Aromatic L-Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson's Disease

John G Nutt, Carolin Curtze, Amie Hiller, Shannon Anderson, Paul S Larson, Amber D Van Laar, R Mark Richardson, Marin E Thompson, Alexander Sedkov, Mika Leinonen, Bernard Ravina, Krystof S Bankiewicz, Chadwick W Christine, John G Nutt, Carolin Curtze, Amie Hiller, Shannon Anderson, Paul S Larson, Amber D Van Laar, R Mark Richardson, Marin E Thompson, Alexander Sedkov, Mika Leinonen, Bernard Ravina, Krystof S Bankiewicz, Chadwick W Christine

Abstract

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-AADC01 administration.

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 substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, 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-AADC01 administration.

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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: AADC; Parkinson's disease; VY-AADC01; gene therapy; levodopa.

© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Figures

Figure 1
Figure 1
Change from baseline in UPDRS III scores over time during and following threshold and suprathreshold infusions of intravenous levodopa pre– and post–VY‐AADC01 administration. A reduction in UPDRS III scores represents improvement. Gray shaded area shows actual time of infusion. Figure is a modified reproduction from reference 26, used with permission under the author reuse policy of the publisher. SEM, standard error of the mean; UPDRS, Unified Parkinson's Disease Rating Scale.
Figure 2
Figure 2
Time to 30% change in UPDRS III scores (A) and duration of ≥30% UPDRS response (B) after threshold and suprathreshold IV levodopa infusion pre– and post–VY‐AADC01 administration. IV, intravenous; SEM, standard error of the mean; UPDRS, Unified Parkinson's Disease Rating Scale.
Figure 3
Figure 3
Change from baseline in finger‐tapping speed over time during and following threshold and suprathreshold infusions of intravenous levodopa pre– and post–VY‐AADC01 administration. Increase in finger‐tapping speed represents improvement. Gray shaded area shows actual time of infusion. SEM, standard error of the mean.
Figure 4
Figure 4
Change from baseline in dyskinesia rating scale scores during and following threshold and suprathreshold infusions of intravenous levodopa pre– and post–VY‐AADC01 administration. Increase in dyskinesia rating scale score indicates worsened dyskinesia. Gray shaded area shows actual time of infusion. SEM, standard error of the mean.
Figure 5
Figure 5
UPDRS III scores (A) and finger‐tapping speeds (B) at baseline of intravenous levodopa challenge pre– and post–VY‐AADC01 administration. Baseline score for each participant is the mean of baseline scores from threshold and suprathreshold infusion days. A reduction in UPDRS III score represents improvement. Increase in finger‐tapping speed represents improvement. SEM, standard error of the mean; UPDRS, Unified Parkinson's Disease Rating Scale.

