title: Treatment of adult MPSI mouse brains with IDUA-expressing mesenchymal stem cells decreases GAG deposition and improves exploratory behavior.
abstract: BACKGROUND
  Mucopolysaccharidosis type I (MPSI) is caused by a deficiency in alpha-L iduronidase (IDUA), which leads to lysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate. While the currently available therapies have good systemic effects, they only minimally affect the neurodegenerative process. Based on the neuroprotective and tissue regenerative properties of mesenchymal stem cells (MSCs), we hypothesized that the administration of MSCs transduced with a murine leukemia virus (MLV) vector expressing IDUA to IDUA KO mouse brains could reduce GAG deposition in the brain and, as a result, improve neurofunctionality, as measured by exploratory activity.
  
  
  METHODS
  MSCs infected with an MLV vector encoding IDUA were injected into the left ventricle of the brain of 12- or 25-month-old IDUA KO mice. The behavior of the treated mice in the elevated plus maze and open field tests was observed for 1 to 2 months. Following these observations, the brains were removed for biochemical and histological analyses.
  
  
  RESULTS
  After 1 or 2 months of observation, the presence of the transgene in the brain tissue of almost all of the treated mice was confirmed using PCR, and a significant reduction in GAG deposition was observed. This reduction was directly reflected in an improvement in exploratory activity in the open field and the elevated plus maze tests. Despite these behavioral improvements and the reduction in GAG deposition, IDUA activity was undetectable in these samples. Overall, these results indicate that while the initial level of IDUA was not sustainable for a month, it was enough to reduce and maintain low GAG deposition and improve the exploratory activity for months.
  
  
  CONCLUSIONS
  These data show that gene therapy, via the direct injection of IDUA-expressing MSCs into the brain, is an effective way to treat neurodegeneration in MPSI mice.
authors.affiliation: Research center for gene therapy, Universidade Federal de São Paulo, São Paulo, Brazil. sang.han@unifesp.br.
authors.forename: Flávia Helena
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authors.lastname: da Silva
authors.forename: Vanessa Gonçalves
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authors.lastname: Pereira
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authors.forename: Lígia Zacchi
authors.initials: LZ
authors.lastname: Tenório
authors.forename: Leonardo Pinto
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authors.lastname: de Carvalho
authors.forename: Bianca Cristina Garcia
authors.initials: BC
authors.lastname: Lisboa
authors.forename: Priscila Keiko
authors.initials: PK
authors.lastname: Matsumoto
authors.forename: Roberta Sessa
authors.initials: RS
authors.lastname: Stilhano
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Samoto
authors.forename: Bruno Frederico Aguilar
authors.initials: BF
authors.lastname: Calegare
authors.forename: Letícia de Campos
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authors.lastname: Brandão
authors.forename: Vânia
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authors.lastname: D'Almeida
authors.forename: Thaís Rm
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authors.lastname: Filippo
authors.forename: Marimélia
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authors.lastname: Porcionatto
authors.forename: Leny
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authors.lastname: Toma
authors.forename: Helena Bonciani
authors.initials: HB
authors.lastname: Nader
authors.forename: Valderez Bastos
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authors.lastname: Valero
authors.forename: Melissa
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authors.lastname: Camassola
authors.forename: Nance Beyer
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authors.lastname: Nardi
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Han