alpha-L-iduronidase gene-based therapy using the phiC31 system to treat mucopolysaccharidose type I mice

Author(s):Show less -

Stilhano, Roberta Sessa ^[1] ; Matsumoto Martin, Priscila Keiko ^[1] ; de Melo, Suely Maymone ^[1] ; Samoto, Vivian Yochiko ^[1] ; Peres, Giovani Bravin ^[2] ; Correa da Silva Michelacci, Yara Maria ^[2] ; da Silva, Flavia Helena ^[1] ; Pereira, Vanessa Goncalves ^[3] ; D'Almeida, Vania ^[3] ; da Cruz, Adriana Taveira ^[4] ; Jasiulionis, Miriam Galvonas ^[4] ; Han, Sang Won ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Biophys, BR-04044010 Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Biochem, BR-04044010 Sao Paulo, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Pediat, BR-04044010 Sao Paulo, SP - Brazil

^[4] Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, BR-04044010 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF GENE MEDICINE; v. 17, n. 1-2, p. 1-13, JAN-FEB 2015.
• Web of Science Citations: 3

Abstract

BackgroundMucopolysaccharidose type I (MPSI) is a lysosomal monogenic disease caused by mutations in the gene for - l-iduronidase (IDUA). MPSI patients need a constant supply of IDUA to alleviate progression of the disease. IDUA gene transfer using integrative vectors might provide a definitive solution and support advancement to clinical trials, although studies have not yet been satisfactory. To achieve a stable IDUA gene expression in vivo, phiC31 was tested in the present study. MethodsSeveral plasmid vectors were constructed and IDUA-/- mice were treated with cyclophosphamide and transfected with these vectors hydrodynamically via tail veins. IDUA expression was monitored over time. Treated and nontreated mice underwent an open-field test at age 8 months, and IDUA activity and glycosaminoglycan (GAG) content of tissues were evaluated. ResultsHigh levels of IDUA activity were detected initially (>1000 U/ml), although these levels decayed over time. The reinjection of vectors produced a similar profile of IDUA decay. Three out of six treated mice had IDUA activity in the livers, and also showed lower GAG content, reduced lysosomes and better locomotion. To investigate unsustained IDUA production, wild-type mice were submitted to the same gene therapy procedure, which generated a similar profile of IDUA decay. Anti-IDUA antibody was detected in the sera of these animals. In addition, we also found three methylated sites in the cytomegalovirus promoter region. ConclusionsphiC31-mediated gene therapy resulted in an important improvement in IDUA-/- mice, including locomotion, although the obstacles that need to be overcome to enable long-term gene therapy for MPSI are also noted. Copyright (c) 2015 John Wiley \& Sons, Ltd. (AU)

• FAPESP's process: 09/52235-6 - Gene therapy for mucopolysaccharidosis type I in mice
• Grantee: Sang Won Han
• Support Opportunities: Regular Research Grants