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Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease

An Addendum to this article was published on 01 April 2006

Abstract

Glial cell line–derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.

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Figure 1: Surgical targeting and changes in MRI after chronic GDNF delivery.
Figure 2: UPDRS scores for patients, 0, 3, 6 and 12 months after GDNF infusion.
Figure 3: GDNF increases [18F]dopa influx.

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References

  1. Rascol, O., Goetz, C., Koller, W., Poewe, W. & Sampaio, C. Treatment interventions for Parkinson's disease: an evidence based assessment. Lancet 359, 1589–1598 (2002).

    Article  Google Scholar 

  2. Lin, L.F., Doherty, D.H., Lile, J.D., Bektesh, S. & Collins, F. GDNF: a glial cell line–derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132 (1993).

    Article  CAS  Google Scholar 

  3. Beck, K.D. et al. Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. Nature 373, 339–341 (1995).

    Article  CAS  Google Scholar 

  4. Tomac, A. et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373, 335–339 (1995).

    Article  CAS  Google Scholar 

  5. Bjorklund, A., Rosenblad, C., Winkler, C. & Kirik, D. Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson's disease. Neurobiol. Dis. 4, 186–200 (1997).

    Article  CAS  Google Scholar 

  6. Gash, D.M. et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380, 252–255 (1996).

    Article  CAS  Google Scholar 

  7. Gash, D.M., Zhang, Z. & Gerhardt, G. Neuroprotective and neurorestorative properties of GDNF. Ann. Neurol. 44, S121–S125 (1998).

    Article  CAS  Google Scholar 

  8. Grondin, R. et al. Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys. Brain 125, 1–11 (2002).

    Article  Google Scholar 

  9. Kordower, J.H. et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290, 767–773 (2000).

    Article  CAS  Google Scholar 

  10. Kordower, J.H. et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease. Ann. Neurol. 46, 419–424 (1999).

    Article  CAS  Google Scholar 

  11. Nutt, J.G. et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60, 69–73 (2003).

    Article  CAS  Google Scholar 

  12. Golden, J.P. et al. Expression of neurturin, GDNF, and their receptors in the adult mouse CNS. J. Comp. Neurol. 398, 139–150 (1998).

    Article  CAS  Google Scholar 

  13. Langston, J.W. et al. Core assessment program for intracerebral transplantations (CAPIT). Mov. Disord. 7, 2–13 (1992).

    Article  CAS  Google Scholar 

  14. Peto, V., Jenkinson, C., Fitzpatrick, R. & Greenhall, R. The development and validation of a short measure of functioning and well being for individuals with Parkinson's disease. Qual. Life Res. 4, 241–248 (1995).

    Article  CAS  Google Scholar 

  15. McCarter, R.J., Walton, N.H., Rowan, A.F., Gill, S.S. & Palomo, M. Cognitive functioning after subthalamic nucleotomy for refractory Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 69, 60–66 (2000).

    Article  CAS  Google Scholar 

  16. Morrish, P.K., Sawle, G.V. & Brooks, D.J. An 18F-dopa-PET and clinical study of the rate of progression in Parkinson's disease. Brain 119 (Pt 2), 585–591 (1996).

    Article  Google Scholar 

  17. Brooks, D.J. et al. The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson's disease, studied with PET. Brain 113 (Pt 5), 1539–1552 (1990).

    Article  Google Scholar 

  18. Rakshi, J.S. et al. Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease. A 3D 18F-dopa-PET study. Brain 122 (Pt 9), 1637–1650 (1999).

    Article  Google Scholar 

  19. Whone, A.L. et al. The REAL-PET study: slower progression in early Parkinson's disease treated with ropinirole compared with L-dopa. Neurology 58, A82–A83 (2002).

    Google Scholar 

  20. Miyoshi, Y. et al. Glial cell line-derived neurotrophic factor-levodopa interactions and reduction of side effects in parkinsonian monkeys. Ann. Neurol. 42, 208–214 (1997).

    Article  CAS  Google Scholar 

  21. Freed, C.R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med. 344, 710–719 (2001).

    Article  CAS  Google Scholar 

  22. Hagell, P. et al. Dyskinesias following neural transplantation in Parkinson's disease. Nat. Neurosci. 5, 627–628 (2002).

