title: Efficient gene therapy for Parkinson's disease using astrocytes as hosts for localized neurotrophic factor delivery.
abstract: Current gene therapy approaches for Parkinson's disease (PD) deliver neurotrophic factors like glial cell line-derived neurotrophic factor (GDNF) or neurturin via neuronal transgene expression. Since these potent signaling-inducing neurotrophic factors can be distributed through long-distance neuronal projections to unaffected brain sites, this mode of delivery may eventually cause side effects. To explore a localized and thus potentially safer alternative for gene therapy of PD, we expressed GDNF exclusively in astrocytes and evaluated the efficacy of this approach in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rat 6-hydroxy-dopamine (6-OHDA) models of PD. In terms of protection of dopaminergic cell bodies and projections, dopamine (DA) synthesis and behaviour, astrocyte-derived GDNF demonstrated the same efficacy as neuron-derived GDNF. In terms of safety, unilateral striatal GDNF expression in astrocytes did not result in delivery of bio-active GDNF to the contralateral hemispheres (potential off-target sites) as happened when GDNF was expressed in neurons. Thus, astrocytic GDNF expression represents a localized but efficient alternative to current gene therapeutic strategies for the treatment of PD, especially if viral vectors with enhanced tissue penetration are considered. Astrocytic neurotrophic factor expression may open new venues for neurotrophic factor-based gene therapy targeting severe diseases of the brain.
authors.affiliation: DFG Research Center Molecular Physiology of the Brain (CMPB) at University Medicine Göttingen, Göttingen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Drinkut
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Tereshchenko
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors
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