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Localized striatal delivery of GDNF as a treatment for Parkinson disease

Nature Neuroscience volume 7, pages 105–110 (2004)Cite this article

Ten years ago, a glial cell line–derived neurotrophic factor (GDNF) that has prominent actions on nigral dopaminergic neurons, both in vitro and in animal models of Parkinson disease (PD), was discovered. A recently published open-label clinical trial now reports that long-term intracerebral delivery of GDNF may also markedly improve symptoms in patients with PD. Here we review the experimental data underlying the current clinical trial and discuss the types of structural and functional changes induced by GDNF that may provide symptomatic benefit in PD patients. Data obtained in rodent and primate models of PD highlight the importance of how and where the factor is administered, supporting the view that GDNF has to be delivered locally in the brain parenchyma, at the receptive target site, to provide therapeutic benefit in PD patients.

The cardinal symptoms of PD, including a difficulty in initiating movement, slowness of movement and stiffness and shaking at rest, are to a large extent caused by the progressive degeneration of the dopamine-producing neurons in the substantia nigra. Nigral cell loss proceeds over many years, during the early symptomatic stage, during manifest PD and during severe, end-stage disease. At the onset of disease, about 50% of dopaminergic neurons have been lost, and there is on average a further loss of 45% within the first decade, accompanied by a profound striatal dopaminergic denervation. It is this slow and protracted degenerative process that creates opportunities for disease intervention, such as blocking nigral cell loss and promoting recovery by improved function—and possibly by inducing regeneration and sprouting—of the surviving nigral dopaminergic neurons. Results obtained in animal models of PD indicate that GDNF may possess the desired properties to be used as a disease-modifying therapeutic factor for PD.

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Figure 1: Protective effects of GDNF in the intrastriatal 6-OHDA model.
Figure 2: Summary of behavioral recovery documented in two experiments using the recombinant AAV and LV vectors in rodent and primate models of PD, respectively.

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Acknowledgements

Our studies have been supported by grants from the Swedish Research Council (A.B. and D.K.). We thank B. Mattsson for technical assistance in preparation of the illustrations.

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  1. Department of Physiological Sciences, Wallenberg Neuroscience Center, Lund University, BMC A11, Lund, 22184, Sweden

    Deniz Kirik, Biljana Georgievska & Anders Björklund

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Correspondence to Deniz Kirik.

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Kirik, D., Georgievska, B. & Björklund, A. Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat Neurosci 7, 105–110 (2004). https://doi.org/10.1038/nn1175

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