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

Autor: Christine CW; Department of Neurology, University of California, San Francisco., Bankiewicz KS; Department of Neurological Surgery, University of California, San Francisco., Van Laar AD; Department of Neurology, University of Pittsburgh., Richardson RM; Department of Neurological Surgery, University of Pittsburgh., Ravina B; Voyager Therapeutics, Inc., Kells AP; Voyager Therapeutics, Inc., Boot B; Voyager Therapeutics, Inc., Martin AJ; Department of Radiology and Biomedical Imaging, University of California, San Francisco., Nutt J; Department of Neurology, Oregon Health Sciences University., Thompson ME; Department of Neurological Surgery, University of California, San Francisco., Larson PS; Department of Neurological Surgery, University of California, San Francisco.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2019 May; Vol. 85 (5), pp. 704-714. Date of Electronic Publication: 2019 Mar 26.
DOI: 10.1002/ana.25450
Abstrakt: 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 × 10 11 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 10 11 vg); cohort 2 received the same concentration (8.3 × 10 11 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 10 12 vg); and cohort 3 received 2.6 × 10 12 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 10 12 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.
(© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)
Databáze: MEDLINE
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