Treatment of congenital neurotransmitter deficiencies by intracerebral ventricular injection of an adeno-associated virus serotype 9 vector
Journal
Human Gene Therapy
Journal Volume
25
Journal Issue
3
Pages
189-198
Date Issued
2014
Author(s)
Hu M.-H.
Chen P.-W.
Wang W.-H.
Byrne B.J.
KAI-YUAN TZEN
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 (DdcKI 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 DdcKI 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 DdcKI mice and normalized their hindlimb clasping and cardiovascular dysfunctions. The behavioral abnormalities of the DdcKI mice were partially corrected, and the treated DdcKI 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. ? Copyright 2014, Mary Ann Liebert, Inc. 2014.
SDGs
Other Subjects
aromatic levo amino acid decarboxylase; dopamine; neurotransmitter; parvovirus vector; serotonin; AADC gene; Adeno associated virus; Adeno associated virus serotype 9; animal experiment; animal model; animal tissue; article; brain homogenate; congenital disorder; controlled study; dopamine deficiency; drug safety; gene; gene expression; gene mutation; growth rate; hindlimb; mouse; newborn; nonhuman; serotonin deficiency; serotype; survival; viral gene therapy; Animals; Animals, Newborn; Aromatic-L-Amino-Acid Decarboxylases; Behavior, Animal; Blood Pressure; Body Weight; Brain; Brain Diseases, Metabolic, Inborn; Dependovirus; Disease Models, Animal; Enzyme Activation; Genetic Therapy; Genetic Vectors; Humans; Injections, Intraventricular; Mice; Mice, Knockout; Motor Activity; Neurotransmitter Agents; Tissue Distribution
Publisher
Mary Ann Liebert Inc.
Type
journal article