Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease
Chadwick W Christine, Krystof S Bankiewicz, Amber D Van Laar, R Mark Richardson, Bernard Ravina, Adrian P Kells, Brendon Boot, Alastair J Martin, John Nutt, Marin E Thompson, Paul S Larson, Chadwick W Christine, Krystof S Bankiewicz, Amber D Van Laar, R Mark Richardson, Bernard Ravina, Adrian P Kells, Brendon Boot, Alastair J Martin, John Nutt, Marin E Thompson, Paul S Larson
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.
Conflict of interest statement
The authors report the following potential conflicts of interest during the conduct of this study: C.W.C. and J.N. received grants from Voyager Therapeutics, Inc.; K.S.B. received grants and personal fees from Voyager Therapeutics and holds a patent on the use of AAV2‐AADC for the treatment of Parkinson's disease licensed to Genzyme and Voyager Therapeutics, and a patent on the step cannula for gene delivery with royalties paid by MRI Interventions to UCSF; A.D.V.L., R.M.R., and A.J.M. received grants from Voyager Therapeutics; B.R. was an employee of Voyager Therapeutics and has a patent on AADC gene transfer in Parkinson's disease pending; A.P.K. was an employee of Voyager Therapeutics; B.B. was an employee of Voyager Therapeutics; M.E.T. received grants and nonfinancial support from Voyager Therapeutics; and P.S.L. received grants from Voyager Therapeutics and nonfinancial support from MRI Interventions, the company that makes the surgical delivery platform and step cannula used for gene delivery.
© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
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Source: PubMed