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Vector-mediated l-3...
Vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson's disease
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- Rosenblad, Carl (author)
- Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Regeneration in Movement Disorders,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups,Skåne University Hospital
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- Li, Qin (author)
- Motac Neuroscience
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- Pioli, Elsa Y (author)
- Motac Neuroscience
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- Dovero, Sandra (author)
- University of Bordeaux
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- Antunes, André S L M (author)
- King's College London
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- Agúndez, Leticia (author)
- King's College London
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- Bardelli, Martino (author)
- King's College London
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- Linden, R Michael (author)
- King's College London
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- Henckaerts, Els (author)
- King's College London
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- Björklund, Anders (author)
- Lund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups
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- Bezard, Erwan (author)
- University of Bordeaux
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- Björklund, Tomas (author)
- Lund University,Lunds universitet,Molekylär neuromodulering,Forskargrupper vid Lunds universitet,Molecular Neuromodulation,Lund University Research Groups
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(creator_code:org_t)
- 2019-06-26
- 2019
- English.
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; , s. 2402-2416
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Rosenblad, Carl
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Li, Qin
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Pioli, Elsa Y
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Dovero, Sandra
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Antunes, André S ...
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Agúndez, Leticia
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show more...
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Bardelli, Martin ...
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Linden, R Michae ...
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Henckaerts, Els
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Björklund, Ander ...
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Bezard, Erwan
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Björklund, Tomas
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Brain : a journa ...
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Brain
- By the university
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Lund University