Minicircle DNA-based gene therapy coupled with immune modulation permits long-term expression of α-L-iduronidase in mice with mucopolysaccharidosis type i

Mark J. Osborn, Ron T. McElmurry, Christopher J. Lees, Anthony P. Defeo, Zhi Ying Chen, Mark A. Kay, Luigi Naldini, Gordon Freeman, Jakub Tolar, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)450-460
Number of pages11
JournalMolecular Therapy
Volume19
Issue number3
DOIs
StatePublished - Mar 2011

Bibliographical note

Funding Information:
We are grateful to Katherine P. Ponder (Washington University) for helpful discussions in developing the IDUA enzymatic assay. We thank Andrew P. Price and John Oleksowicz (University of Minnesota) for excellent technical assistance. M.J.O. is supported by a grant from the National MPS Society. M.J.O., J.T., & B.R.B. are also supported by the Minnesota Medical Foundation and the Children's Cancer Research Fund.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

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