In vivo expression of therapeutic human genes for dopamine production in the caudales of MPTP-treated monkeys using an AAV vector

M. J. During, R. J. Samulski, J. D. Elsworth, M. G. Kaplitt, P. Leone, X. Xiao, J. Li, A. Freese, J. R. Taylor, R. H. Roth, J. R. Sladek, K. L. O'Malley, Redmond De

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155 Scopus citations


An adeno-associated virus (AAV) vector, expressing genes for human tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC), demonstrated significantly increased production of dopamine in 293 (human embryonic kidney) cells. This bicistronic vector was used to transduce striatal cells of six asymptomatic but dopaminedepleted monkeys which had been treated with the neurotoxin MPTP. Striatal cells were immunoreactive for the vector-encoded TH after stereotactic injection for periods up to 134 days, with biochemical effects consistent with dopamine biosynthetic enzyme expression. A subsequent experiment was carried out in six more severely depleted and parkinsonian monkeys. Several THJaadc-treated monkeys showed elevated levels of dopamine near injection tracts after 2.5 months. Two monkeys that received a ß-galactosidase expressing vector showed no change in striatal dopamine. Behavioral changes could not be statistically related to the vector treatment groups. Toxicity was limited to transient fever in several animals and severe hyperactivity in one animal in the first days after injection with no associated histological evidence of inflammation. This study shows the successful transfection of primate neurons over a period up to 2.5 months with suggestive evidence of biochemical phenotypic effects and without significant toxicity. While supporting the idea of an in vivo gene therapy for Parkinson's disease, more consistent and longer lasting biochemical and behavioral effects will be necessary to establish the feasibility of this approach in a primate model of parkinsonism.

Original languageEnglish (US)
Pages (from-to)820-827
Number of pages8
JournalGene Therapy
Issue number6
StatePublished - 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics


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