Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC.
Dopamine, the major neurotransmitter depleted in Parkinson disease, can be synthesized and regulated in vivo with a combination of intrastriatal AAV-hAADC gene therapy and administration of the dopamine precursor l-Dopa. When tested in MPTP-lesioned monkeys, this approach resulted in long-term improvement in clinical rating scores, significantly lowered l-Dopa requirements, and a reduction in l-Dopa-induced side effects. Positron emission tomography with [(18)F]FMT confirmed persistent AADC activity, demonstrating for the first time that infusion of AAV vector into primate brain results in at least 6 years of transgene expression. AAV-hAADC restores the ability of the striatum to convert l-Dopa into dopamine efficiently. Introduction of this therapy into the clinic holds promise for Parkinson patients experiencing the motor complications that result from escalating l-Dopa requirements against a background of disease progression.
Bankiewicz
Krystof S
KS
Department of Neurosurgery, University of California at San Francisco, Room MCB 226, 1855 Folsom Street, San Francisco, CA 94103-0555, USA. kbank@itsa.ucsf.edu
Forsayeth
John
J
Eberling
Jamie L
JL
Sanchez-Pernaute
Rosario
R
Pivirotto
Philip
P
Bringas
John
J
Herscovitch
Peter
P
Carson
Richard E
RE
Eckelman
William
W
Reutter
Bryan
B
Cunningham
Janet
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D007980:Levodopa / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D018419:Primate Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D013997:Time Factors
D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001142:Aromatic-L-Amino-Acid Decarboxylases