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

Authors: Stilhano, Roberta Sessa  Martin, Priscila Keiko Matsumoto  de Melo, Suely Maymone  Samoto, Vivian Yochiko  Peres, Giovani Bravin  da Silva Michelacci, Yara Maria Correa  da Silva, Flavia Helena  Pereira, Vanessa Gonçalves  D'Almeida, Vania  da Cruz, Adriana Taveira  Jasiulionis, Miriam Galvonas  Han, Sang Won 
Citation: Stilhano RS, etal., J Gene Med. 2015 Jan-Feb;17(1-2):1-13. doi: 10.1002/jgm.2818.
Pubmed: (View Article at PubMed) PMID:25597593
DOI: Full-text: DOI:10.1002/jgm.2818

BACKGROUND: Mucopolysaccharidose type I (MPSI) is a lysosomal monogenic disease caused by mutations in the gene for α- 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.
METHODS: Several 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.
RESULTS: High 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.
CONCLUSIONS: phiC31-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.


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CRRD Object Information
CRRD ID: 12910503
Created: 2017-06-16
Species: All species
Last Modified: 2017-06-16
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.