Bilateral Putaminal Convection of Adeno-Associated Virus Vector Serotype 2 Glial Cell Line-Derived Neurotrophic Factor Gene Therapy in Parkinson's Disease May Provide Glial Cell Line-Derived Neurotrophic Factor Transgene Expression to Caudate Nucleus: Potential Role of Perivascular and Other Low Resistance Leakage Pathways.

Abstract

Direct putaminal infusion of an adeno-associated virus vector serotype 2 (AAV2) containing the human glial cell line-derived neurotrophic factor transgene with gadoteridol tracer was investigated in a Phase I clinical trial involving participants with advanced Parkinson disease. Using convection-enhanced delivery with real-time intraoperative MRI, gadoteridol served as a surrogate imaging tracer to track infusate distribution. In 13 participants, bilateral putaminal infusions demonstrated unintended distribution of gadoteridol within the caudate nucleus in 3 cases (23% of study participants), suggesting involvement of perivascular leakage pathways and other low-resistance leakage pathways. Volumetric analysis indicated that caudate contributions ranged from 3% to 18% of the total gadolinium signal distribution. These findings highlight anatomical and perivascular interconnections as potential contributors to off-target dispersion. Although no clinical benefit was observed, this study underscores the potential for targeted caudate transduction with optimized infusion strategies. The results emphasize the need for further exploration of perivascular dynamics and volumetric coverage in future gene therapy trials for Parkinson disease and other central nervous system disorders.