ArticleMolecular therapy : the journal of the American Society of Gene Therapy2008
Immunization against the transgene but not the TetON switch reduces expression from gutless adenoviral vectors in the brain.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 34 citations in OpenAlex.
- Oxidative stress induced by sustained supraphysiological intrastriatal GDNF delivery is prevented by dose regulation.Molecular therapy. Methods & clinical development · 2023Article
- Gene Therapy for Regenerative Medicine.Pharmaceutics · 2023Review
- Platforms Exploited for SARS-CoV-2 Vaccine Development.Vaccines · 2020Review
- High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy.International journal of molecular sciences · 2020Review
- Adenovirus-Mediated Gene Delivery: Potential Applications for Gene and Cell-Based Therapies in the New Era of Personalized Medicine.Genes & diseases · 2017Article
- Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn "On" Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model.Human gene therapy methods · 2016Article
- Feasibility of Applying Helper-Dependent Adenoviral Vectors for Cancer Immunotherapy.Biomedicines · 2014Review
- There must be a way out of here: identifying a safe and efficient combination of promoter, transgene, and vector backbone for gene therapy of neurological disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
- Effectiveness and preclinical safety profile of doxycycline to be used "off-label" to induce therapeutic transgene expression in a phase I clinical trial for glioma.Human gene therapy. Clinical development · 2013Article
- A next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting.British journal of clinical pharmacology · 2013Review
- Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma.Toxicology and applied pharmacology · 2013Article
- Prolonged regulatable expression of EPO from an HSV vector using the LAP2 promoter element.Gene therapy · 2012Article
- Targeted toxins for glioblastoma multiforme: pre-clinical studies and clinical implementation.Anti-cancer agents in medicinal chemistry · 2011Review
- Gene therapy and targeted toxins for glioma.Current gene therapy · 2011Review
- Current progress in the development of a prophylactic vaccine for HIV-1.Drug design, development and therapy · 2010Review
- Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- HIV antigen incorporation within adenovirus hexon hypervariable 2 for a novel HIV vaccine approach.PloS one · 2010Article
- A novel bicistronic high-capacity gutless adenovirus vector that drives constitutive expression of herpes simplex virus type 1 thymidine kinase and tet-inducible expression of Flt3L for glioma therapeutics.Journal of virology · 2010Article
- Lack of humoral immune response to the tetracycline (Tet) activator in rats injected intracranially with Tet-off rAAV vectors.Gene therapy · 2010Article
- Progress and prospects: Immunobiology of gene therapy for neurodegenerative disease: prospects and risks.Gene therapy · 2010Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Immune responses against vectors or encoded transgenes can impose limitations on gene therapy. We demonstrated that tetracycline-regulated high-capacity adenoviral vectors (HC-Ads) sustain regulated transgene expression in the brain even in the presence of systemic pre-existing immune responses against adenoviruses. In this study we assessed whether systemic pre-existing immune responses against the transgene products, i.e., beta-Gal or the tetracycline-dependent (TetON) regulatory transcription factors (rtTA2(S)M2 and the tTS(Kid)), affect transgene expression levels and the safety profile of HC-Ads in the brain. We pre-immunized mice with plasmids encoding the TetON switch expressing rtTA2(S)M2 and the tTS(Kid) or beta-Gal. HC-Ads expressing beta-Gal under the control of the TetON switch were then injected into the striatum. We assessed levels and distribution of beta-Gal expression, and evaluated local inflammation and neuropathological changes. We found that systemic immunity against beta-Gal, but not against the TetON switch, led to inflammation and reduction of transgene expression in the striatum. Therefore, the regulatory TetON switch appears to be safe to use, and capable of sustaining transgene expression in the brain even in the presence of an immune response against its components. Systemic immunity against the transgene had the effect of curtailing its expression, thereby affecting the efficacy and safety of gene delivery to the brain. This factor should be considered when developing gene therapies for neurological use.
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