Insulators coupled to a minimal bidirectional tet cassette for tight regulation of rAAV-mediated gene transfer in the mammalian brain
Open Access
- 1 November 2001
- journal article
- research article
- Published by Springer Nature in Gene Therapy
- Vol. 8 (22) , 1675-1681
- https://doi.org/10.1038/sj.gt.3301582
Abstract
Recombinant AAV is increasingly becoming the vector of choice for many gene therapy applications in the CNS, due to its lack of toxicity and high level of sustained expression. With recent improvements in the generation of pure, high titer vector stocks, the regulation of gene expression is now a key issue for successful translation of gene therapy-based treatments to the clinic. The level of the transgene protein may need to be maintained within a narrow therapeutic window for the successful treatment of human disease. The doxycycline responsive system directs a dose-responsive, tightly regulated level of gene expression and has been used successfully in transgenic mouse models. Here, we have optimized an autoregulatory, bidirectional doxycyline responsive cassette specifically for use in rAAV. We minimized the size of the cassette and decreased the basal leakiness of the system, leading to tight regulation in the rat brain.Keywords
This publication has 26 references indexed in Scilit:
- Combined Injection of rAAV with Mannitol Enhances Gene Expression in the Rat BrainMolecular Therapy, 2001
- Triple Transduction with Adeno-Associated Virus Vectors Expressing Tyrosine Hydroxylase, Aromatic-L-Amino-Acid Decarboxylase, and GTP Cyclohydrolase I for Gene Therapy of Parkinson's DiseaseHuman Gene Therapy, 2000
- AAV vectors: is clinical success on the horizon?Gene Therapy, 2000
- Gene therapy in the CNSGene Therapy, 2000
- Efficient gene transfer and long-term expression in neurons using a recombinant adenovirus with a neuron-specific promoterGene Therapy, 1999
- Enhanced Expression of Transgenes from Adeno-Associated Virus Vectors with the Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element: Implications for Gene TherapyHuman Gene Therapy, 1999
- Highly Purified Recombinant Adeno-Associated Virus Vectors Are Biologically Active and Free of Detectable Helper and Wild-Type VirusesHuman Gene Therapy, 1999
- Inducible long-term gene expression in brain with adeno-associated virus gene transferGene Therapy, 1998
- In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vectorGene Therapy, 1998
- Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice.Proceedings of the National Academy of Sciences, 1996