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Dimerizer regulation of AADC expression and behavioral response in AAV-transduced 6-OHDA lesioned rats
- Source :
- Molecular Therapy. 13(1):167-174
- Publication Year :
- 2006
- Publisher :
- Elsevier BV, 2006.
-
Abstract
- Recombinant AAV vectors containing a dimerizer-inducible system of transcriptional activation provide a strategy for control of therapeutic gene expression in the CNS. Here we explored this system for regulated expression of human aromatic L-amino acid decarboxylase (hAADC) in a rodent model of Parkinson disease. Expression of hAADC, the enzyme that converts L-dopa to dopamine, was dependent on reconstitution of a functional transcription factor (TF) by the dimerizer rapamycin. Two vectors, AAV-CMV-TF and AAV-Z12-hAADC, were infused into striata of 6-OHDA-lesioned rats. Rapamycin-induced increases in expression of hAADC repeatedly produced robust rotational behavior in response to low doses of L-dopa. Seven weeks after vector infusion, AADC expression in brain was quantitated by both stereology and Western blot analysis following the final rapamycin treatment. While a low level of hAADC was observed in rats that were not induced with rapamycin, this basal expression was not significant enough to elicit a rotational response to L-dopa. This study demonstrated a robust behavioral response of parkinsonian rats to regulated hAADC expression. Recombinant AAV vectors controlled by rapamycin or its analogs show promise as candidates for CNS therapies in which regulation of the transgene is desired.
- Subjects :
- Dopamine
Transgene
Genetic Vectors
Gene Dosage
Biology
Pharmacology
medicine.disease_cause
Cell Line
Antiparkinson Agents
Levodopa
Rats, Sprague-Dawley
chemistry.chemical_compound
Transduction, Genetic
Gene expression
Drug Discovery
medicine
Genetics
Animals
Humans
Vector (molecular biology)
Parkinson Disease, Secondary
Oxidopamine
Adeno-associated virus
Molecular Biology
Recombination, Genetic
Sirolimus
Regulation of gene expression
Aromatic L-amino acid decarboxylase
Genetic Therapy
Dependovirus
Molecular biology
Corpus Striatum
Rats
Disease Models, Animal
Gene Expression Regulation
chemistry
Aromatic-L-Amino-Acid Decarboxylases
Molecular Medicine
Stereotyped Behavior
Dimerization
medicine.drug
Subjects
Details
- ISSN :
- 15250016
- Volume :
- 13
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....836e1fef6ec162129f7d0ee07fb73fcf
- Full Text :
- https://doi.org/10.1016/j.ymthe.2005.06.480