5-Year Data Support Safety of MRI-Guided AAV2-GDNF Gene Therapy in Advanced Parkinson Disease

A phase 1 study (NCT01621581) of bilateral putaminal delivery of adeno-associated virus serotype 2 encoding glial cell line-derived neurotrophic factor (AAV2-GDNF) using MRI-guided convection-enhanced delivery (CED) showed that the investigational gene therapy was well tolerated over 5 years in patients with advanced Parkinson disease (PD). No protocol-defined stopping events reported from the study, but exploratory clinical measures did not demonstrate significant changes from baseline over the follow-up period.¹

Published in Movement Disorders, the single-center, open-label, dose-escalation study included 13 adults with advanced PD who received bilateral putaminal AAV2-GDNF infusions across 3 dose cohorts. Six participants received 9 × 10¹⁰ vector genomes (vg), 6 received 3 × 10¹¹ vg, and 1 received 9 × 10¹¹ vg. Participants were followed for 5 years after treatment.

The primary objective was to assess the long-term safety and tolerability of the approach. Investigators also conducted exploratory assessments of clinical outcomes using the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr staging, Lang-Fahn Dyskinesia Rating Scale, modified Rankin Scale (mRS), Schwab and England Activities of Daily Living Scale, and levodopa equivalent daily dose (LEDD).

5-Year Safety Findings

Across the 5-year follow-up period, 562 adverse events (AEs) were recorded, 45 of which were considered possibly or probably related to the study drug. Thirteen serious AEs occurred, none of which were attributed to AAV2-GDNF.¹

One participant died 45 months after receiving the investigational therapy from aspiration pneumonia following anterior cervical diskectomy and fusion performed at an outside institution. Postmortem examination confirmed aspiration pneumonia as the cause of death, and investigators determined that the event was not related to the study drug.

Importantly, none of the study's prespecified stopping guidelines were triggered during follow-up. These included death within 1 year of treatment, clinically significant intracerebral hemorrhage, central nervous system infection, brain tumor or malignancy, suicide, clinical or MRI evidence of cerebellar damage, or multiple serious AEs of grade 3 or 4 severity considered at least possibly related to the gene transfer product.

Most AEs were considered related to the surgical procedure rather than the vector. These included several transient laboratory abnormalities as well as events such as electrolyte disturbances and pain.

The long-term findings provide safety data for an approach designed to overcome a major challenge associated with neurotrophic therapies in PD: achieving sufficient delivery and distribution throughout the putamen.

Putaminal Coverage and Biological Activity

Intraoperative MRI demonstrated that the AAV2-GDNF infusions covered a mean 26% [±10%] of the putamen. Investigators also observed off-target distribution of the co-infused gadoteridol contrast agent, with spread beyond the putamen occurring through perivascular spaces or cannula backflow.¹

A subsequent analysis of the same cohort found unintended gadoteridol distribution in the caudate nucleus in 3 of 13 participants, with caudate signal accounting for 3% to 18% of total gadolinium distribution. These findings further highlighted the influence of anatomic pathways and infusion technique on vector distribution.

The investigators had previously reported evidence of increased [18F]F-DOPA positron emission tomography (PET) uptake at the bilateral infusion sites following AAV2-GDNF administration. Changes in PET-derived influx constant values from baseline to postoperative assessments were statistically significant (P <.0002), suggesting localized biological activity and a potential neurotrophic effect on residual nigrostriatal dopaminergic neurons.

However, the imaging findings did not translate into statistically significant improvements across the study's global clinical measures. The investigators noted that this apparent dissociation may reflect the limited spatial coverage of the infusion, as well as the difficulty of detecting localized biological effects with clinical measures that assess broader disease severity.

"Delivery remains a central constraint for intraputaminal trophic strategies," the investigators wrote, noting that real-time contrast monitoring could help refine catheter trajectories, infusion parameters, and infusion volumes to improve on-target coverage in future studies.

This issue may be particularly relevant as AAV2-GDNF development moves toward delivery strategies designed to achieve greater putaminal coverage. The authors cited a 2025 phase 1b study in less advanced PD in which a higher dose of AAV2-GDNF achieved approximately 63% putaminal coverage, along with preliminary clinical and motor-complication signals.

Clinical Outcomes and Study Limitations

Across the 5-year follow-up, exploratory clinical outcomes generally remained stable, although the study was not designed or powered to establish efficacy.

For UPDRS Part III, which assesses motor function, mixed-effects models showed no evidence of change over time in either the OFF medication state (P = .82) or ON state (P = .62). UPDRS Part IV, assessing motor complications, also did not significantly change over time (P = .054).¹

There was similarly no significant change in LEDD over the study period (P = .10). Mean LEDD decreased descriptively following treatment and remained lower through approximately 18 months before gradually increasing at later time points. The increase at 60 months was substantially influenced by a marked increase in medication requirements in 1 participant. Investigators also found no significant changes in Hoehn and Yahr staging (P = .09), Lang-Fahn dyskinesia measures, mRS scores (P = .97), or Schwab and England Activities of Daily Living scores (P = .73).

Although UPDRS Parts I and II showed significant increases over time in mixed-effects models, these findings were driven primarily by differences at the 60-month time point. The authors emphasized that the broader clinical findings should be interpreted cautiously given the small cohort and exploratory nature of the analyses.

The study had several limitations, including its phase 1, single-center, open-label design, small sample size, lack of a blinded control group, and incomplete enrollment across dose cohorts. Only 1 participant received the highest dose, limiting the ability to assess dose-response relationships.

The absence of a control group also makes it difficult to distinguish potential treatment effects from expectancy effects, medication optimization, or the additional specialist contact associated with long-term study participation. Attrition and incomplete follow-up data further limited interpretation of late time points, while the study was not powered to detect modest clinical changes across heterogeneous trajectories of advanced PD.

Taken together, the 5-year findings support the long-term tolerability of MRI-guided CED for bilateral intraputaminal AAV2-GDNF delivery in advanced PD while highlighting the importance of improving vector distribution and establishing controlled clinical endpoints. The investigators noted that the findings provide long-term safety and clinical trajectory data that can serve as a reference for subsequent studies evaluating delivery-optimized approaches to AAV2-GDNF gene therapy.

Reference
1. Heiss JD, Ehrlich DJ, Lungu C, et al. A phase 1 study of convection-enhanced delivery of intraputaminal AAV2-GDNF in advanced Parkinson's disease. Mov Disord. Published online July 6, 2026. doi:10.1002/mds.70393