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Sci Rep. 2017 Apr 18;7:46280. doi: 10.1038/srep46280.

Recombinant Adeno-Associated Virus-mediated rescue of function in a mouse model of Dopamine Transporter Deficiency Syndrome.

Author information

1
Department of Neuroscience and Brain Technologies, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy.
2
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
3
Department of Advanced Robotics, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy.
4
Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, 199034, Russia.
5
Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston- Salem, NC, USA.
6
Skolkovo Institute of Science and Technology (Skoltech) Skolkovo, Moscow region, 143025, Russia.

Abstract

Dopamine Transporter Deficiency Syndrome (DTDS) is a rare autosomal recessive disorder caused by loss-of-function mutations in dopamine transporter (DAT) gene, leading to severe neurological disabilities in children and adults. DAT-Knockout (DAT-KO) mouse is currently the best animal model for this syndrome, displaying functional hyperdopaminergia and neurodegenerative phenotype leading to premature death in ~36% of the population. We used DAT-KO mouse as model for DTDS to explore the potential utility of a novel combinatorial adeno-associated viral (AAV) gene therapy by expressing DAT selectively in DA neurons and terminals, resulting in the rescue of aberrant striatal DA dynamics, reversal of characteristic phenotypic and behavioral abnormalities, and prevention of premature death. These data indicate the efficacy of a new combinatorial gene therapy aimed at rescuing DA function and related phenotype in a mouse model that best approximates DAT deficiency found in DTDS.

PMID:
28417953
PMCID:
PMC5394687
DOI:
10.1038/srep46280
[Indexed for MEDLINE]
Free PMC Article

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