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Volume 2
     

European network to develop new therapeutic strategies for Parkinson's Disease using lentiviral vector technology ((N)EUROPARK)

   
Project

QLK3-2002-02114

Cell factory area

3.1.3

EU Contribution

1,612,800 Euro

Duration

36 months

Type

RS

Starting date

Foreseen 01 January 2003 (contract not yet signed at date of printing)

Keywords
alpha-synuclein
lentiviral vectors
neurodegeneration
parkin
ABSTRACT

Parkinson's Disease (PD) is the second most common neurodegenerative disease.

The recent identification of genes underlying familial PD (alpha-synuclein and parkin) opens perspectives for a better understanding of the disease. (N)EUROPARK proposes to develop new cell culture and animal models for PD based on these two genes using optimised lentiviral vector technology. Lentiviral vectors are efficient tools to transfer genes into the brain. Using lentiviral vector technology we will explore the role of alpha-synuclein and parkin in the pathogenesis of PD, which will enable rational development of new therapies. The potential neuroprotective role of parkin will be used as a new gene therapeutic approach. The established disease model systems will allow evaluation and validation of new gene therapeutic strategies and new drugs for the treatment of PD.

OBJECTIVES

Our objective is the development and testing of new therapeutic strategies for Parkinson's disease based on the understanding of the role of the PD-associated genes alpha-synuclein and parkin in neurodegeneration. We will use the technological power of lentiviral vectors (LV) for gene transfer into neurons both in cell culture and in rodent brain. We will combine lentiviral vector technology with classical transgenesis.

We can summarise the general objectives of our project:

  1. the optimalisation of LV technology for gene transfer in the brain.
  2. the study of the role of alpha-synuclein and parkin in PD and related disorders.
  3. elaboration of a cell culture model for synucleinopathy.
  4. the establishment of novel animal models for PD.
  5. the identification of new pharmaco- and/or gene-therapeutic strategies and targets for PD.
DESCRIPTION OF THE WORK

1. Development of neurolentivectors

We will optimise LV production by developing a reliable quantification method based on real-time PCR, by establishing high-throughput production, concentration and purification methods, and by constructing packaging cells for the production of alpha-synuclein (a-SYN) and parkin LV. New highly-active and neuron-specific promoters will be inserted into the LV and detection methods for transgene expression will be optimised. And finally, an inducible LV expression system will be developed.

2. Development of a cell culture model for synucleinopathy based on a-SYN and parkin

We want to establish a cell culture system, reproducing two fundamental features of PD in cell culture, namely a-SYN inclusions (Lewy bodies) and dopaminergic cell death, based on (over)expression and/or inhibition of a-SYN and parkin. The establishment of such a cell culture system will allow large-scale evaluation of new therapeutics prior to evaluation in animal models.

3. Development of new animal models for PD based on a-SYN and parkin

We will generate novel PD models in rodents based on a-SYN and parkin, combining LV technology, classical transgenesis and knock-out technology. Our goal is to create animal models that truly reflect the pathogenesis and motor symptoms of PD. The animal model(s) will be validated by behavioural testing and by treatment with known compounds and therapeutic genes.

4. Identification and evaluation of new therapeutic strategies for PD

We will evaluate the therapeutic potential of the new neurolentivectors in the established cell culture and animal models. We will also test the effect of new gene therapeutic strategies (e.g. overexpression of parkin as neuroprotective factor) and new compounds in these model systems.

DELIVERABLES
  • a generic neurolentivector that achieves high-level, neuron-specific and regulatable expression in rodent brain.
  • a cell culture model for synucleinopathy based on a-SYN and parkin.
  • a fully characterised animal model for PD based on a-SYN and parkin.
  • demonstration of therapeutic potential of neurolentivectors.
  • demonstration that parkin can act as neuroprotective factor.
  • proof-of-principle that the PD models can be used to evaluate gene therapeutic strategies.
CONSORTIUM
COORDINATOR
 
Veerle Baekelandt
Gene Therapy Program
Experimental Neurosurgery and Neuroanatomy
Katholieke Universiteit Leuven
3000 Leuven, Belgium
Tel: +32-16-33 78 43
Fax: +32-16-33 78 55
Veerle.Baekelandt@med.kuleuven.ac.be
 
PARTNERS
 
Luigi Naldini
Department of Oncological Sciences
University of Torino
10060 Candiolo (TO), Italy
Tel: +39-011-993 3347
Fax: +39-011-993 3225
lnaldini@ircc.unito.it

Eero Vasar
Visgenyx Ltd.
51010 Tartu, Estonia
Tel: +372-7-374 331
Fax: +372-7-374 332
eero.vasar@ut.ee

Philipp Kahle
Adolf Butenandt Institute
Ludwig Maximilians University of Munich
80336 München, Germany
Tel: +49-89-5996 480
Fax: +49-89-5996 415
pkahle@pbm.med.uni-muenchen.de

Edilio Borroni
CNS Pharmaceutical Research Department
F. Hoffmann-La Roche Ltd.
4070 Basel, Switzerland
Tel: +41-61-688 4248
Fax: +41-61-688 4484
edilio.borroni@roche.com