title: In vivo modification of tRNA with an artificial nucleobase leads to full disease remission in an animal model of multiple sclerosis.
abstract: Queuine is a modified pyrrolopyrimidine nucleobase derived exclusively from bacteria. It post-transcriptionally replaces guanine 34 in transfer RNA isoacceptors for Asp, Asn, His and Tyr, in almost all eukaryotic organisms, through the activity of the ancient tRNA guanine transglycosylase (TGT) enzyme. tRNA hypomodification with queuine is a characteristic of rapidly-proliferating, non-differentiated cells. Autoimmune diseases, including multiple sclerosis, are characterised by the rapid expansion of T cells directed to self-antigens. Here, we demonstrate the potential medicinal relevance of targeting the modification of tRNA in the treatment of a chronic multiple sclerosis model—murine experimental autoimmune encephalomyelitis. Administration of a de novo designed eukaryotic TGT substrate (NPPDAG) led to an unprecedented complete reversal of clinical symptoms and a dramatic reduction of markers associated with immune hyperactivation and neuronal damage after five daily doses. TGT is essential for the therapeutic effect, since animals deficient in TGT activity were refractory to therapy. The data suggest that exploitation of the eukaryotic TGT enzyme is a promising approach for the treatment of multiple sclerosis.
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: Sreeja
authors.initials: S
authors.lastname: Varghese
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cotter
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: Franciane
authors.initials: F
authors.lastname: Chevot
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Fergus
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: Colm
authors.initials: C
authors.lastname: Cunningham
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: Kingston H
authors.initials: KH
authors.lastname: Mills
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Connon
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: John M
authors.initials: JM
authors.lastname: Southern
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000235:genetics / Q000628:therapy*; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D012343:RNA, Transfer / Q000737:chemistry / Q000494:pharmacology*; D013866:Thioguanine / Q000737:chemistry
chemical_list: C000624202:NPPDAG compound; D011744:Pyrimidinones; D011758:Pyrroles; D012343:RNA, Transfer; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase; D013866:Thioguanine