Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain
Molecular Therapy - Methods & Clinical Development. 2018-12-01; 11: 29-39
DOI: 10.1016/j.omtm.2018.08.008
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1. Mol Ther Methods Clin Dev. 2018 Sep 4;11:29-39. doi: 10.1016/j.omtm.2018.08.008.
eCollection 2018 Dec 14.
Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in
the Brain.
Quintino L(1), Namislo A(1), Davidsson M(2), Breger LS(1), Kavanagh P(1),
Avallone M(1), Elgstrand-Wettergren E(1), Isaksson C(1), Lundberg C(1).
Author information:
(1)CNS Gene Therapy, Department of Experimental Medical Science, Lund University,
Lund, Sweden.
(2)Molecular Neuromodulation, Department of Experimental Medical Sciences, Lund
University, Lund, Sweden.
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.
DOI: 10.1016/j.omtm.2018.08.008
PMCID: PMC6187056
PMID: 30324128