Authors: Davis Palmer Argersinger, B.S.; Codrin Lungu, MD; Dima Hammoud, MD; Peter Herscovitch, MD; Debra Ehrlich, MD; Gretchen Scott; Krystof Bankiewicz, MD, PhD; Kareem Zaghloul, MD, PhD; Mark Hallett, MD; Russell Lonser, MD; John Heiss, MD (Washington, DC)

Introduction: Parkinson’s disease is progressive and presently incurable. GDNF is a neurotrophic factor that prevented the death of dopaminergic neurons in culture and animal models of Parkinson’s disease (PD). Methods: In this Phase 1 clinical trial, 13 adult patients with advanced PD underwent convection-enhanced delivery (CED) of an adeno-associated virus, serotype 2 vector containing glial cell line-derived neurotrophic factor (AAV2-GDNF) to investigate the safety, tolerability, and potential clinical effects of CED of AAV2-GDNF and gadoteridol, a surrogate magnetic resonance imaging (MRI) tracer, into the bilateral putamina (450 µl per hemisphere). Three escalating dose levels were evaluated: 1) 9 x 10 10 vg (6 patients); 2) 3 x 10 11 vg (6 patients); and 3) 9 x 10 11 vg (1 patient). Intraoperative MRI was performed during infusions. Pre-operatively, and at 6-12 month intervals post-operatively, Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 assessed motor function and positron emission tomography (PET) scanning with [ 18 F]DOPA assessed F-DOPA uptake, a sign of presynaptic dopaminergic integrity. Results: The patients tolerated AAV2-GDNF infusion without short- or long-term clinical or radiographic toxicity. MRI tracked AAV2-GDNF infusion within the bilateral putamina. Average coverage of the putamina was 22%. UPDRS Part 3 assessment scores remained stable throughout the study. Increased [ 18 F]DOPA uptake in the infused areas was seen bilaterally in 10/13 patients at 6 months (range: 5-274%, median: 36%), and in 12/13 patients at 18 months after infusion (range: 8-130%, median: 54%). Conclusion: Patients with advanced PD tolerated bilateral CED of AAV2-GDNF without toxicity. Gadoteridol in the infusion solution tracked putaminal AAV2-GDNF distribution. PET findings of increased putaminal [ 18 F]DOPA uptake suggest a neurotrophic effect on dopaminergic neurons. Based on a satisfactory safety profile, a follow-up clinical trial is planned to increase putaminal coverage and possibly reverse PD progression and signs.