Carbidopa-based modulation of the functional effect of the AAV2-hAADC gene therapy in 6-OHDA lesioned rats

Progressively blunted response to L-DOPA in Parkinson's disease (PD) is a critical factor that complicates long-term pharmacotherapy in view of the central importance of this drug in management of the PD-related motor disturbance. This phenomenon is likely due to progressive loss of one of the...

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Published in:PloS one 2015-04, Vol.10 (4), p.e0122708-e0122708
Main Authors: Ciesielska, Agnieszka, Sharma, Nitasha, Beyer, Janine, Forsayeth, John, Bankiewicz, Krystof
Format: Article
Language:English
Subjects:
Amino acids
Animals
Aromatic-L-amino-acid decarboxylase
Aromatic-L-Amino-Acid Decarboxylases - chemistry
Aromatic-L-Amino-Acid Decarboxylases - genetics
Aromatic-L-Amino-Acid Decarboxylases - metabolism
Basal ganglia
Behavior, Animal - drug effects
Carbidopa
Carbidopa - pharmacology
Care and treatment
Central nervous system diseases
Chromatography, High Pressure Liquid
Control
Corpus Striatum - metabolism
Dependovirus - genetics
Development and progression
Dihydroxyphenylalanine
Dopamine
Dopamine - analogs & derivatives
Dopamine - analysis
Electrochemical Techniques
Ganglia
Gene therapy
Genetic aspects
Genetic Therapy
Genetic Vectors - genetics
Genetic Vectors - metabolism
Health aspects
Humans
Immunohistochemistry
Levodopa
Levodopa - blood
Levodopa - pharmacology
Male
Metabolism
Movement disorders
Neostriatum
Neostriatum - metabolism
Neostriatum - pathology
Neurodegenerative diseases
Oxidopamine - toxicity
Parkinson disease
Parkinson Disease - etiology
Parkinson Disease - metabolism
Parkinson's disease
Patient outcomes
Pharmacology
Product safety
Rats
Rats, Sprague-Dawley
Viruses
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Summary:Progressively blunted response to L-DOPA in Parkinson's disease (PD) is a critical factor that complicates long-term pharmacotherapy in view of the central importance of this drug in management of the PD-related motor disturbance. This phenomenon is likely due to progressive loss of one of the key enzymes involved in the biosynthetic pathway for dopamine in the basal ganglia: aromatic L-amino acid decarboxylase (AADC). We have developed a gene therapy based on an adeno-associated virus encoding human AADC (AAV2-hAADC) infused into the Parkinsonian striatum. Although no adverse clinical effects of the AAV2-hAADC gene therapy have been observed so far, the ability to more precisely regulate transgene expression or transgene product activity could be an important long-term safety feature. The present study was designed to define pharmacological regulation of the functional activity of AAV2-hAADC transgene product by manipulating L-DOPA and carbidopa (AADC inhibitor) administration in hemi-parkinsonian rats. Thirty days after unilateral striatal infusion of AAV2-hAADC, animals displayed circling behavior and acceleration of dopamine metabolism in the lesioned striatum after administration of a low dose of L-DOPA (5 mg/kg) co-administered with 1.25 mg/kg of carbidopa. This phenomenon was not observed in control AAV2-GFP-treated rats. Withdrawal of carbidopa from a daily L-DOPA regimen decreased the peripheral L-DOPA pool, resulting in almost total loss of L-DOPA-induced behavioral response in AAV2-hAADC rats and a significant decline in striatal dopamine turnover. The serum L-DOPA level correlated with the magnitude of circling behavior in AAV2-hAADC rats. Additionally, AADC activity in homogenates of lesioned striata transduced by AAV2-AADC was 10-fold higher when compared with AAV2-GFP-treated control striata, confirming functional transduction. Our data suggests that the pharmacological regulation of circulating L-DOPA might be effective in the controlling of function of AAV2-hAADC transgene product in PD gene therapy.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0122708