Safety and Efficacy of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes

The PD-1101 trial, a phase 1b, open-label, dose escalation study, evaluated the safety and clinical outcomes of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme, in patients with moderately advanced Parkinson disease (PD) and motor fluctuations. The therapy was administered via bilateral, intraoperative MRI-guided putaminal infusions across three cohorts with escalating doses.

Over the three-year follow-up, no serious adverse events (SAEs) attributed to VY-AADC01 were reported. The study observed a reduction in PD medication requirements by 21%-30% in the two highest dose cohorts. Motor function, as measured by the Unified Parkinson's Disease Rating Scale III (UPDRS III) and PD diary, showed stability or improvement compared to baseline. Quality of life assessments also indicated stability or improvement across cohorts.

The trial's findings suggest that VY-AADC01 and the surgical administration procedure are well-tolerated, with potential long-term benefits for motor function and quality of life in patients with moderately advanced PD. The study provides Class IV evidence supporting the safety and potential efficacy of putaminal infusion of VY-AADC01 in this patient population.

This research highlights the promise of gene therapy as a durable treatment option for PD, offering a single administration that could provide lasting clinical benefits. However, the study acknowledges the need for further research, including sham surgery-controlled trials, to robustly assess the efficacy of VY-AADC01.