Systemic correction of storage disease in MPS I NOD/SCID mice using the sleeping beauty transposon system

Elena L Aronovich, Jason B. Bell, Shaukat A. Khan, Lalitha Belur, Roland Gunther, Brenda Koniar, Patricia A. Schachern, Josh B. Parker, Cathy S Carlson, Chester B Whitley, R S Mc Ivor, Pankaj Gupta, Perry B Hackett

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Abstract

The Sleeping Beauty (SB) transposon system is a nonviral vector that directs transgene integration into vertebrate genomes. We hydrodynamically delivered SB transposon plasmids encoding human α-L-iduronidase (hIDUA) at two DNA doses, with and without an SB transposase gene, to NOD.129(B6)-Prkdcscid IDUAtm1Clk/J mice. In transposon-treated, nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with mucopolysaccharidosis type I (MPS I), plasma IDUA persisted for 18 weeks at levels up to several hundred-fold wild-type (WT) activity, depending on DNA dose and gender. IDUA activity was present in all examined somatic organs, as well as in the brain, and correlated with both glycosaminoglycan (GAG) reduction in these organs and level of expression in the liver, the target of transposon delivery. IDUA activity was higher in the treated males than in females. In females, omission of transposase source resulted in significantly lower IDUA levels and incomplete GAG reduction in some organs, confirming the positive effect of transposition on long-term IDUA expression and correction of the disease. The SB transposon system proved efficacious in correcting several clinical manifestations of MPS I in mice, including thickening of the zygomatic arch, hepatomegaly, and accumulation of foamy macrophages in bone marrow and synovium, implying potential effectiveness of this approach in treatment of human MPS I.

Original languageEnglish (US)
Pages (from-to)1136-1144
Number of pages9
JournalMolecular Therapy
Volume17
Issue number7
DOIs
StatePublished - Apr 22 2009

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Mucopolysaccharidosis I
Beauty
Severe Combined Immunodeficiency
Transposases
Glycosaminoglycans
Iduronidase
Zygoma
Hepatomegaly
Synovial Membrane
DNA
Transgenes
Vertebrates
Plasmids
Bone Marrow
Macrophages
Genome
Liver
Brain
Genes

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Systemic correction of storage disease in MPS I NOD/SCID mice using the sleeping beauty transposon system. / Aronovich, Elena L; Bell, Jason B.; Khan, Shaukat A.; Belur, Lalitha; Gunther, Roland; Koniar, Brenda; Schachern, Patricia A.; Parker, Josh B.; Carlson, Cathy S; Whitley, Chester B; Mc Ivor, R S; Gupta, Pankaj; Hackett, Perry B.

In: Molecular Therapy, Vol. 17, No. 7, 22.04.2009, p. 1136-1144.

Research output: Contribution to journalArticle

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