1163 Bilateral Putaminal AAV2-GDNF Gene Therapy in Parkinson’s Disease: Potential Transgene Expression to Caudate Nucleus via Perivascular and Other Low Resistance Leakage Pathways

INTRODUCTION: Advancements in CNS gene therapies have led to precise volumetric targeting of infusate distributions within subcortical brain regions using convection-enhanced delivery (CED). This study evaluates the incidence and extent of caudate nucleus distribution following bilateral putaminal infusions of AAV2-GDNF gene therapy in Parkinson's disease (PD) patients, leveraging CED. METHODS: Thirteen PD patients enrolled in a Phase I clinical trial (NCT01621581) received bilateral putaminal infusions of AAV2-GDNF and gadolinium contrast. Infusions were performed using ClearPoint Neuro Navigation Platform® and SmartFlow® cannulae, monitored by intraoperative MRI to ensure precise delivery. Infusions targeted anterior and posterior putaminal regions with escalating doses of AAV2-GDNF. Serial T1-weighted MRI sequences monitored the real-time distribution of the infusate. RESULTS: Three of the thirteen participants exhibited MRI contrast in the left caudate nucleus post-infusion. Volumetric analysis showed gadoteridol distribution volumes of 8.0 µL, 27.3 µL, and 4.9 µL in the caudate of subjects 1, 4, and 5, respectively. This indicates potential off-target infusate spread via perivascular spaces and other low resistance leakage pathways. CONCLUSIONS: Perivascular and other low resistance leakage pathways may facilitate extension of putaminal infusates to the caudate nucleus. These findings could inform future CED planning, optimizing gene therapy delivery to encompass broader striatal regions for enhanced efficacy with larger infusion volumes in PD treatment. Understanding these pathways is crucial for maximizing therapeutic impact.