title: Treatment of neurological disorders by introducing mRNA in vivo using polyplex nanomicelles.
abstract: Sensory nerve disorders are difficult to cure completely considering poor nerve regeneration capacity and difficulties in accurately targeting neural tissues. Administering mRNA is a promising approach for treating neurological disorders because mRNA can provide proteins and peptides in their native forms for mature non-dividing neural cells, without the need of entering their nuclei. However, direct mRNA administration into neural tissues in vivo has been challenging due to too unstable manner of mRNA and its strong immunogenicity. Thus, using a suitable carrier is essential for effective mRNA administration. For this purpose, we established a novel carrier based on the self-assembly of polyethylene glycol (PEG)-polyamino acid block copolymer, i.e. polyplex nanomicelles. To investigate the feasibility and efficacy of mRNA administration for the treatment of sensory nerve disorders, we used a mouse model of experimentally induced olfactory dysfunction. Intranasal administration of mRNA-loaded nanomicelles provided an efficient and sustained protein expression for nearly two days in nasal tissues, particularly in the lamina propria which contains olfactory nerve fibers, with effectively regulating the immunogenicity of mRNA. Consequently, once-daily intranasal administration of brain-derived neurotrophic factor (BDNF)-expressing mRNA using polyplex nanomicelles remarkably enhanced the neurological recovery of olfactory function along with repairing the olfactory epithelium to a nearly normal architecture. To the best of our knowledge, this is the first study to show the therapeutic potential of introducing exogenous mRNA for the treatment of neurological disorders. These results indicate the feasibility and safety of using mRNA, and provide a novel strategy of mRNA-based therapy.
authors.affiliation: Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Baba
authors.affiliation: Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: itaka-ort@umin.net.
authors.forename: Keiji
authors.initials: K
authors.lastname: Itaka
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
authors.affiliation: Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Electronic address: kataoka@bmw.t.u-tokyo.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D018014:Gene Transfer Techniques; D015850:Interleukin-6 / Q000235:genetics; D008713:Methimazole; D008807:Mice, Inbred BALB C; D008823:Micelles; D049329:Nanostructures / Q000008:administration & dosage*; D000857:Olfaction Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051842:Olfactory Marker Protein / Q000235:genetics; D009831:Olfactory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015850:Interleukin-6; D008823:Micelles; D051842:Olfactory Marker Protein; C497598:Omp protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D008713:Methimazole
keywords: Brain-derived neurotrophic factor (BDNF); Messenger RNA (mRNA) administration; Neurological disorders; Olfactory dysfunction; mRNA-based therapy