A Phase 1 Study of Convection‐Enhanced Delivery of Intraputaminal AAV2 ‐ GDNF in Advanced Parkinson's Disease

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Neurotrophic therapeutic approaches have been limited in part by incomplete delivery to the putamen. We developed image-guided convection-enhanced delivery with real-time monitoring to improve intraputaminal distribution of neurotrophic gene therapy. OBJECTIVES: To evaluate the 5-year safety and tolerability of bilateral putaminal delivery of adeno-associated virus serotype 2 encoding glial cell line-derived neurotrophic factor (AAV2-GDNF), and to describe exploratory long-term clinical outcomes. METHODS: This was a single-center, open-label, phase 1, dose-escalation study in adults with advanced PD. Thirteen participants received bilateral putaminal infusions across three dose cohorts (six low-dose, six medium-dose, one high-dose) and were followed for 5 years. Adverse events, including serious adverse events, were collected, and their relationship to the study agent was determined. Longitudinal clinical outcomes were analyzed with a mixed-effects model. RESULTS: Across follow-up, 562 adverse events were recorded; 45 were considered possibly or probably related to the study drug. The 13 serious adverse events that occurred were not attributed to the study drug. One participant died 45 months after infusion from aspiration pneumonia following cervical spine surgery at an outside institution. The study drug had a mean putaminal coverage of 26% ± 10%. Exploratory clinical measures did not change significantly between baseline and final follow-up. CONCLUSIONS: Bilateral putaminal neurotrophic gene therapy delivered with real-time image guidance was well tolerated over 5 years, without protocol-defined stopping events.