfei Xu, Charles Vite, Ping Wang, Patricia A. O'Donnell, N. Matthew Ellinwood, Mark E. Haskins, Katherine Parker Ponder

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB) that results in accumulation of glycosaminoglycans in many organs. We have previously reported that neonatal intravenous injection of a gamma retroviral vector (RV) expressing canine GUSB resulted in transduction of hepatocytes, high levels of GUSB modified with mannose 6-phosphate in blood, and reduction in disease manifestations in the heart, bone, and eye. However, it was unclear if liver was the only site of expression, and the effect upon other organs was not assessed. We demonstrate here that blood cells from these RV-treated MPS VII dogs had substantial copies of RV DNA, and expressed the RNA at 2% of the level found in liver. Therefore, expression of GUSB in blood cells may synergize with uptake of GUSB from blood to reduce storage in organs. The RV-treated dogs had marked biochemical and pathological evidence of reduction in storage in liver, thymus, spleen, small intestines, and lung, and partial reduction of storage in kidney tubules. The brain had 6% of normal GUSB activity, and biochemical and pathological evidence of reduction in storage in neurons and other cell types. Thus, this neonatal gene therapy approach is effective and might be used in humans if it proves to be safe. Both secretion of enzyme into blood by hepatocytes, and expression in blood cells that migrate into organs, may contribute to correction of disease.

Original languageEnglish
Pages (from-to)8-21
Number of pages14
JournalMolecular genetics and metabolism
Volume87
Issue number1
DOIs
StatePublished - Jan 2006

Keywords

  • Gene therapy
  • Glycosaminoglycan
  • Lysosomal storage disease
  • Mucopolysaccharidosis
  • Retroviral vector

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