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

• Published in: Brain (London, England : 1878) Vol. 142; no. 8; pp. 2402 - 2416
• Main Authors: Rosenblad, Carl, Li, Qin, Pioli, Elsa Y, Dovero, Sandra, Antunes, André Slm, Agúndez, Leticia, Bardelli, Martino, Linden, R Michael, Henckaerts, Els, Björklund, Anders, Bezard, Erwan, Björklund, Tomas
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2019
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - analogs & derivatives; Animals; Antiparkinson Agents - administration & dosage; Antiparkinson Agents - therapeutic use; Basic Medicine; Cognitive science; Dependovirus - genetics; Drug Evaluation, Preclinical; Female; Genes, Reporter; Genes, Synthetic; Genetic Vectors - administration & dosage; Genetic Vectors - therapeutic use; GTP Cyclohydrolase - administration & dosage; GTP Cyclohydrolase - analysis; GTP Cyclohydrolase - genetics; GTP Cyclohydrolase - metabolism; Humans; Levodopa - biosynthesis; Macaca mulatta; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Motor Activity - drug effects; Neuroscience; Neurosciences; Neurovetenskaper; Original; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - therapy; Pars Compacta - chemistry; Pars Compacta - pathology; Proof of Concept Study; Putamen - metabolism; Rats; Rats, Sprague-Dawley; Recombinant Proteins - administration & dosage; Recombinant Proteins - analysis; Recombinant Proteins - therapeutic use; Tyrosine 3-Monooxygenase - administration & dosage; Tyrosine 3-Monooxygenase - analysis; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; l-DOPA; gene therapy; non-human primate; MPTP; adeno-associated viral vector
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awz176

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.