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

Quintino, Luis LU ; Namislo, Angrit LU ; Davidsson, Marcus LU ; Breger, Ludivine S. LU ; Kavanagh, Patrick LU ; Avallone, Martino LU ; Elgstrand-Wettergren, Erika LU ; Isaksson, Christina LU and Lundberg, Cecilia LU (2018) In Molecular Therapy - Methods and Clinical Development 11. p.29-39
Abstract

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,... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
destabilizing domains, GDNF, gene therapy, in vivo, Parkinson's disease
in
Molecular Therapy - Methods and Clinical Development
volume
11
pages
11 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85054563476
ISSN
2329-0501
DOI
10.1016/j.omtm.2018.08.008
language
English
LU publication?
yes
id
8887b62e-f87c-44c6-a57f-40ae04ed8877
date added to LUP
2018-10-26 13:47:50
date last changed
2019-04-10 04:15:46
@article{8887b62e-f87c-44c6-a57f-40ae04ed8877,
  abstract     = {<p>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.</p>},
  author       = {Quintino, Luis and Namislo, Angrit and Davidsson, Marcus and Breger, Ludivine S. and Kavanagh, Patrick and Avallone, Martino and Elgstrand-Wettergren, Erika and Isaksson, Christina and Lundberg, Cecilia},
  issn         = {2329-0501},
  keyword      = {destabilizing domains,GDNF,gene therapy,in vivo,Parkinson's disease},
  language     = {eng},
  pages        = {29--39},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy - Methods and Clinical Development},
  title        = {Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain},
  url          = {http://dx.doi.org/10.1016/j.omtm.2018.08.008},
  volume       = {11},
  year         = {2018},
}