title: Persistent phenotypic correction of central diabetes insipidus using adeno-associated virus vector expressing arginine-vasopressin in Brattleboro rats.
abstract: Adeno-associated virus (AAV) vector is suitable for gene transfer to the central nervous system. However, the efficacy of gene therapy for neuroendocrine disease is still unknown. In this study, we injected AAV vector encoding arginine-vasopressin (AVP) stereotaxically into the bilateral hypothalamus of Brattleboro rats. Brattleboro rats show a central diabetes insipidus (CDI) phenotype and growth retardation due to a complete deficiency of AVP. Following injection, both urine volume and urine osmolality normalized, and these therapeutic effects persisted for more than 50 weeks. In addition to phenotypic correction, secretion of transgene-derived AVP was enhanced after 24 h water deprivation or hypertonic saline injection, and water diuresis was demonstrated after acute water loading. Also, reduced body weight and low plasma insulin-like growth factor I levels of Brattleboro rats were restored after AVP gene transduction, suggesting the importance of AVP in growth. These findings indicate that hypothalamic neurons of Brattleboro rats can produce and release mature AVP following AAV-mediated gene transduction, resulting in long-term phenotypic correction of CDI. Moreover, the fact that transgene-derived AVP was secreted adequately in response to stimuli, even if it was expressed constitutively, suggests advantages of gene therapy for neuroendocrine diseases and offers a basis to investigate AVP function.
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi 329-0498, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Ideno
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Honda
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hanazono
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kume
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Saito
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus; D020790:Diabetes Insipidus, Neurogenic / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D007032:Hypothalamus, Anterior / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D009994:Osmolar Concentration; D010904:Pituitary Gland, Posterior / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D011910:Rats, Brattleboro
chemical_list: D001127:Arginine Vasopressin