Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats.
In animal models of Parkinson's disease, gene transfer of aromatic L-amino acid decarboxylase (AADC) leads to an increase in the capacity of the striatum to decarboxylate exogenous L-DOPA. However, the functional effects of enhanced L-DOPA to dopamine conversion have not been explored. Here, we show that following adeno-associated virus (AAV)-AADC transduction, the transgenic AADC is able to decarboxylate exogenous L-DOPA more efficiently so that a dose of L-DOPA ineffective before gene transfer elicits a motor asymmetry (rotational behavior) following gene transfer. Furthermore, rotation scores showed a strong correlation with AADC activity in the lesioned striatum, thus allowing for behavioral screening of successful gene transfer in the brain. In animals receiving AAV2-AADC, dopamine production was restored to 50% of normal levels 12 weeks after the infusion. Microdialysis experiments demonstrated an in vivo enhanced conversion of L-DOPA to dopamine, but no storage capacity as dopamine was released to the extracellular space in a continuous, nonregulated fashion. In addition to the potential clinical benefit of improving decarboxylation efficiency in Parkinson's disease, our approach may be relevant for the treatment of AADC deficiency, a rare, autosomal recessive disorder causing a severe movement disorder and progressive cognitive impairment.
Sánchez-Pernaute
R
R
Molecular Therapeutics Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892, USA.
Harvey-White
J
J
Cunningham
J
J
Bankiewicz
K S
KS
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D007980:Levodopa / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D014161:Transduction, Genetic
D007980:Levodopa; D016627:Oxidopamine; D001142:Aromatic-L-Amino-Acid Decarboxylases; D001058:Apomorphine; D004298:Dopamine