Tight Long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector.
Mol Ther
; 17(11): 1857-67, 2009 Nov.
Article
em En
| MEDLINE
| ID: mdl-19707186
ABSTRACT
Glial cell line-derived neurotrophic factor (GDNF) gene transfer is being developed as a treatment for Parkinson's disease (PD). Due to the potential for side effects, external transgene regulation should enhance this strategy's safety profile. Here, we demonstrate dynamic control during long-term expression of GDNF using a recombinant adeno-associated virus (rAAV)-based bicistronic tetracycline (tet)-off construct. Nigrostriatal GDNF overexpression induces body weight alterations in rodents, enabling longitudinal in vivo tracking of GDNF expression after nigral vector delivery. Regulated GDNF expression was highly sensitive to dietary doxycycline (DOX), displaying undetectable striatal GDNF levels at serum DOX levels below those required for antimicrobial activity. However, in the absence of DOX, striatal GDNF levels exceeded levels required for efficacy in PD models. We also demonstrate the absence of a series of known GDNF-associated side effects when using direct intrastriatal vector delivery. Therefore, this single rAAV vector system meets most of the requirements for an experimental reagent for treatment of PD.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doxiciclina
/
Dependovirus
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Fator Neurotrófico Derivado de Linhagem de Célula Glial
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article