Objective: To investigate the safety, tolerability, and early clinical efficacy of escalating doses of AAV2-GDNF delivered into the bilateral putamen of patients with advanced PD by image-guided convection-enhanced infusion.

Background: We have previously shown that MRI-guided convection-enhanced delivery (CED) of AAV2-GDNF within the putamen was safe and able to reverse PD signs in MPTP macaques after 6 months and up to 2 years. AAV2-GDNF utilized anterograde axonal transport via striato-nigral projections that are resistant to both MPTP and idiopathic PD.

Method: Thirteen adult subjects with advanced PD received co-infusions of AAV2-GDNF and an MRI tracer into the bilateral putamen (450 µL/hemisphere). Three escalating vector genome (vg) doses (9×10^10vg, 3×10^11vg n=6 each and 9×10^11vg; n=1) were evaluated. Intraoperative MRI allowed real-time monitoring of the CED. Pre-operatively, and at 6-12-month intervals post-operatively, a UPDRS score and FDOPA PET provided assessments of motor and DA function, respectively.

Results: Three escalating doses of AAV2-GDNF delivered by CED into the bilateral putamina of advanced PD patients appeared safe and well-tolerated up to 60 months of maximum post-operative follow-up. No short- or long-term clinical or radiographic toxicities were observed. The MR tracer co-infused with the vector displayed the extent of target and off-target coverage. The average putaminal coverage attained was 26% ± 10%. UPDRS scores and levodopa equivalent daily dose remained relatively stable in all dose cohorts throughout the study. Post-operative FDOPA PET uptake within the volume of distribution was increased bilaterally in 10/13 patients at 6 months (median percentage increase = 39%; and interquartile range [IQR] of 14%-60%) and in 12/13 patients at 18 months (57%; 35%-73%). Differences in PET Ki values from baseline to post-operative timepoints were statistically significant for the bilateral CED sites (p <0.0002) suggesting a possible neurotrophic effect on residual nigrostriatal DA neurons.

Conclusion: The safety of this GDNF gene therapy in advanced PD patients, as shown by the preliminary results obtained in this Phase I trial to date, supports a new human trial  in early and advanced PD patients that extends similar and higher vector doses and maximizes putaminal coverage by increasing infusion volume and utilizing a novel surgical trajectory.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/bilateral-putaminal-aav2-gdnf-delivery-the-treatment-of-advanced-parkinsons-disease/