A Phase 1 Open-Label Dose Escalation Safety Study of Convection Enhanced Delivery (CED) of Adeno-Associated Virus Encoding Glial Cell Line-Derived Neurotrophic Factor (AAV2-GDNF) in Subjects with Advanced Parkinson’s Disease

Active, No Longer Recruiting
National Institute of Neurological Disorders and Stroke (NINDS)
Study Design: 
This is a phase 1 single center, open-label, dose escalation, safety and tolerability study of the AAV2-GDNF (adeno-associated virus, serotype 2 containing the human GDNF complementary DNA). The active drug will be delivered surgically by convection-enhanced delivery to bilateral putamina. The study includes 4 cohorts to evaluate the four escalating dose levels. Each cohort will have 6 subjects. The drug level for each cohort is as follows: Cohort 1: 9 x 10 sup.10 vg; Cohort 2: 3 x 10 sup.11 vg; Cohort 3: 9 x 10 sup.11 vg; Cohort 4: 3 x 10 sup.12 vg. The study includes individuals 18 years and above with clinical idiopathic PD of at least 5 years disease duration with no other known or suspected cause for parkinsonism. An Off state UPDRS score of more than or equal to 30 and Hoehn and Yahr stage of III and IV are required for inclusion. The study also requires a 30% or greater improvement in the UPDRS total motor score on sinemet study according to the CAPSIT guidelines. The participants in the study will be followed for 5 years with 18 outpatient study visits and a 3-day stay in the hospital post-surgery. Lumbar puncture for CSF analysis will be done at the time of surgery, 6 months and 18 months after surgery.
Primary outcome measure: To assess the safety and tolerability of 4 different dose levels of AAV2-GDNF over a period of 12 years. Secondary outcome measures: To obtain preliminary data regarding the potential for clinical responses of the 4 dose levels testing by assessing the magnitude and variability of any treatment effects including clinical, laboratory and neuroimaging studies.
GDNF and neurturin have been studied extensively as potential neuroprotective interventions in PD so far with disappointing results despite reproducibly positive data in preclinical models. It remains to be determined if lack of success in PD clinical trials reflects a lack of biological effect of intervention, limitations of the technical delivery modes (insufficient coverage of putamen, dose, etc) or failure to reverse the course of the advanced disease at the time of intervention. The ongoing study will be closely followed.