Improved retroviral vector design results in sustained expression after adult gene therapy in mucopolysaccharidosis I mice

Ramin Sedaghat Herati, Xiucui Ma, Mindy Tittiger, Kevin K. Ohlemiller, Attila Kovacs, Katherine P. Ponder

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Background: Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to α-L-iduronidase (IDUA) deficiency that results in the accumulation of glycosaminoglycans (GAG). Gene therapy can reduce most clinical manifestations, but mice that receive transfer as adults lose expression unless they receive immunosuppression. Increasing liver specificity of transgene expression has reduced immune responses to other genes. Methods: A gamma retroviral vector was generated with a liver-specific human α1-antitrypsin promoter and the canine IDUA cDNA inverted relative to the retroviral long-terminal repeat. Adult MPS I mice received the vector intravenously at 6 weeks of age and were assessed for expression via serial serum IDUA assays. Functional testing and organ analysis were performed at 8 months. Results: This vector resulted in high specificity of expression in liver, and serum IDUA activity was stable in 90% of animals. Although the average serum IDUA activity was relatively low at 12.6 ± 8.1 units/ml in mice with stable expression, a relatively high percentage of enzyme contained the mannose 6-phosphorylation necessary for uptake by other cells. At 6.5 months after transduction, most organs had high IDUA activity and normalized GAG levels. There was complete correction of hearing and vision abnormalities and significant improvements in bone, although the aorta was refractory to treatment. Conclusions: Stable expression of IDUA in adult MPS I mice can be achieved without immunosuppression by modifying the vector to reduce expression in the spleen. This approach may be effective in patients with MPS I or other lysosomal storage diseases.

Original languageEnglish
Pages (from-to)972-982
Number of pages11
JournalJournal of Gene Medicine
Issue number9
StatePublished - Sep 2008


  • Canine iduronidase
  • Gene therapy
  • Lysosomal storage disease
  • Mucopolysaccharidosis
  • Retroviral vector


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