Trial of magnetic resonance–guided putaminal gene therapy for advanced Parkinson's disease

作者：John D. Heiss, Codrin Lungu, Dima A. Hammoud, Peter Herscovitch, Debra Ehrlich, Davis P. Argersinger, Sanhita Sinharay, Gretchen Scott, Tianxia Wu, Howard J. Federoff, Kareem A. Zaghloul, Mark Hallett, Russell R. Lonser, Krystof S. Bankiewicz · 发表于：Movement Disorders · 年份：2019 · DOI：10.1002/mds.27724 · 被引用次数：124 · 研究领域：Virus-based gene therapy research、CRISPR and Genetic Engineering、Nerve injury and regeneration

Abstract Objective To investigate the safety and tolerability of convection‐enhanced delivery of an adeno‐associated virus, serotype‐2 vector carrying glial cell line‐derived neurotrophic factor into the bilateral putamina of PD patients. Methods Thirteen adult patients with advanced PD underwent adeno‐associated virus, serotype‐2 vector carrying glial cell line‐derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 μL/hemisphere) at escalating doses: 9 × 10 10 vg (n = 6); 3 × 10 11 vg (n = 6); and 9 × 10 11 vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [ 18 F]FDOPA‐PET scanning preoperatively and 6 and 18 months postoperatively. Results Adeno‐associated virus, serotype‐2 vector carrying glial cell line‐derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [ 18 F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5–274% and 8–130%; median, 36% and 54%), respectively. Ki differences between baseline and 6‐ and 18‐month follow‐up were statistically significant ( P < 0.0002). Conclusion Adeno‐associated virus, serotype‐2 vector carrying glial cell line‐derived neurotrophic factor infusion was safe and well tolerated. Increased [ 18 F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. © 2019 International Parkinson and M...