References

    1. Caminiti SP, Presotto L, Baroncini D, et al. Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease. Neuroimage Clin 2017;14:734–740.
    1. Kordower JH, Olanow CW, Dodiya HB, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. Brain 2013;136(Pt 8):2419–2431.
    1. Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. N Engl J Med 1988;318(14):876–880.
    1. Oh M, Kim JS, Kim JY, et al. Subregional patterns of preferential striatal dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple‐system atrophy. J Nucl Med 2012;53(3):399–406.
    1. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351(24):2498–2508.
    1. Gray R, Ives N, Rick C, et al. Long‐term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open‐label, pragmatic randomised trial. Lancet 2014;384(9949):1196–1205.
    1. Elsworth JD, Roth RH. Dopamine synthesis, uptake, metabolism, and receptors: relevance to gene therapy of Parkinson's disease. Exp Neurol 1997;144(1):4–9.
    1. Kitahama K, Ikemoto K, Jouvet A, et al. Aromatic L‐amino acid decarboxylase‐immunoreactive structures in human midbrain, pons, and medulla. J Chem Neuroanat 2009;38(2):130–140.
    1. Ciesielska A, Samaranch L, San Sebastian W, et al. Depletion of AADC activity in caudate nucleus and putamen of Parkinson's disease patients; implications for ongoing AAV2‐AADC gene therapy trial. PLoS One 2017;12(2):e0169965.
    1. Pavese N, Rivero‐Bosch M, Lewis SJ, et al. Progression of monoaminergic dysfunction in Parkinson's disease: a longitudinal 18F‐dopa PET study. NeuroImage 2011;56(3):1463–1468.
    1. Chan PL, Nutt JG, Holford NH. Pharmacokinetic and pharmacodynamic changes during the first four years of levodopa treatment in Parkinson's disease. J Pharmacokinet Pharmacodyn 2005;32(3–4):459–484.
    1. Obeso JA, Olanow CW, Nutt JG. Levodopa motor complications in Parkinson's disease. Trends Neurosci 2000;23(10 Suppl):S2–S7.
    1. Antonini A, Tolosa E, Mizuno Y, et al. A reassessment of risks and benefits of dopamine agonists in Parkinson's disease. Lancet Neurol 2009;8(10):929–937.
    1. Aquino CC, Fox SH. Clinical spectrum of levodopa‐induced complications. Mov Disord 2015;30(1):80–89.
    1. Olanow CW, Kieburtz K, Rascol O, et al. Factors predictive of the development of Levodopa‐induced dyskinesia and wearing‐off in Parkinson's disease. Mov Disord 2013;28(8):1064–1071.
    1. Voon V, Fernagut PO, Wickens J, et al. Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders. Lancet Neurol 2009;8(12):1140–1149.
    1. Voon V, Napier TC, Frank MJ, et al. Impulse control disorders and levodopa‐induced dyskinesias in Parkinson's disease: an update. Lancet Neurol 2017;16(3):238–250.
    1. Jost WH. Gastrointestinal motility problems in patients with Parkinson's disease. Effects of antiparkinsonian treatment and guidelines for management. Drugs Aging 1997;10(4):249–258.
    1. Bankiewicz KS, Eberling JL, Kohutnicka M, et al. Convection‐enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro‐drug approach. Exp Neurol 2000;164(1):2–14.
    1. Bankiewicz KS, Forsayeth J, Eberling JL, et al. Long‐term clinical improvement in MPTP‐lesioned primates after gene therapy with AAV‐hAADC. Mol Ther 2006;14(4):564–570.
    1. Hadaczek P, Eberling JL, Pivirotto P, et al. Eight years of clinical improvement in MPTP‐lesioned primates after gene therapy with AAV2‐hAADC. Mol Ther 2010;18(8):1458–1461.
    1. Christine CW, Starr PA, Larson PS, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009;73(20):1662–1669.
    1. Mittermeyer G, Christine CW, Rosenbluth KH, et al. Long‐term evaluation of a phase 1 study of AADC gene therapy for Parkinson's disease. Hum Gene Ther 2012;23(4):377–381.
    1. Muramatsu S, Fujimoto K, Kato S, et al. A phase I study of aromatic L‐amino acid decarboxylase gene therapy for Parkinson's disease. Mol Ther 2010;18(9):1731–1735.
    1. Valles F, Fiandaca MS, Eberling JL, et al. Qualitative imaging of adeno‐associated virus serotype 2‐human aromatic L‐amino acid decarboxylase gene therapy in a phase I study for the treatment of Parkinson disease. Neurosurgery 2010;67(5):1377–1385.
    1. Christine CW, Bankiewicz KS, Van Laar AD, et al. Magnetic resonance imaging‐guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease. Ann Neurol 2019;85(5):704–714.
    1. Brodsky MA, Park BS, Nutt JG. Effects of a dopamine agonist on the pharmacodynamics of levodopa in Parkinson disease. Arch Neurol 2010;67(1):27–32.
    1. Nutt JG, Carter JH, Sexton GJ. The dopamine transporter: importance in Parkinson's disease. Ann Neurol 2004;55(6):766–773.
    1. Fahn S, Elton RL, Program Members UPDRS. Unified Parkinson's Disease Rating Scale In: Fahn S, Marsden CD, Goldstiein M, Calne DB, eds. Recent Developments in Parkinson's Disease. Florham Park, NJ: Macmillan Healthcare Information; 1987. 153–163.
    1. Nutt JG, Woodward WR, Hammerstad JP, et al. The "on‐off" phenomenon in Parkinson's disease. Relation to levodopa absorption and transport. N Engl J Med 1984;310(8):483–488.
    1. Boraud T, Tison F, Gross C. Quantification of motor slowness in Parkinson's disease: correlations between the tapping test and single joint ballistic movement parameters. Parkinsonism Relat Disord 1997;3(1):47–50.
    1. van Hilten JJ, Wagemans EA, Ghafoerkhan SF, et al. Movement characteristics in Parkinson's disease: determination of dopaminergic responsiveness and threshold. Clin Neuropharmacol 1997;20(5):402–408.
    1. Nutt JG, Gancher ST, Woodward WR. Does an inhibitory action of levodopa contribute to motor fluctuations? Neurology 1988;38(10):1553–1557.
    1. Stern MB, Marek KL, Friedman J, et al. Double‐blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients. Mov Disord 2004;19(8):916–923.
    1. Nutt JG, Woodward WR. Levodopa pharmacokinetics and pharmacodynamics in fluctuating parkinsonian patients. Neurology 1986;36(6):739–744.
    1. Verhagen Metman L, van den Munckhof P, Klaassen AA, et al. Effects of supra‐threshold levodopa doses on dyskinesias in advanced Parkinson's disease. Neurology 1997;49(3):711–713.
    1. Mouradian MM, Juncos JL, Fabbrini G, et al. Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, part II. Ann Neurol 1988;24(3):372–378.
    1. Nutt JG, Chung KA, Holford NH. Dyskinesia and the antiparkinsonian response always temporally coincide: a retrospective study. Neurology 2010;74(15):1191–1197.
    1. Nutt JG, Holford NH. The response to levodopa in Parkinson's disease: imposing pharmacological law and order. Ann Neurol 1996;39(5):561–573.
    1. Olanow CW, Bartus RT, Baumann TL, et al. Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: a double‐blind, randomized, controlled trial. Ann Neurol 2015;78(2):248–257.

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