Inducible long-term gene expression in brain with adeno-associated virus gene transfer
Abstract
Recombinant adeno-associated virus (rAAV) vectors hold promise for treating a number of neurological disorders due to the ability to deliver long-term gene expression without toxicity or immune response. Critical to these endeavors will be controlled expression of the therapeutic gene in target cells. We have constructed and tested a dual cassette rAAV vector carrying a reporter gene under the control of the tetracycline-responsive system and the tetracycline transactivator. Transduction in vitro resulted in stable expression from the vector that can be suppressed 20-fold by tetracycline treatment. In vivo experiments, carried out to 6 weeks, demonstrated that vector-transduced expression is sustained until doxycycline administration upon which reporter gene expression is reduced. Moreover, the suppression of vector-driven expression can be reversed by removal of the drug. These studies demonstrate long-term regulated gene expression from rAAV vectors. This system will provide a valuable approach for controlling vector gene expression both in vitro and in vivo.
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The AAV2 ITR sequence has inherent transcriptional activity and is a promoter capable of driving transgene expression.
“Previous work from our lab and others have demonstrated that the AAV ITR2 sequence has inherent transcriptional activity, which may confound intended transgene expression in therapeutic applications.”
From Adeno-Associated Virus Serotype-Specific Inverted Terminal Repeat Sequence Role in Vector Transgene Expression (2020) · cites this paper as [19]
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Gray, S. J., Foti, S. B., Schwartz, J. W., Bachaboina, L., Taylor-Blake, B., Coleman, J., Ehlers, M. D., Zylka, M. J., McCown, T. J., & Samulski, R. J. (2011) · Human Gene Therapy · doi:10.1089/hum.2010.245 · Cited by 420 · see citing works
Self-citationBucher, K., Rodríguez-Bocanegra, E., Dauletbekov, D., & Fischer, M. D. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100915 · Cited by 242 · see citing works
Nectow, A. R., & Nestler, E. J. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-00382-z · Cited by 159 · see citing works
The advent of AAV9 expands applications for brain and spinal cord gene delivery
Dayton, R. D., Wang, D. B., & Klein, R. L. (2012) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2012.681463 · Cited by 144 · see citing works
Haberman, R. P., McCown, T. J., & Samulski, R. J. (2000) · Journal of Virology · doi:10.1128/jvi.74.18.8732-8739.2000 · Cited by 139 · see citing works
Self-citationEarley, L. F., Conatser, L. M., Lue, V. M., Dobbins, A. L., Li, C., Hirsch, M. L., & Samulski, R. J. (2020) · Human Gene Therapy · doi:10.1089/hum.2019.274 · Cited by 116 · see citing works
Self-citationRecombinant AAV-mediated delivery of a tet-inducible reporter gene to the rat retina
McGee Sanftner, L. H., Rendahl, K. G., Quiroz, D., Coyne, M., Ladner, M., Manning, W. C., & Flannery, J. G. (2001) · Molecular Therapy · doi:10.1006/mthe.2001.0308 · Cited by 94 · see citing works
Insight into the mechanism of inhibition of adeno-associated virus by the Mre11/Rad50/Nbs1 complex
Lentz, T. B., & Samulski, R. J. (2015) · Journal of Virology · doi:10.1128/jvi.01990-14 · Cited by 48 · see citing works
Self-citationTetracyclines in the control of gene expression in eukaryotes
Gossen, M., & Bujard, H. (2001) · Tetracyclines in Biology, Chemistry and Medicine · doi:10.1007/978-3-0348-8306-1_5 · Cited by 29 · see citing works
- Authors
- Haberman, R., McCown, T., & Samulski, R.
- Venue
- Gene Therapy
- Published
- 1998-12-01
- Volume
- 5
- Issue
- 12
- Pages
- 1604-1611
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- OpenAlex
- W2313069436
- Cited by
- 102
- References
- 0
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 1 · 2020: 5 · 2019: 2 · 2017: 1 · 2015: 1 · 2014: 1 · 2013: 4 · 2012: 3
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hl048347-09, 5t32ns007166-18)
- National Heart, Lung, and Blood Institute (HL 48347)
- National Institute of Neurological Disorders and Stroke (NS 35633, NS 07166, R01NS035633)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- adeno-associated virus vectors, tetracycline-responsive promoter, tetracycline transactivator, inducible gene expression, doxycycline, reporter gene expression, long-term gene expression, neurological disorders
- MeSH terms
- Dependovirus, Animals, Brain, Doxycycline, Genetic Vectors, HeLa Cells, Humans, Male, Microinjections, Microscopy, Fluorescence, Protein Synthesis Inhibitors, Tetracycline, Time Factors, Transfection, Genetic Therapy, Gene Expression, Rats, Sprague-Dawley, Transgenes, Rats
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