GDNF: A Novel Treatment for Parkinson’s Disease?

Parkinson's disease (PD), a degenerative disorder of the central nervous system, affects nearly 1% of the global population aged 65 and older.1, 2 Primary symptoms of PD include muscle rigidity, tremor, and bradykinesia.1 As the disease progresses, individuals with PD experience postural instability, cognitive dysfunction (dementia and psychosis), sleep abnormalities, and mood disorders.1, 2 The pathophysiology of the disease stems from the loss of pigmented dopaminergic (DA) neurons in the substantia nigra (SN).1 These neurons project to the striatum, and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement.1

Of the pharmacological treatments currently available, none prevent the progressive loss of DA neurons observed during the course of PD.3 For several years, trophic factors have been pursued as potential therapeutic agents due to their ability to regulate the survival of specific neuronal populations in the central nervous system.3 One such trophic factor is glial cell-derived neurotrophic factor (GDNF), a member of the transforming growth factor beta superfamily. GDNF was first identified on the basis of its ability to support the development of embryonic DA neurons.4 It has since been shown to protect and restore mature DA neurons in the SN in many different lesion models. The challenge in assessing its therapeutic potential has been finding a way to deliver GDNF to PD patients.

GDNF Delivery Methods Investigated in Animal Models of Parkinson's Disease (PD).
View Larger Image 		GDNF Delivery Methods Investigated in Animal Models of Parkinson's Disease (PD). Several methods of GDNF delivery have proven to be effective in preventing the loss of dopaminergic neurons in neurotoxin-induced animal models of PD. Ad-GDNF: Adenoviral-expressed GDNF; Lenti-GDNF: Lentiviral-expressed GDNF; hNPCs: Human Neural Progenitor Cells; Cop-1: Copolymer-1 immune cell transfer; HACs: Human Amniotic Cells.

One strategy for delivering GDNF to target tissues that has been explored in animal models of PD is in vivo gene transfer using viral vectors. Bensadoun et al. unilaterally injected lentiviral vectors carrying GDNF or inactivated GDNF above the SN in mice.5 Two weeks later, the animals were lesioned on the same side of the striatum with the neurotoxin, 6-hydroxydopamine (6-OHDA). Apomorphine-induced rotational behavior (i.e. circling), indicative of DA neuron loss, was significantly decreased in the GDNF-injected group compared to control animals. GDNF also protected 70% of the tyrosine hydroxylase-positive cells in the SN against 6-OHDA-induced toxicity, compared to 33% in control animals injected with mutated, inactive GDNF. These findings were sup­ported by Kordower et al., who used lentiviral vectors to show that GDNF could prevent nigrostriatal degeneration and reverse functional defects in monkeys treated with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra­hydropyridine (MPTP).6 Adenoviral infection has also been shown to be an effective means of delivering GDNF in animal models of PD. Choi-Lundberg et al. demonstrated that 6-OHDA-induced degeneration of DA neurons could be reduced by injecting the SN of rats with a replication-defective adenovirus expressing human GDNF.7 Six weeks after treatment with 6-OHDA, the loss of DA neurons was reduced approximately three-fold in GDNF-infected rats, relative to control rats. Similarly, adenoviral expression of GDNF in mice prevented the depletion of striatal dopamine and the loss of synaptic plasticity associated with MPTP-induced damage.8

Other methods of GDNF delivery or induced upregulation have also shown promise in animal models of PD. GDNF-releasing, biodegradable microspheres implanted into the striatum of PD model rats were shown to induce DA fiber sprouting and synaptogenesis.9 In addition, GDNF expression was shown to be stimulated in MPTP-treated mice both by adoptive transfer of copolymer-1 (Cop-1) immune cells and by striatal transplantation of human amniotic cells.10, 11 A similar increase in GDNF production was observed in MPTP-treated monkeys following intrastriatal or intranigral injection of transgenic human neural progenitor cells, providing hope that one of these strategies may be effective in humans.12 Recently, advancements have also been reported in the development of therapeutic approaches in monkeys utilizing GDNF-mediated transplantation of fetal DA neurons.13 These results suggest that GDNF gene therapy combined with neural transplantation may improve the modest gains that have been made thus far in clinical studies of neural grafting.13

The neuroprotective and neurorestorative effects of GDNF in MPTP- or 6-OHDA-induced animal models of PD imply that GDNF may be useful for treating PD patients. Unfortunately, GDNF delivery in humans by intra­ce­re­broventricular injection or intra­striatal infusion has proven ineffective and other methods of GDNF delivery have yet to be tested.14 Thus, finding a safe and effective approach to exploit the neuro­protective effects of GDNF remains an active area of research in developing a treatment to inhibit the progression of PD.

References

  1. Recchia, A. et al. (2008) Neurobiol. Dis. 30:8.
  2. Lee, V.M. & J.Q. Trojanowski (2006) Neuron 52:33.
  3. Backman, C.M. et al. (2006) Mol. Cell. Endocrinol. 252:160.
  4. Lin, L.F. et al. (1993) Science 260:1130.
  5. Bensadoun, J-C. et al. (2000) Exp. Neurol. 164:15.
  6. Kordower, J.H. et al. (2000) Science 290:767.
  7. Choi-Lundberg, D.L. et al. (1997) Science 275:838.
  8. Chen, Y.H. et al. (2008) FASEB J. 22:261.
  9. Jollivet, C. et al. (2004) Biomaterials 25:933.
  10. Benner, E.J. et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101:9435.
  11. Kong, X.Y. et al. (2008) Brain Res. 1205:108.
  12. Emborg, M.E. et al. (2008) Cell Transplant. 17:383.
  13. Elsworth, J.D. et al. (2008) Exp. Neurol. 211:252.
  14. Peterson, A.L. & J.G. Nutt (2008) Neurotherapeutics 5:270

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