    Article  CAS  Google Scholar 

  23. Bhatia, K.P. & Marsden, C.D. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 117 (Pt 4), 859–876 (1994).

    Article  Google Scholar 

  24. Goetz, C.G., Leurgans, S., Raman, R. & Stebbins, G.T. Objective changes in motor function during placebo treatment in PD. Neurology 54, 710–714 (2000).

    Article  CAS  Google Scholar 

  25. The Deep-Brain Stimulation for Parkinson's Disease Study Group. Deep brain stimulation of the subthalamic nucleus or the pars interna of the globus palidus in Parkinson's Disease. N. Engl. J. Med. 345, 956–963 (2001).

  26. Lindvall, O. & Hagell, P. Clinical observations after neural transplantation in Parkinson's disease. Prog. Brain Res. 127, 299–320 (2000).

    Article  CAS  Google Scholar 

  27. Quinn, N.P., Rossor, M.N. & Marsden, C.D. Olfactory threshold in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 50, 88–89 (1987).

    Article  CAS  Google Scholar 

  28. Daniel, S.E. & Hawkes, C.H. Preliminary diagnosis of Parkinson's disease by olfactory bulb pathology. Lancet 340, 186 (1992).

    Article  CAS  Google Scholar 

  29. Wenning, G.K. et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. Ann. Neurol. 42, 95–107 (1997).

    Article  CAS  Google Scholar 

  30. Hoffman, A.F., van Horne, C.G., Eken, S., Hoffer, B.J. & Gerhardt, G.A. In vivo microdialysis studies on somatodendritic dopamine release in the rat substantia nigra: effects of unilateral 6-OHDA lesions and GDNF. Exp. Neurol. 147, 130–141 (1997).

    Article  CAS  Google Scholar 

  31. Zurn, A.D., Widmer, H.R. & Aebischer, P. Sustained delivery of GDNF: towards a treatment for Parkinson's disease. Brain Res. Rev. 36, 222–229 (2001).

    Article  CAS  Google Scholar 

  32. Akerud, P., Canals, J.M., Snyder, E.Y. & Arenas, E. Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease. J. Neurosci. 21, 8108–8118 (2001).

    Article  CAS  Google Scholar 

  33. Ostenfeld, T. et al. Neurospheres modified to produce glial cell line-derived neurotrophic factor increase the survival of transplanted dopamine neurons. J. Neurosci. Res. 69, 955–965 (2002).

    Article  CAS  Google Scholar 

  34. Sofroniew, M.V., Howe, C.L. & Mobley, W.C. Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 24, 1217–1281 (2001).

    Article  CAS  Google Scholar 

  35. Beck, M., Karch, C., Wiese, S. & Sendtner, M. Motoneuron cell death and neurotrophic factors: basic models for development of new therapeutic strategies in ALS. Amyotroph. Lateral. Scler. Other Motor Neuron Disord. 2 (Suppl. 1), S55–S68 (2001).

    Article  CAS  Google Scholar 

  36. Kordower, J.H., Isacson, O. & Emerich, D.F. Cellular delivery of trophic factors for the treatment of Huntington's disease: is neuroprotection possible? Exp. Neurol. 159, 4–20 (1999).

    Article  CAS  Google Scholar 

  37. Patlak, C.S. & Blasberg, R.G. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J. Cereb. Blood Flow Metab. 5, 584–590 (1985).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Amgen for providing the GDNF and information on their previous GDNF infusion trial; M. Traub for critical reading of this manuscript; the Parkinson Disease Society (UK) for a support grant towards equipment and salary; M. Klein and B. Schultz for discussions and technical support; D. Kistler for help with the statistical analysis; G. Gerhardt and D. Gash for sharing unpublished data; and A. Björklund and O. Lindvall for discussions regarding this trial.

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Correspondence to Steven S. Gill or Clive N. Svendsen.

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Gill, S., Patel, N., Hotton, G. et al. Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease. Nat Med 9, 589–595 (2003). https://doi.org/10.1038/nm850

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