GDNF delivery for Parkinson's disease.

The mainstays of Parkinson's disease (PD) treatment remain symptomatic, including initial dopamine replacement and subsequent deep brain stimulation, however, neither of these approaches is neuroprotective. Neurotrophic factors - proteins that activate cell signalling pathways regulating neuronal survival, differentiation, growth and regeneration - represent an alternative for treating dopaminergic neurons in PD but are difficult to administer clinically because they do not pass through the blood-brain barrier. Glial cell line-derived neurotrophic factor (GDNF) has potent neurotrophic effects particularly but not exclusively on dopaminergic neurons; in animal models of PD, it has consistently demonstrated both neuroprotective and neuroregenerative effects when provided continuously, either by means of a viral vector or through continuous infusion either into the cerebral ventricles (ICV) or directly into the denervated putamen. This led to a human PD study in which GDNF was administered by monthly bolus intracerebroventricular injections, however, no clinical benefit resulted, probably because of the limited penetration to the target brain areas, and instead significant side effects occurred. In an open-label study of continuous intraputamenal GDNF infusion in five patients (one unilaterally and four bilaterally), we reported excellent tolerance, few side effects and clinical benefit evident within three months of the commencement of treatment. The clinical improvement was sustained and progressive, and by 24-months patients demonstrated a 57 and 63% improvement in their off-medication motor and activities of daily living UPDRS subscores, respectively, with clear benefit in dyskinesias. The benefit was associated with a significant increase in putamenal 18F-dopa uptake on positron emission tomography (PET), and in one patient coming to autopsy after 43 months of unilateral infusion there was evident increased tyrosine hydroxylase immunopositive nerve fibres in the infused putamen. A second open trial in 10 patients using unilateral intraputamenal GDNF infusions has also demonstrated a greater than 30% bilateral benefit in both on- and off-medication scores at 24 weeks. Based on our 6-month results, a randomized controlled clinical trial was conducted to confirm the open-label results, however, GDNF infusion over 6-months did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake surrounding the catheter tip. It is possible that technical differences between this trial and the positive open label studies contributed to this negative outcome.