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

Abstract

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.

Keywords: GDNF; Parkinson's Disease; gene therapy; movement disorders.

FIG. 1

(A) Mean (±SE) putaminal coverage. Mild cohort, n = 6; moderate cohort, n = 5. (B) Baseline and postoperative MRIs of infusion trajectories. (C) MRIs highlighting a radiographic finding. Red circles on insets indicate hypointensity adjacent to the putamen.

FIG. 2

Mean (±SE) MDS‐UPDRS scores: (A) mild and (B) moderate cohorts. Mean time in Good on, off, and with troublesome dyskinesia: (C) mild (n = 5) and (D) moderate (*n = 4) cohorts. Mean (±SE) LEDD change from baseline: (E) mild and (F) moderate cohorts. LEDD, levodopa equivalent daily dose; MDS‐UPDRS, Movement Disorder Society–revised Unified Parkinson's Disease Rating Scale.

FIG. 3

Mean (±SE) specific binding ratio recorded from DaTscan imaging analysis in the mild and moderate cohorts. DaTscan imaging was not completed for one participant in each cohort (mild cohort, n = 5; moderate cohort, n = 4).