Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia.
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.
Jarraya
Béchir
B
Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France. bechir.jarraya@cea.fr
Boulet
Sabrina
S
Ralph
G Scott
GS
Jan
Caroline
C
Bonvento
Gilles
G
Azzouz
Mimoun
M
Miskin
James E
JE
Shin
Masahiro
M
Delzescaux
Thierry
T
Drouot
Xavier
X
Hérard
Anne-Sophie
AS
Day
Denise M
DM
Brouillet
Emmanuel
E
Kingsman
Susan M
SM
Hantraye
Philippe
P
Mitrophanous
Kyriacos A
KA
Mazarakis
Nicholas D
ND
Palfi
Stéphane
S
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*
D004298:Dopamine