Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease
| Autor: | Alastair J. Martin, Adrian P. Kells, Marin E. Thompson, Bernard Ravina, Amber D. Van Laar, Brendon P. Boot, Chadwick W. Christine, Paul S. Larson, R. Mark Richardson, John G. Nutt, Krystof S. Bankiewicz |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Male Parkinson's disease Genetic enhancement Clinical Sciences 03 medical and health sciences 0302 clinical medicine Clinical Research medicine Humans Research Articles Aged Neurology & Neurosurgery medicine.diagnostic_test Gadoteridol business.industry Putamen Gene Transfer Techniques Neurosciences Magnetic resonance imaging Parkinson Disease Genetic Therapy Middle Aged medicine.disease Magnetic Resonance Imaging 030104 developmental biology Neurology Dyskinesia Positron emission tomography Aromatic-L-Amino-Acid Decarboxylases Cohort Biomedical Imaging Female Neurology (clinical) medicine.symptom business Nuclear medicine 030217 neurology & neurosurgery medicine.drug Research Article |
| Zdroj: | Annals of neurology, vol 85, iss 5 Annals of Neurology |
| Popis: | Author(s): 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 | Abstract: ObjectiveTo 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.MethodsFifteen 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.ResultsMRI-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.InterpretationNovel 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. |
| Databáze: | OpenAIRE |
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