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Background: As Parkinson’s disease progresses, levodopa treatment loses efﬁcacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson’s disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements.
Objectives: This substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01administration.
Methods: Participants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Uniﬁed Parkinson’s Disease Rating Scale motor scores, ﬁnger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion.
Results: Of 15 PD-1101 patients, 13 participated in the sub-study. Uniﬁed Parkinson’s Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and67%, respectively, after VY-AADC01; ﬁnger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre–VY-AADC01 and 2 participants post–VY-AADC01administration.
Conclusions: VY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and ﬁndings from the parent study support further clinical development of AADC gene therapy for people with Parkinson’s disease.
Nutt JG, Curtze C, Hiller A, Anderson S, Larson PS, Van Laar AD, Richardson RM, Thompson ME, Sedkov A, Leinonen M, Ravina B, Bankiewicz KS, Christine CW (2020). Aromatic L-amino acid decarboxylase gene therapy enhances levodopa response in Parkinson's disease. Movement Disorders, 35(5), pp.851-858. doi: 10.1002/mds.27993 (IF 8.324)
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