AAV2-GDNF for Advanced Parkinson s Disease

Background: \- Glial cell line-derived neurotrophic factor (GDNF) is a chemical that may help protect and strengthen brain cells that produce dopamine. Dopamine is a chemical that affects brain function. People with Parkinson's disease (PD) have problems producing dopamine in the brain. Researchers want to see if gene transfer can help deliver GDNF into the area of the brain that is damaged by PD. The gene transferred in this study, called AAV2-GDNF, may help produce GDNF to protect the damaged brain cells. Objectives: \- To test the safety and effectiveness of AAV2-GDNF gene transfer for advanced PD. Eligibility: \- Individuals at least 18 years of age who have advanced PD that is not well controlled by medications. Design: * Participants will be in the study for about 5 years. There will be 18 outpatient study visits and a 3-day stay in the hospital. There may also be overnight stays for followup visits. * Participants will be screened with a physical exam and medical history. Blood samples will be collected. Tests of PD symptoms and mood and memory will be given. Imaging studies will be used to find the right part of the brain to infuse the gene. The screening visit will take place up to 60 days before surgery. * Participants will have a baseline visit about a month before the surgery. For 1 week before the baseline visit, participants will keep a diary on any motor problems. The visit will involve movement tests given before and after taking a regular dose of levodopa. * Participants will have surgery to infuse AAV2-GDNF into the brain. The surgery will also include a lumbar puncture (spinal tap) to collect cerebrospinal fluid. After surgery, participants will recover in the hospital for at least 2 days. * Participants will have another lumbar puncture 6 and 18 months after surgery. This will be an outpatient visit. * Participants will have regular followup visits after the surgery. These visits will include neurological tests and movement studies. Visits with a neurosurgeon will take place 1, 2, and 4 weeks after surgery. Additional visits will take place every 3 months for the first 3 years, and then at longer intervals for up to 5 years.

* INCLUSION CRITERIA: Greater than 18 years of age. Diagnosed with Idiopathic PD. * Bradykinesia and * At least 3 of the following clinical features: resting tremor, cogwheel rigidity, bradykinesia, postural reflex impairment. The above clinical features must not be due to trauma, brain tumor, infection, cerebrovascular disease, other known neurological disease (e.g., hereditary form of PD, multiple system atrophy, progressive supranuclear palsy, striatonigral degeneration, Huntington s disease, Wilson s disease), or to known drugs, chemicals or toxicants. Disease duration of \> 5 years. Hoehn and Yahr Stage III or IV off medication. Disability present despite optimal antiparkinsonian medication therapy. Disability will be operationally defined as a Modified Schwab and England Activities of Daily Living Scale score of 80% or lower (during the off state). Unified PD Rating Scale (UPDRS) (Fahn et al., 1987) total motor score greater than or equal to 30 in the defined off state. Unequivocal responsiveness to levodopa, based on the single-dose levodopa test (as described in the CAPIT and CAPSIT guidelines). A 30% or greater improvement in the UPDRS total motor score will be required to establish unequivocal responsiveness to levodopa. Able to provide proper Informed Consent. Laboratory values at screening visit (unless other visit specified): * Platelets \>100,000/mm3 (transfusion independent) * PT/PTT in normal range and INR less than or equal to 1.3 (on day prior to surgery, if taking anti-coagulants) * Absolute neutrophil count (ANC) \>1500/mm3 * Hemoglobin \>10.0 g/dL (transfusion allowed) * Aspartate aminotransferase or alanine aminotransferase \