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

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Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain. / Quintino, Luis; Namislo, Angrit; Davidsson, Marcus; Breger, Ludivine S.; Kavanagh, Patrick; Avallone, Martino; Elgstrand-Wettergren, Erika; Isaksson, Christina; Lundberg, Cecilia.

I: Molecular Therapy - Methods and Clinical Development, Vol. 11, 2018, s. 29-39.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Quintino, Luis ; Namislo, Angrit ; Davidsson, Marcus ; Breger, Ludivine S. ; Kavanagh, Patrick ; Avallone, Martino ; Elgstrand-Wettergren, Erika ; Isaksson, Christina ; Lundberg, Cecilia. / Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain. I: Molecular Therapy - Methods and Clinical Development. 2018 ; Vol. 11. s. 29-39.

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TY - JOUR

T1 - Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain

AU - Quintino, Luis

AU - Namislo, Angrit

AU - Davidsson, Marcus

AU - Breger, Ludivine S.

AU - Kavanagh, Patrick

AU - Avallone, Martino

AU - Elgstrand-Wettergren, Erika

AU - Isaksson, Christina

AU - Lundberg, Cecilia

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - destabilizing domains

KW - GDNF

KW - gene therapy

KW - in vivo

KW - Parkinson's disease

U2 - 10.1016/j.omtm.2018.08.008

DO - 10.1016/j.omtm.2018.08.008

M3 - Article

C2 - 30324128

AN - SCOPUS:85054563476

VL - 11

SP - 29

EP - 39

JO - Molecular Therapy - Methods and Clinical Development

JF - Molecular Therapy - Methods and Clinical Development

SN - 2329-0501

ER -