Vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease
| Autor: | Leticia Agúndez, Sandra Dovero, Anders Björklund, Carl Rosenblad, André S L M Antunes, Elsa Y. Pioli, Els Henckaerts, R. Michael Linden, Qin Li, Tomas Björklund, Martino Bardelli, Erwan Bezard |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Parkinson's disease animal diseases Drug Evaluation Preclinical non-human primate Striatum Antiparkinson Agents Levodopa Rats Sprague-Dawley chemistry.chemical_compound Genes Reporter Genes Synthetic Medicine GTP Cyclohydrolase MPTP Putamen Dopaminergic Dependovirus gene therapy Recombinant Proteins 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Female adeno-associated viral vector medicine.drug Tyrosine 3-Monooxygenase Genetic Vectors Motor Activity Proof of Concept Study Parkinsonian Disorders Dopamine Animals Humans Pars Compacta Tyrosine hydroxylase business.industry nutritional and metabolic diseases Original Articles medicine.disease Macaca mulatta Dihydroxyphenylalanine nervous system diseases Rats nervous system chemistry l-DOPA Neurology (clinical) business Neuroscience |
| Zdroj: | Brain |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awz176 |
| Popis: | Heterozygous variants in SOD1 are a major cause of familial amyotrophic lateral sclerosis. Park et al. report the first known case of SOD1 deficiency, a disorder distinct from ALS characterized by mild cerebellar atrophy and hyperekplexia-like symptoms. The findings may have implications for the use of SOD1 silencing to treat ALS. 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. |
| Databáze: | OpenAIRE |
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