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

• Published in: Annals of neurology Vol. 85; no. 5; pp. 704 - 714
• Main Authors: Christine, Chadwick W., Bankiewicz, Krystof S., Van Laar, Amber D., Richardson, R. Mark, Ravina, Bernard, Kells, Adrian P., Boot, Brendon, Martin, Alastair J., Nutt, John, Thompson, Marin E., Larson, Paul S.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.05.2019; Wiley Subscription Services, Inc
• Subjects: AADC gene; Adult; Aged; Amino acids; Aromatic-L-Amino-Acid Decarboxylases - administration & dosage; Aromatic-L-Amino-Acid Decarboxylases - genetics; Clinical outcomes; Complementary DNA; Deoxyribonucleic acid; Dihydroxyphenylalanine; DNA; Dosage; Dyskinesia; Emission analysis; Enzymatic activity; Enzyme activity; Enzymes; Female; Gene expression; Gene therapy; Gene Transfer Techniques; Genetic Therapy - methods; Humans; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Medical imaging; Middle Aged; Monitoring; Movement disorders; Neurodegenerative diseases; NMR; Nuclear magnetic resonance; Parkinson Disease - diagnostic imaging; Parkinson Disease - genetics; Parkinson Disease - therapy; Parkinson's disease; Positron emission; Positron emission tomography; Putamen; Putamen - diagnostic imaging; Quality of life; Resonance; Tomography
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.25450

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 × 1011vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 1011vg); cohort 2 received the same concentration (8.3 × 1011vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 1012vg); and cohort 3 received 2.6 × 1012vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 1012vg). (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