title: Minicircle DNA-based gene therapy coupled with immune modulation permits long-term expression of α-L-iduronidase in mice with mucopolysaccharidosis type I.
abstract: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease characterized by mutations to the α-L-iduronidase (IDUA) gene resulting in inactivation of the IDUA enzyme. The loss of IDUA protein results in the progressive accumulation of glycosaminoglycans within the lysosomes resulting in severe, multi-organ system pathology. Gene replacement strategies have relied on the use of viral or nonviral gene delivery systems. Drawbacks to these include laborious production procedures, poor efficacy due to plasmid-borne gene silencing, and the risk of insertional mutagenesis. This report demonstrates the efficacy of a nonintegrating, minicircle (MC) DNA vector that is resistant to epigenetic gene silencing in vivo. To achieve sustained expression of the immunogenic IDUA protein we investigated the use of a tissue-specific promoter in conjunction with microRNA target sequences. The inclusion of microRNA target sequences resulted in a slight improvement in long-term expression compared to their absence. However, immune modulation by costimulatory blockade was required and permitted for IDUA expression in MPS I mice that resulted in the biochemical correction of pathology in all of the organs analyzed. MC gene delivery combined with costimulatory pathway blockade maximizes safety, efficacy, and sustained gene expression and is a new approach in the treatment of lysosomal storage disease.
authors.affiliation: Department of Pediatrics, Division of Bone Marrow Transplant, University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA. osbor026@umn.edu
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Osborn
authors.forename: Ron T
authors.initials: RT
authors.lastname: McElmurry
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lees
authors.forename: Anthony P
authors.initials: AP
authors.lastname: DeFeo
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Chen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kay
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Gordon
authors.initials: G
authors.lastname: Freeman
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D004270:DNA, Circular / Q000008:administration & dosage / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000235:genetics* / Q000378:metabolism*; D007110:Immunity, Active; D056747:Immunomodulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D010957:Plasmids / Q000235:genetics / Q000378:metabolism
chemical_list: D004270:DNA, Circular; D006025:Glycosaminoglycans; D035683:MicroRNAs; D007068:Iduronidase