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Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain

Author:
  • Luis Quintino
  • Angrit Namislo
  • Marcus Davidsson
  • Ludivine S. Breger
  • Patrick Kavanagh
  • Martino Avallone
  • Erika Elgstrand-Wettergren
  • Christina Isaksson
  • Cecilia Lundberg
Publishing year: 2018
Language: English
Pages: 29-39
Publication/Series: Molecular Therapy - Methods and Clinical Development
Volume: 11
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

Regulation of therapeutic transgene expression can increase the safety of gene therapy interventions, especially when targeting critical organs such as the brain. Although several gene expression systems have been described, none of the current systems has the required safety profile for clinical applications. Our group has previously adapted a system for novel gene regulation based on the destabilizing domain degron technology to successfully regulate glial cell-line derived neurotrophic factor in the brain (GDNF-F-DD). In the present study, we used GDNF-F-DD as a proof-of-principle molecule to fully characterize DD regulation in the brain. Our results indicate that DD could be regulated in a dose-dependent manner. In addition, GDNF-F-DD could also be induced in vivo repeatedly, without loss of activity or efficacy in vivo. Finally, DD regulation was able to be sustained for 24 weeks without loss of expression or any overt toxicity. The present study shows that DD has great potential to regulate gene expression in the brain.

Keywords

  • Medical Genetics
  • Neurosciences
  • destabilizing domains
  • GDNF
  • gene therapy
  • in vivo
  • Parkinson's disease

Other

Published
  • CNS Gene Therapy
  • Molecular Neuromodulation
  • Neurobiology
  • ISSN: 2329-0501
Marcus Davidsson
E-mail: marcus [dot] davidsson [at] med [dot] lu [dot] se

Molecular Neuromodulation unit
Wallenberg Neuroscience Center
Department of Experimental Medical Science
BMC A10, 221 84 Lund, Sweden
 
Phone: +46 46 222 68 36
e-Mail: tomas [dot] bjorklund [at] med [dot] lu [dot] se