Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency

• Published in: Molecular therapy Vol. 23; no. 10; pp. 1572 - 1581
• Main Authors: Lee, Ni-Chung, Muramatsu, Shin-Ichi, Chien, Yin-Hsiu, Liu, Wen-Shin, Wang, Wei-Hua, Cheng, Chia-Hao, Hu, Meng-Kai, Chen, Pin-Wen, Tzen, Kai-Yuan, Byrne, Barry J, Hwu, Wuh-Liang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015; Elsevier Limited; Nature Publishing Group
• Subjects: Age; Amino Acid Metabolism, Inborn Errors - diagnostic imaging; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Metabolism, Inborn Errors - mortality; Amino Acid Metabolism, Inborn Errors - physiopathology; Amino Acid Metabolism, Inborn Errors - therapy; Animals; Aromatic-L-Amino-Acid Decarboxylases - deficiency; Aromatic-L-Amino-Acid Decarboxylases - genetics; Aromatic-L-Amino-Acid Decarboxylases - metabolism; Behavior; Behavior, Animal; Blood pressure; Blood Pressure - genetics; Body temperature; Brain - metabolism; Dependovirus - genetics; Disease Models, Animal; Dopamine; Dopamine - metabolism; Enzyme Activation; Fluorodeoxyglucose F18; Gene Expression; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Heart Rate; Hospitals; Hyperactivity; Immunohistochemistry; Medical prognosis; Medical schools; Medical screening; Medicine; Mice; Mice, Transgenic; Motor Activity; Neurons - metabolism; Neurotransmitter Agents - deficiency; Organ Specificity - genetics; Original; Positron-Emission Tomography; Serotonin; Transduction, Genetic; University colleges; Vectors (Biology); Weight Gain - genetics; Japan; Taiwan
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2015.122

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 (DdcKI 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 DdcKI 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.