Intraputaminal Delivery of Adeno-Associated Virus Serotype 2-Glial Cell Line-Derived Neurotrophic Factor in Mild or Moderate Parkinson's Disease.

BACKGROUND Glial cell line-derived neurotrophic factor (GDNF) is required for development and survival of dopaminergic neurons. A previous trial evaluating lower-dose adeno-associated virus serotype 2-GDNF (AAV2-GDNF) bilateral intraputaminal infusion in participants with advanced Parkinson's disease (PD) achieved 26% mean putaminal coverage and was associated with stable motor features with no unexpected adverse events (AEs) over 60 months. OBJECTIVE We assessed safety and preliminary clinical outcomes of optimized bilateral intraputaminal infusion of a single, higher dose of AAV2-GDNF (product code AB-1005) for PD after 18 months. METHODS This phase 1b single-arm, open-label clinical trial enrolled participants with mild (Movement Disorder Society-revised Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III off score ≤ 32) and moderate (MDS-UPDRS Part III off score of 33-60) PD. The primary outcome was safety. Clinical outcomes were assessed using PD-specific clinical measures. RESULTS Eleven participants were enrolled (n = 6 mild; n = 5 moderate). Mean (±SE) putaminal coverage of AAV2-GDNF was 63% (±2%). All participants experienced treatment-emergent AEs (63 events); most were transient and perioperative. Six serious AEs in three participants were unrelated to AAV2-GDNF. At 18 months posttreatment, the mild cohort exhibited numerically stable MDS-UPDRS, motor diary, Unified Dyskinesia Rating Scale (UDysRS) scores, and levodopa equivalent daily dose (LEDD). The moderate cohort demonstrated numerical improvements in mean (±SE) MDS-UPDRS Part III off scores (-20.4 [±4.5]), motor diary off time (-1.7 [±1.1] hours), and UDysRS scores (-2.2 [±1.9]) and reduced LEDD (-257.6 [±162.2] mg). CONCLUSIONS Bilateral intraputaminal AAV2-GDNF gene therapy was well tolerated and associated with numerical stability (mild cohort) and improvement (moderate cohort) in clinical assessments at 18 months posttreatment. © 2025 AskBio Inc and The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.