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Tight Long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector.

Authors
  • Manfredsson, Fredric P1
  • Burger, Corinna
  • Rising, Aaron C
  • Zuobi-Hasona, Kheir
  • Sullivan, Layla F
  • Lewin, Alfred S
  • Huang, Julia
  • Piercefield, Emily
  • Muzyczka, Nicholas
  • Mandel, Ronald J
  • 1 Department of Neuroscience, Powell Gene Therapy Center, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida 32611, USA.
Type
Published Article
Journal
Molecular Therapy
Publisher
Elsevier
Publication Date
November 2009
Volume
17
Issue
11
Pages
1857–1867
Identifiers
DOI: 10.1038/mt.2009.196
PMID: 19707186
Source
Medline
License
Unknown

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.

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