Vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease

Abstract

Ever since its introduction 40 years ago l-3,4-dihydroxyphenylalanine (l-DOPA) therapy has retained its role as the leading standard medication for patients with Parkinson’s disease. With time, however, the shortcomings of oral l-DOPA treatment have become apparent, particularly the motor fluctuations and troublesome dyskinetic side effects. These side effects, which are caused by the excessive swings in striatal dopamine caused by intermittent oral delivery, can be avoided by delivering l-DOPA in a more continuous manner. Local gene delivery of the l-DOPA synthesizing enzymes, tyrosine hydroxylase and guanosine-tri-phosphate-cyclohydrolase-1, offers a new approach to a more refined dopaminergic therapy where l-DOPA is delivered continuously at the site where it is needed i.e. the striatum. In this study we have explored the therapeutic efficacy of adeno-associated viral vector-mediated l-DOPA delivery to the putamen in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys, the standard non-human primate model of Parkinson’s disease. Viral vector delivery of the two enzymes, tyrosine hydroxylase and guanosine-5’-tri-phosphate-cyclohydrolase-1, bilaterally into the dopamine-depleted putamen, induced a significant, dose-dependent improvement of motor behaviour up to a level identical to that obtained with the optimal dose of peripheral l-DOPA. Importantly, this improvement in motor function was obtained without any adverse dyskinetic effects. These results provide proof-of-principle for continuous vector-mediated l-DOPA synthesis as a novel therapeutic strategy for Parkinson’s disease. The constant, local supply of l-DOPA obtained with this approach holds promise as an efficient one-time treatment that can provide long-lasting clinical improvement and at the same time prevent the appearance of motor fluctuations and dyskinetic side effects associated with standard oral dopaminergic medication.

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

“…In a recent proof-of-principle study, an adenovirus-associated vector was applied to deliver two L-dopa synthesizing enzymes in the striatum of parkinsonian monkeys, and this treatment determined a significant improvement in motor functions without pro-dyskinetic effects. 149 Based on clinical data showing a direct correlation between the risk of LID development and the total amount of L-dopa intake, 150 another strategy consists in reducing the daily L-dopa dosage using L-dopa-sparing pharmacological (ie, combination of low L-dopa doses with non-dopaminergic therapies) and non-pharmacological interventions (ie, deep brain stimulation). 13,22,[151][152][153] Regarding direct approaches, the only drugs currently approved for LID treatment are amantadine and clozapine.…”

Rational Design of Thermosensitive Hydrogel to Deliver Nanocrystals with Intranasal Administration for Brain Targeting in Parkinson’s Disease

“…To confirm the satisfactory therapeutic efficacy of MAG-NCs@Gel as a treatment for the behavioral deficits of MPTP-induced mice, a series of comprehensive experiments was performed ( Figure 4(a) ). Initially, MPTP was administered for mice (18 mg kg −1 ), resulting in significant motor behavioral deficits [ 57 ]. The effects of intranasal MAG-NCs@Gel administration on these deficits were then assessed, with mice being examined using the rotarod, pole, and open field tests seven days later.…”

Modeling Parkinson’s Disease: Not Only Rodents?

“…Nonhuman primates allow disease modeling in species more closely related to humans. Despite the obvious drawback of the high cost of work using primates, interest in these models has grown in recent years, primarily because primates can be used to develop new treatments for PD associated with the use of deep brain stimulation and transplantation of neuronal cells into the substantia nigra and striatum, as well as for testing newly developed drugs in the final stages of preclinical research (Fiandaca and Bankiewicz, 2010;Sundberg et al, 2013;Faggiani and Benazzouz, 2017;Wianny and Vezoli, 2017;Morissette and Di Paolo, 2018;Pignataro et al, 2018;Wichmann et al, 2018;Deffains and Bergman, 2019;Rosenblad et al, 2019;Teil et al, 2020). Moreover, the similarity of the organization of the nervous systems of humans and primates is fundamentally important because it allows the assessment in greater detail of the involvement of different brain structures in the development of the pathological process of PD, to analyze the temporal dynamics of this disorder (Verhave et al, 2011;Fifel et al, 2014;Vezoli et al, 2014;Ko et al, 2018;Sgambato and Tremblay, 2018;Wang et al, 2018;Deffains and Bergman, 2019;McGregor and Nelson, 2019).…”

“…Previously, the injection of the MPTP toxin into primates was widely used in disease modeling (Fifel et al, 2014;Johnston and Fox, 2015;Rosenblad et al, 2019), to simulate the acute and chronic development of the pathological process in various nonhuman primates. Moreover, the exact dosage of the toxin to be administered to each animal is extremely important, with the possibility of correcting the amount of toxin injected according to the comprehensive assessment of the behavior of animals during the modeling process (Seo et al, 2019).…”