title: Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia.
abstract: In Parkinson's disease, degeneration of specific neurons in the midbrain can cause severe motor deficits, including tremors and the inability to initiate movement. The standard treatment is administration of pharmacological agents that transiently increase concentrations of brain dopamine and thereby discontinuously modulate neuronal activity in the striatum, the primary target of dopaminergic neurons. The resulting intermittent dopamine alleviates parkinsonian symptoms but is also thought to cause abnormal involuntary movements, called dyskinesias. To investigate gene therapy for Parkinson's disease, we simulated the disease in macaque monkeys by treating them with the complex I mitochondrial inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which induces selective degeneration of dopamine-producing neurons. In this model, we demonstrated that injection of a tricistronic lentiviral vector encoding the critical genes for dopamine synthesis (tyrosine hydroxylase, aromatic L-amino acid decarboxylase, and guanosine 5'-triphosphate cyclohydrolase 1) into the striatum safely restored extracellular concentrations of dopamine and corrected the motor deficits for 12 months without associated dyskinesias. Gene therapy-mediated dopamine replacement may be able to correct Parkinsonism in patients without the complications of dyskinesias.
authors.affiliation: Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France. bechir.jarraya@cea.fr
authors.forename: Béchir
authors.initials: B
authors.lastname: Jarraya
authors.forename: Sabrina
authors.initials: S
authors.lastname: Boulet
authors.forename: G Scott
authors.initials: GS
authors.lastname: Ralph
authors.forename: Caroline
authors.initials: C
authors.lastname: Jan
authors.forename: Gilles
authors.initials: G
authors.lastname: Bonvento
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
authors.forename: James E
authors.initials: JE
authors.lastname: Miskin
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shin
authors.forename: Thierry
authors.initials: T
authors.lastname: Delzescaux
authors.forename: Xavier
authors.initials: X
authors.lastname: Drouot
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hérard
authors.forename: Denise M
authors.initials: DM
authors.lastname: Day
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kingsman
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Kyriacos A
authors.initials: KA
authors.lastname: Mitrophanous
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Mazarakis
authors.forename: Stéphane
authors.initials: S
authors.lastname: Palfi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency / Q000235:genetics*; D020820:Dyskinesias / Q000150:complications; D015316:Genetic Therapy; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics; D008253:Macaca mulatta; D009043:Motor Activity / Q000235:genetics; D010300:Parkinson Disease / Q000150:complications / Q000628:therapy*
chemical_list: D004298:Dopamine