Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease

Abstract

Objective: 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.

Methods: 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 × 10¹¹ vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 10¹¹ vg); cohort 2 received the same concentration (8.3 × 10¹¹ vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 10¹² vg); and cohort 3 received 2.6 × 10¹² vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 10¹² vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes.

Results: 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.

Interpretation: 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.

Figure 1

Representative MP‐RAGE images during simultaneous bilateral administration of VY‐AADC01 in the putamen. Axial image (left) shows gadoteridol enhancement as a surrogate marker for vector distribution with two administrations in the posterior portion of each putamen. Coronal oblique image (right) in‐plane with the right infusion cannula during vector delivery; part of the skull mounted SmartFrame aiming device is visible above the burr hole (white arrow), as is the SmartFlow cannula (black arrow). MP‐RAGE = magnetization‐prepared rapid gradient echo.

Figure 2

Percentage increase from baseline in ¹⁸F‐dopa PET signal of AADC activity and corresponding reductions in levodopa equivalent dose at 6 months. The top of the figure shows the increase in ¹⁸F‐dopa PET assessment of AADC activity by cohort with increasing administration volume in cohort 2 and the same volume with an increase in genome concentration in cohort 3. The bottom of the figure shows corresponding reductions in levodopa equivalent dosing. LED = levodopa equivalent dose; PET = positron emission tomography.

Figure 3

Mean (±SE) change from baseline in UPDRS‐III assessed in the on‐ (A) and off‐medication (B) states. Change in UPDRS‐III scores in the on‐ (A) and off‐medication (B) states. Mean score reductions (improvements) were observed in cohorts 2 and 3 on medication and all three cohorts off medication through last follow‐up. Note that UPDRS data were not collected at month 18 for cohorts 1 and 2. UPDRS = Unified Parkinson's Disease Rating Scale.

Figure 4

Time‐action curve for UPDRS‐III for threshold and suprathreshold infusions of intravenous levodopa at baseline and approximately 6 months after administration of VY‐AADC01. The figure shows the UPDRS‐III time‐action curves following a threshold (0.6 mg/kg/h; left side) and suprathreshold (1.2 mg/kg/h; right side) intravenous dose of levodopa by cohort (A,B: cohort 1; C,D: cohort 2; E,F: cohort 3). Lower scores indicate improvement. Dashed lines in each figure show data before VY‐AADC01 administration and solid lines postadministration. The gray box shows the actual infusion time. Note in cohort 2 the time‐action curve for threshold (low‐dose) intravenous levodopa post‐VY‐AADC01 administration (C) appears similar to the suprathreshold (high‐dose) intravenous levodopa pre‐VY‐AADC01 administration (D). AUC = area under the curve; UPDRS = Unified Parkinson's Disease Rating Scale.

Figure 5

Mean diary ON and OFF time per 16‐hour waking day. Across cohorts, good quality ON time (green bars; ON time with no dyskinesia plus ON time with nontroublesome dyskinesia) increased over time, and both OFF time and ON time with troublesome dyskinesia decreased over time. NTD = nontroublesome dyskinesia; TD = troublesome dyskinesia.