title: Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency.
abstract: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (Ddc(KI) mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old Ddc(KI) mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment.
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ni-Chung
authors.initials: NC
authors.lastname: Lee
authors.affiliation: Division of Neurology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.|Division of Genetic Therapeutics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Muramatsu
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wen-Shin
authors.initials: WS
authors.lastname: Liu
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Wang
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chia-Hao
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Meng-Kai
authors.initials: MK
authors.lastname: Hu
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Pin-Wen
authors.initials: PW
authors.lastname: Chen
authors.affiliation: Molecular Imaging Center, National Taiwan University, Taipei, Taiwan.|Department of Nuclear Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kai-Yuan
authors.initials: KY
authors.lastname: Tzen
authors.affiliation: Powell Gene Therapy Center, University of Florida, Gainesville, Florida, USA.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D001522:Behavior, Animal; D001794:Blood Pressure / Q000235:genetics; D001921:Brain / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation; D019788:Fluorodeoxyglucose F18; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006339:Heart Rate; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000172:deficiency*; D009928:Organ Specificity / Q000235:genetics; D049268:Positron-Emission Tomography; D014161:Transduction, Genetic; D015430:Weight Gain / Q000235:genetics
chemical_list: D018377:Neurotransmitter Agents; D019788:Fluorodeoxyglucose F18; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine