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56. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e. V. (DGNC)
3èmes journées françaises de Neurochirurgie (SFNC)

Deutsche Gesellschaft für Neurochirurgie e. V.
Société Française de Neurochirurgie

07. bis 11.05.2005, Strasbourg

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Dopamine production mediated by a tricistronic lentiviral vector reverses motor deficits in a primate model of Parkinson’s disease

Meeting Abstract

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  • corresponding author B. Jarraya - CEA-CNRS URA 2210, SHFJ, Orsay, France
  • M. Azzouz - Oxford BioMedica (UK) Ltd., Medawar Centre, The Oxford Science Park, Oxford, UK
  • S. M. Kingsman - Oxford BioMedica (UK) Ltd., Medawar Centre, The Oxford Science Park, Oxford, UK
  • P. Hantraye - CEA-CNRS URA 2210, SHFJ, Orsay, France
  • N. D. Mazarakis - Oxford BioMedica (UK) Ltd., Medawar Centre, The Oxford Science Park, Oxford, UK
  • S. Palfi - CEA-CNRS URA 2210, SHFJ, Orsay, France

Deutsche Gesellschaft für Neurochirurgie. Société Française de Neurochirurgie. 56. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3èmes journées françaises de Neurochirurgie (SFNC). Strasbourg, 07.-11.05.2005. Düsseldorf, Köln: German Medical Science; 2005. DocP032

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dgnc2005/05dgnc0300.shtml

Published: May 4, 2005

© 2005 Jarraya et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

Text

Objective

To evaluate the therapeutic potential of striatal injection of tricistronic lentiviral vector (equine infectious anemia virus, EIAV) encoding for the three major enzymes of the dopamine (DA) biosynthetic pathway [tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC) and the GTP cyclohydrolase 1 (CH1) ] as a DA replacement therapy in Parkinson’s disease (PD).

Methods

Six macaques (M. fascicularis) received daily injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) i.m. until they reached a severe and stable parkinsonian syndrome. Parkinsonian animals were stereotactically injected bilaterally into the sensorimotor part of the putamen with either EIAV encoding β-galactosidase (EIAV-βGal, n=3, control group) or TH-AADC-CH1 (EIAV-TRIC, n=3), using MRI guidance. By the end of the experiment, putaminal samples were processed and analysed for dopamine content by HPLC separation and electrochemical detection.

Results

EIAV-TRIC animals displayed a significant functional recovery as compared to EIAV-TRIC animals (p<0.05), on both clinical rating scales and objective video-movement analysis study (Ethovision®). Whereas the two groups displayed an equivalent dramatic decrease of the number of nigral dopaminergic neurons, the EIAV-TRIC animals showed significant recovery in a number of dopaminergic indices in the transduced putamen including increases in TH, AADC and DA immunoreactivity. Elevated putaminal DA levels were observed in animals injected with EIAV-TRIC compared with EIAV-TRIC (p<0.05).

Conclusions

Striatal delivery of multicistronic EIAV lentiviral vector encoding for AADC, TH, and CH1, resulted in transduction of striatal neurons, robust expression of transgenes and significant reversal of parkinsonian symptoms in MPTP macaques, thus opening a potential use in gene therapy for PD.