Lentiviral-mediated gene correction of mucopolysaccharidosis type IIIA

doi:10.1186/1479-0556-5-1

Genetic Vaccines and Therapy

Volume 5

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Anson DS
McIntyre C
Thomas B
Koldej R
Ranieri E
Roberts A
Clements PR
Dunning K
Byers S

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McIntyre C
Thomas B
Koldej R
Ranieri E
Roberts A
Clements PR
Dunning K
Byers S
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Research

Lentiviral-mediated gene correction of mucopolysaccharidosis type IIIA

Donald S Anson¹^,2^,3^,4 , Chantelle McIntyre¹^,2 , Belinda Thomas¹^,5 , Rachel Koldej¹^,2 , Enzo Ranieri¹^,2 , Ainslie Roberts¹^,2 , Peter R Clements¹^,2 , Kylie Dunning¹^,6 and Sharon Byers¹^,2

¹Department 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

²Department of Paediatrics, University of Adelaide, SA 5005, Australia

³Department of Biotechnology, Flinders University, GPO Box 2100, Adelaide, SA 5001, Australia

⁴School of Pharmacy & Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, SA 5001, Australia

⁵Department of Respiratory and Sleep Medicine, Monash Medical Centre, VIC 3168, Australia

⁶Department of Obstetrics and Gynaecology, University of Adelaide, SA 5005, Australia

author email corresponding author email

Genetic Vaccines and Therapy 2007, 5:1doi:10.1186/1479-0556-5-1


Published:	16 January 2007

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.

Conclusion

Lentiviral vectors appear promising vehicles for the development of gene therapy for MPS IIIA.