Department of Neurology, University of California, San Francisco.
Department of Neurological Surgery, University of California, San Francisco.
Ann Neurol. 2019 May;85(5):704-714. doi: 10.1002/ana.25450. Epub 2019 Mar 26.
To understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.
Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 10 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 10 vg); cohort 2 received the same concentration (8.3 × 10 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 10 vg); and cohort 3 received 2.6 × 10 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 10 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes.
MRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life.
Novel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714.
了解使用新型术中监测技术进行靶向传递时，腺相关病毒血清型 2 载体编码酶（芳香族 L-氨基酸脱羧酶，VY-AADC01）的安全性、壳核覆盖率和酶表达情况，以优化传递。
15 名处于中度晚期帕金森病阶段且药物难治性运动波动的患者（每 5 例为一组，共 3 组）接受双侧 VY-AADC01 联合钆喷酸葡胺治疗，使用术中磁共振成像（MRI）引导以可视化输注物的解剖扩散并计算覆盖率。第 1 组接受 8.3×10 vg/ml 和≤450μl/壳核（总剂量，≤7.5×10 vg）；第 2 组接受相同浓度（8.3×10 vg/ml）和≤900μl/壳核（总剂量，≤1.5×10 vg）；第 3 组接受 2.6×10 vg/ml 和≤900μl/壳核（总剂量，≤4.7×10 vg）。基线和术后 6 个月时进行 18F-氟代 L-二羟苯丙氨酸正电子发射断层扫描（PET）评估酶活性；标准评估测量临床结果。
MRI 引导的递增 VY-AADC01 剂量给药导致壳核覆盖率分别为 21%（第 1 组）、34%（第 2 组）和 42%（第 3 组）。第 1、2 和 3 组分别通过 PET 评估酶活性增加 13%、56%和 79%，抗帕金森病药物减少-15%、-33%和-42%，相应地在 6 个月时得到改善。12 个月时，与剂量相关的临床结局得到改善，包括患者报告的无明显运动障碍的 ON 时间增加（分别为 1.6、3.3 和 1.5 小时）和生活质量提高。
本 1 期研究中，新型术中给药监测促进了 VY-AADC01 的靶向传递，且具有良好的耐受性。酶表达的增加和临床改善与剂量相关。临床试验注册：NCT01973543 Ann Neurol 2019;85:704-714。
