Phase 1b Safety and Preliminary Efficacy of Bilateral Intraputaminal Delivery of AAV2 GDNF (AB-1005) in Participants With Mild or Moderate Parkinson’s Disease
Amber Van Laar1, Chadwick Christine2, Aristide Merola3, Nicolás Phielipp5, Bradley Elder4, Paul Larson6, Waldy San Sebastian1, Massimo Fiandaca1, Adrian Kells1, Krystof Bankiewicz4
1CNS, Asklepios BioPharmaceutical, Inc., 2Neurology, University of California San Francisco, 3Neurology, 4Neurological Surgery, The Ohio State University, 5Neurology, University California, Irvine Health, 6Neurosurgery, University of Arizona College of Medicine
Objective:
To assess safety and preliminary efficacy of adeno-associated virus vector serotype 2 containing glial cell‒derived neurotrophic factor (AAV2-GDNF), AB-1005, in participants with mild or moderate Parkinson’s disease (PD) administered using magnetic resonance imaging (MRI)-monitored, one-time bilateral, convection-enhanced delivery (CED).
Background:

GDNF is required for development and survival of dopaminergic neurons. GDNF putaminal transduction via gene therapy is a promising approach to durably restore dopaminergic network function.

Design/Methods:
This phase 1b trial (NCT04167540) enrolled participants with mild (<5 years post-diagnosis, Movement Disorder Society Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] III OFF score ≤32) and moderate (≥4 years; MDS-UPDRS III 33‒60) PD. Participants received up to 1.8 mL AAV2-GDNF (3.3e12 vg/mL/gadoteridol 2mM co-infusion) per putamen via MRI-monitored CED and optimized neurosurgical technique. The primary outcome was safety (adverse events [AE]). Outcomes were assessed using PD clinical-rating scales.
Results:
Of 11 participants enrolled (n=5, Mild Cohort; n=6, Moderate Cohort), 10 are 18-months post-treatment. Mean (SE) putaminal coverage was 63% (2%). Asymptomatic, small, unilateral T1 hypointensities were observed in 3 participations at 6 months. All participants experienced treatment-emergent AE; most were transient and perioperative. Serious AEs (n=5) were unrelated to AAV2-GDNF. The Mild Cohort exhibited stable MDS-UPDRS, motor diary, unified dyskinesia rating scale (UDysRS) scores, and levodopa equivalent daily dose (LEDD). One Mild Cohort participant had heterozygous tyrosine hydroxylase mutation of unknown significance. At 18 months post-treatment, the Moderate Cohort demonstrated improvements from baseline in mean±SE MDS-UPDRS Part III OFF scores (–18.8±6.6), motor diary OFF time (−2.20±1.26 h), UDysRS (−2.75±2.29), and LEDD (−321.9±192.15 mg).
Conclusions:
Analysis of this phase 1b trial is ongoing; topline 18-month data will be presented. These preliminary findings suggest AAV2-GDNF is well tolerated in participants with PD, demonstrating general stability of the Mild Cohort and possible clinical benefit in the Moderate Cohort. A phase 2 randomized controlled study is planned to confirm these findings.
10.1212/WNL.0000000000206690