title: Co-delivery of indoleamine 2,3-dioxygenase prevents loss of expression of an antigenic transgene in dystrophic mouse muscles.
abstract: A significant problem affecting gene therapy approaches aiming at achieving long-term transgene expression is the immune response against the protein product of the therapeutic gene, which can reduce or eliminate the therapeutic effect. The problem is further exacerbated when therapy involves targeting an immunogenic tissue and/or one with a pre-existing inflammatory phenotype, such as dystrophic muscles. In this proof-of-principle study, we co-expressed a model antigen, bacterial β-galactosidase, with an immunosuppressive factor, indoleamine 2,3-dioxygenase 1 (IDO1), in muscles of the mdx mouse model of Duchenne muscular dystrophy. This treatment prevented loss of expression of the transgene concomitant with significantly elevated expression of T-regulatory (Treg) markers in the IDO1-expressing muscles. Moreover, co-expression of IDO1 resulted in reduced serum levels of anti-β-gal antibodies. These data indicate that co-expression of genes encoding immunomodulatory enzymes controlling kynurenine pathways provide a viable strategy for preventing loss of transgenes targeted into dystrophic muscles with pre-existing inflammation.
authors.affiliation: Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: D
authors.identifier: 0000-0001-8439-4665
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: R
authors.initials: R
authors.lastname: Al-Khalidi
authors.affiliation: Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: S
authors.initials: S
authors.lastname: Edgar
authors.affiliation: Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: Q
authors.initials: Q
authors.lastname: An
authors.affiliation: Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: C
authors.initials: C
authors.lastname: Young
authors.affiliation: Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Nowis
authors.affiliation: Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Gorecki
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000008:administration & dosage / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000276:immunology* / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019076:Transgenes / Q000502:physiology*; D001616:beta-Galactosidase / Q000276:immunology / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D001616:beta-Galactosidase