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- Title
Real-time MRI-guided intraputaminal AADC gene therapy for advanced Parkinson's disease.
- Authors
Richarson, Mark; Christine, Chadwick W.; Bankiewicz, Krystof S.; Van Laar, Amber; Ravina, Bernard; Kells, Adrian; Boot, Brendon; Larson, Paul S.
- Abstract
In PD, loss of aromatic L-amino acid decarboxylase (AADC), which converts levodopa into dopamine, is associated with loss of oral levodopa effectiveness. We are evaluating the safety of AADC gene therapy in an ongoing Phase 1b clinical trial. To improve upon limited coverage of the anatomic target in prior studies, intraputaminal gene expression is achieved by intraoperative-MRI-guided co-infusion of AAV2-hAADC and gadoteridol. Fifteen subjects (N=5/cohort) with advanced PD received bilateral infusions of either a lower concentration (0.83x1012vg/ml), ≤ 450 μl/putamen (cohort 1), ≤ 900 μl/putamen (cohort 2), or higher concentration (2.7x1012vg/ml) ≤ 900 μl/putamen (cohort 3). The infusion strategy evolved to maximize coverage of the putamen by modifying cannula design, altering the position of infusion sites along cannula trajectories, and increasing infusion volumes. These steps resulted in an increase in average infusate coverage of the putamen from 21% to 34% and 42% (cohorts 1,2 and 3, respectively). Infusions were well tolerated. Enzyme activity on 18F-dopa PET increased from 13% (cohort 1) to 56% (cohort 2). Imaging and clinical data are pending for cohort 3. We observed coverage-dependent reductions in dopaminergic medications and improvements in motor function in subjects who have reached 12-month follow-up, including: 10% (cohort 1) and 35% (cohort 2) reductions in dopaminergic medications; 1.8-point (cohort 1) and 9.3-point (cohort 2) improvements in UPDRS III on medications; 1.6-hour (cohort 1) and 4.1-hour (cohort 2) increases in on-time without troublesome dyskinesia. Real-time-MRI-guided delivery allows modification of infusions that maximize target coverage and potential coverage-related clinical benefits.
- Publication
Stereotactic & Functional Neurosurgery, 2017, Vol 95, p170
- ISSN
1011-6125
- Publication type
Article