title: Treatment of congenital neurotransmitter deficiencies by intracerebral ventricular injection of an adeno-associated virus serotype 9 vector.
abstract: Dopamine and serotonin are produced by distinct groups of neurons in the brain, and gene therapies other than direct injection have not been attempted to correct congenital deficiencies in such neurotransmitters. In this study, we performed gene therapy to treat knock-in mice with dopamine and serotonin deficiencies caused by a mutation in the aromatic L-amino acid decarboxylase (AADC) gene (Ddc(KI) mice). Intracerebral ventricular injection of neonatal mice with an adeno-associated virus (AAV) serotype 9 (AAV9) vector expressing the human AADC gene (AAV9-hAADC) resulted in widespread AADC expression in the brain. Without treatment, 4-week-old Ddc(KI) mice exhibited whole-brain homogenate dopamine and serotonin levels of 25% and 15% of normal, respectively. After gene therapy, the levels rose to 100% and 40% of normal, respectively. The gene therapy improved the growth rate and survival of Ddc(KI) mice and normalized their hindlimb clasping and cardiovascular dysfunctions. The behavioral abnormalities of the Ddc(KI) mice were partially corrected, and the treated Ddc(KI) mice were slightly more active than normal mice. No immune reactions resulted from the treatment. Therefore, a congenital neurotransmitter deficiency can be treated safely through inducing widespread expression of the deficient gene in neonatal mice.
authors.affiliation: 1 Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine , Taipei 10041, Taiwan .
authors.forename: Ni-Chung
authors.initials: NC
authors.lastname: Lee
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.forename: Min-Hsiu
authors.initials: MH
authors.lastname: Hu
authors.forename: Wen-Shin
authors.initials: WS
authors.lastname: Liu
authors.forename: Pin-Wen
authors.initials: PW
authors.lastname: Chen
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Wang
authors.forename: Kai-Yuan
authors.initials: KY
authors.lastname: Tzen
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics* / Q000378:metabolism; D001522:Behavior, Animal; D001794:Blood Pressure; D001835:Body Weight; D001921:Brain / Q000276:immunology / Q000378:metabolism; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D018377:Neurotransmitter Agents / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D018377:Neurotransmitter Agents; D001142:Aromatic-L-Amino-Acid Decarboxylases