GDNF in ideopathicParkinsons Disease

Inclusion Criteria: In order to qualify for entry into the presurgery and surgery and healing periods of the study, subjects MUST meet all of the following criteria: 1. Subjects diagnosed with idiopathic PD according to the United Kingdom (UK) Brain Bank Criteria. Bilateral findings must be present at study entry. 2. Duration of PD ≥ 5 years. 3. Age 35-75 years. 4. Presence of motor fluctuations. Subjects must have an average of at least 2.5 hours of OFF-time per day on 3-day fluctuation diaries completed during screening. 5. Ability to reliably distinguish motor states (ON without dyskinesias, ON with non-troublesome dyskinesias, ON with troublesome dyskinesias and OFF) and accurately complete fluctuation diaries. 6. UPDRS motor score (part III) in a practically defined OFF-state between 25-45. 7. Hoehn and Yahr ≤ stage III in the OFF-state. 8. Responsiveness to levodopa (\> 40% improvement in motor UPDRS \[part III\] following a levodopa challenge). 9. No change in anti-parkinsonian medication for 6 weeks before screening. 10. Females of childbearing potential must have a negative pregnancy test at study entry and be willing to use an approved (by the PI or designee) form of contraception until the end of the study. 11. Provision of informed consent. - Exclusion Criteria: Subjects who meet any of the following criteria will NOT be eligible for entry into presurgery and surgery and healing periods of the study: 1. Diagnosed with atypical parkinsonism or any known secondary parkinsonian syndrome including but not limited to medication induced, toxic, vascular, post-traumatic or post-infectious parkinsonism, progressive supranuclear palsy, multiple systems atrophy, or other neurodegenerative disorder associated with parkinsonism. 2. Signs or symptoms suggestive of atypical parkinsonian syndrome including supranuclear gaze palsy, early postural instability and falls (within 3 years of disease onset), cerebellar signs, myoclonus, disproportionate antecollis, extensor plantar responses, cortical sensory loss, emotional incontinence (pseudobulbar affect), severe bulbar dysfunction (dysarthria, dysphonia or dysphagia) or respiratory symptoms such as stridor or inspiratory sighs. 3. Family history of more than 1 first-degree relative with PD. 4. Severe dyskinesias or severe tremor which could interfere with GDNF infusion. 5. Prior neurosurgical treatment for PD, including previous treatment with GDNF or deep brain stimulation. 6. Significant neurological disorder other than PD including clinically significant head trauma, cerebrovascular disease, CSF shunt or other implanted CNS device. 7. Presence of significant depression as defined as a Beck Depression Inventory (BDI) score ≥ 14. 8. Current or past history of psychosis requiring therapy. The presence of benign hallucinosis is not exclusionary. 9. Presence or history of clinically significant impulse control disorder or presence or history of dopamine dysregulation syndrome. 10. MoCA score \< 24. 11. Use within 3 months of planned catheter insertion of concomitant medications known to affect PD symptoms other than prescribed PD therapy including but not limited to neuroleptics or other central dopamine receptor blockers. 12. Any medical condition which might impair outcome measure assessments or safety measures including ability to undergo MRI scanning. 13. Screening MRI demonstrating any abnormality which would suggest an alternative cause for subject's parkinsonism. 14. Any medical condition that would put the subject at undue risk from surgical treatment or chronic implants including but not limited to bleeding disorders, chronic infections, or immunosuppressive illness. 15. History within the last 5 years of cancer with the exception of basal cell carcinoma of the skin. 16. History of drug or alcohol abuse within 2 years of planned catheter insertion. 17. Use of any investigational drug or device within 90 days of planned catheter insertion. 18. Active breastfeeding. 5.3.4 Post-Surgery Randomisation Criteria In order to be eligible for entry into the double-blind period of the study, subjects must meet the following criteria after undergoing surgery: 1. No relevant sequelae from catheter implantation such as clinically significant intracerebral trauma, haemorrhage, or infection. 2. Total distribution volume providing at least 50% volume coverage of a predefined volume of interest in each putamen (approximately 25% volume coverage of total putamen), as assessed by an independent review of an MRI scan taken within 2 hours post-infusion of diluent at the end of the healing period.