ArticlePloS one2012
Destabilizing domains mediate reversible transgene expression in the brain.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 42 citations in OpenAlex.
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- Utility of the DHFR-based destabilizing domain across mouse models of retinal degeneration and aging.iScience · 2022Article
- Inclusion of a degron reduces levelsof undesired inteins after AAV-mediated proteinMolecular therapy. Methods & clinical development · 2021Article
- Applications of Bacterial Degrons and Degraders - Toward Targeted Protein Degradation in Bacteria.Frontiers in molecular biosciences · 2021Review
- Protocol forSTAR protocols · 2020Article
- Simultaneous Control of Endogenous and User-Defined Genetic Pathways Using Unique ecDHFR Pharmacological Chaperones.Cell chemical biology · 2020Article
- Regional Differences in Penetration of the Protein Stabilizer Trimethoprim (TMP) in the Rat Central Nervous System.Frontiers in molecular neuroscience · 2020Article
- Non-antibiotic Small-Molecule Regulation of DHFR-Based Destabilizing DomainsMolecular therapy. Methods & clinical development · 2019Article
- GDNF-mediated rescue of the nigrostriatal system depends on the degree of degeneration.Gene therapy · 2019Article
- Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain.Molecular therapy. Methods & clinical development · 2018Article
- A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- A Destabilizing Domain Allows for Fast, Noninvasive, Conditional Control of Protein Abundance in the Mouse Eye - Implications for Ocular Gene Therapy.Investigative ophthalmology & visual science · 2018Article
- HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells.BMC cancer · 2018Article
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- How to Train a Cell-Cutting-Edge Molecular Tools.Frontiers in chemistry · 2017Review
- A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses.Molecular therapy. Methods & clinical development · 2016Article
- The therapeutic application of CRISPR/Cas9 technologies for HIV.Expert opinion on biological therapy · 2015Review
- Controlled Striatal DOPA Production From a Gene Delivery System in a Rodent Model of Parkinson's Disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2015Article
- Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Regulating transgene expression in vivo by delivering oral drugs has been a long-time goal for the gene therapy field. A novel gene regulating system based on targeted proteasomal degradation has been recently developed. The system is based on a destabilizing domain (DD) of the Escherichia coli dihydrofolate reductase (DHFR) that directs fused proteins to proteasomal destruction. Creating YFP proteins fused to destabilizing domains enabled TMP based induction of YFP expression in the brain, whereas omission of TMP resulted in loss of YFP expression. Moreover, induction of YFP expression was dose dependent and at higher TMP dosages, induced YFP reached levels comparable to expression of unregulated transgene., Transgene expression could be reversibly regulated using the DD system. Importantly, no adverse effects of TMP treatment or expression of DD-fusion proteins in the brain were observed. To show proof of concept that destabilizing domains derived from DHFR could be used with a biologically active molecule, DD were fused to GDNF, which is a potent neurotrophic factor of dopamine neurons. N-terminal placement of the DD resulted in TMP-regulated release of biologically active GDNF. Our findings suggest that TMP-regulated destabilizing domains can afford transgene regulation in the brain. The fact that GDNF could be regulated is very promising for developing future gene therapies (e.g. for Parkinson's disease) and should be further investigated.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.