Objective: Assess the safety and tolerability of intraputaminal AAV2-GDNF in mild to moderate PD

Background: Glial cell line-derived neurotrophic factor (GDNF) is critical for dopaminergic neuron development and survival. The neurorestorative potential of GDNF is evaluated in this Phase Ib trial, using a single high AAV2-GDNF vector dose and increased putaminal coverage to test the safety and possible clinical benefit in 2 PD cohorts on levodopa treatment. An earlier study of lower doses in advanced PD showed safety and stabilization of symptoms for up to 5 years.

Method: Six PD participants in the “Mild Cohort” (MDS-UPDRS III OFF <32; PD diagnosis 2.1±0.6 years; mean LED 541mg/day) and 4 in the “Moderate Cohort” (MDS-UPDRS III 33-60; PD diagnosis 8.3 ± 0.7 years; mean LED 840mg/day) underwent MRI-monitored, direct intracranial convective delivery of AAV2-GDNF (3.3E+12 vg/mL) to cover >50% of each putamen (≤1.8mL per putamen). Safety assessments, including MRIs at 6- and 18-months, and impact of AAV2-GDNF gene delivery on PD symptomatology was measured via neurological assessments (MDS-UPDRS, PD Motor Diary, NMSS, PDQ-39), and changes in LED, are ongoing. Data reported as mean absolute change±SEM.

Results: The neurosurgical procedure was well tolerated and all 10 participants have completed 9-18 months of clinical follow-up. Putaminal coverage was 63%±2% and 6-month MRIs showed expected post-surgical changes. No SAEs were associated with AAV2-GDNF. Reported AEs primarily occurred peri-operatively or were related to underlying PD.

Mild cohort: At the 6-month assessments compared to pre-treatment scores: MDS-UPDRS III in OFF state -2.7±2.3 pts, MDS-UPDRS II 0.8±1.4pts, Diary OFF time 0.8±0.8hrs with similarly unchanged scores on PDQ-39 and NMSS.

Moderate cohort: The 6-month assessments: MDS-UPDRS III in OFF state -13.0±3.7pts, MDS-UPDRS II -2.3±4.3pts, Diary OFF time -3.4±0.7hrs. Improvements were noted on PDQ-39 and NMSS.

Conclusion: A positive safety profile is emerging from this Phase Ib study of AAV2-GDNF in 2 cohorts of levodopa treated PD subjects. Although the placebo effect limits interpretation of small open-label studies, these preliminary findings show stabilization in the Mild Cohort and possible early improvements in the Moderate Cohort. Further longitudinal evaluation and a controlled study is planned to confirm these initial findings.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gdnf-gene-therapy-for-parkinsons-disease-pd-preliminary-safety-and-clinical-findings-from-a-phase-ib-study/