title: Lentiviral-mediated gene correction of mucopolysaccharidosis type IIIA.
abstract: BACKGROUND
  Mucopolysaccharidosis type IIIA (MPS IIIA) is the most common of the mucopolysaccharidoses. The disease is caused by a deficiency of the lysosomal enzyme sulphamidase and results in the storage of the glycosaminoglycan (GAG), heparan sulphate. MPS IIIA is characterised by widespread storage and urinary excretion of heparan sulphate, and a progressive and eventually profound neurological course. Gene therapy is one of the few avenues of treatment that hold promise of a sustainable treatment for this disorder.
  
  
  METHODS
  The murine sulphamidase gene cDNA was cloned into a lentiviral vector and high-titre virus produced. Human MPS IIIA fibroblast cultures were transduced with the sulphamidase vector and analysed using molecular, enzymatic and metabolic assays. High-titre virus was intravenously injected into six 5-week old MPS IIIA mice. Three of these mice were pre-treated with hyperosmotic mannitol. The weight of animals was monitored and GAG content in urine samples was analysed by polyacrylamide gel electrophoresis.
  
  
  RESULTS
  Transduction of cultured MPS IIIA fibroblasts with the sulphamidase gene corrected both the enzymatic and metabolic defects. Sulphamidase secreted by gene-corrected cells was able to cross correct untransduced MPS IIIA cells. Urinary GAG was found to be greatly reduced in samples from mice receiving the vector compared to untreated MPS IIIA controls. In addition, the weight of treated mice became progressively normalised over the 6-months post-treatment.
  
  
  CONCLUSIONS
  Lentiviral vectors appear promising vehicles for the development of gene therapy for MPS IIIA.
authors.affiliation: Department of Genetic Medicine, Women's and Children's Hospital, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, SA 5006, Australia. donald.anson@adelaide.edu.au
authors.forename: Donald S
authors.initials: DS
authors.lastname: Anson
authors.forename: Chantelle
authors.initials: C
authors.lastname: McIntyre
authors.forename: Belinda
authors.initials: B
authors.lastname: Thomas
authors.forename: Rachel
authors.initials: R
authors.lastname: Koldej
authors.forename: Enzo
authors.initials: E
authors.lastname: Ranieri
authors.forename: Ainslie
authors.initials: A
authors.lastname: Roberts
authors.forename: Peter R
authors.initials: PR
authors.lastname: Clements
authors.forename: Kylie
authors.initials: K
authors.lastname: Dunning
authors.forename: Sharon
authors.initials: S
authors.lastname: Byers