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

VanderVeen, Nathan; Raja, Nicholas; Yi, Elizabeth; Appelman, Henry D.; Ng, Philip; Palmer, D. Jason; Zamler, Daniel; Dzaman, Marta; Löwenstein, Pedro R.; Castro, María G.

doi:10.1089/hgtb.2015.168

Cited by 8 publications

(7 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, the ‘all-in-one’ Tet-One vector encodes the Tet-On 3G transactivator protein which specifically binds to the P TRE3G inducible promoter in the presence of Dox and consequently activates transcription of the downstream gene of interest, 2LTRZFP . The expression of 2LTRZFP was induced with a low concentration of Dox, in the range utilized in clinical practice [ 31 ]. In contrast, no 2LTRZFP expression is observed in the absence of Dox, indicating that the P TRE3G inducible promoter is tightly controlled, allowing very low if any basal expression, but high level expression upon activation.…”

Section: Discussionmentioning

confidence: 99%

Modulated expression of the HIV-1 2LTR zinc finger efficiently interferes with the HIV integration process

et al. 2018

View full text Add to dashboard Cite

Lentiviral vectors have emerged as the most efficient system to stably transfer and insert genes into cells. By adding a tetracycline (Tet)-inducible promoter, transgene expression delivered by a lentiviral vector can be expressed whenever needed and halted when necessary. Here we have constructed a doxycycline (Dox)-inducible lentiviral vector which efficiently introduces a designed zinc finger protein, 2-long terminal repeat zinc-finger protein (2LTRZFP), into hematopoietic cell lines and evaluated its expression in pluripotent stem cells. As a result this lentiviral inducible system can regulate 2LTRZFP expression in the SupT1 T-cell line and in pluripotent stem cells. Using this vector, no basal expression was detected in the T-cell line and its induction was achieved with low Dox concentrations. Remarkably, the intracellular regulatory expression of 2LTRZFP significantly inhibited HIV-1 integration and replication in HIV-inoculated SupT1 cells. This approach could provide a potential tool for gene therapy applications, which efficiently control and reduce the side effect of therapeutic genes expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Modulated expression of the HIV-1 2LTR zinc finger efficiently interferes with the HIV integration process

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Haematological and serum biochemical analysis were normal, in contrast with the systemic administration of vectors. No abnormalities were observed in behavioral testing, and animal growth curves were not affected after treatment [153,154]. However, changes in the transcriptome of human midbrain neuroprogenitor cells (hmNPCs) have been observed after infection with HC-AdVs [157].…”

Section: Gene Supplementation For Neurological Diseasesmentioning

confidence: 98%

“…In addition, high cloning capacity is often required to allocate large transgenes (such as ion channels), combinations of genes (such as biosynthetic pathways for dopamine production in Parkinson's disease) or complex regulatory regions to restrict expression to specific cell populations. Parenchymal administration of HC-AdV in rodents (up to 2 × 10 9 vp) was well-tolerated and avoided the generation of NAbs [152][153][154][155].…”

Section: Gene Supplementation For Neurological Diseasesmentioning

confidence: 99%

“…It is worthy to mention that the safety of HC-AdVs can be improved by implementing drug-inducible methods to control expression of transgenes, such as the Tet-on transactivation system. Importantly, the FDA has already approved an administration regimen of doxycycline for this purpose [154]. Controlling the amount and duration of transgene expression can be especially important in the brain, where chronic alteration of proteostasis may lead to neurodegeneration.…”

Section: Gene Supplementation For Neurological Diseasesmentioning

confidence: 99%

“…However, many immunotherapy approaches can benefit from the properties of HC-AdVs, especially when the expression of transgenes should be placed under the control of drug-inducible systems to avoid toxicity, and when a combination of transgenes is needed. The HC-Ad-TK/TetOn-Flt3L vector encodes the suicide gene thymidine kinase (TK) and the dendritic cell chemoattractant FMS-like tyrosine kinase 3 ligand (Flt3L) under the control of a tet-on inducible system [154,164,227]. This vector has demonstrated promising results in rodent models of glioblastoma.…”

Section: Cancermentioning

confidence: 99%

See 2 more Smart Citations

High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy

Ricobaraza

González-Aparicio

Mora-Jimenez

et al. 2020

IJMS

101

View full text Add to dashboard Cite

The adaptation of adenoviruses as gene delivery tools has resulted in the development of high-capacity adenoviral vectors (HC-AdVs), also known, helper-dependent or “gutless”. Compared with earlier generations (E1/E3-deleted vectors), HC-AdVs retain relevant features such as genetic stability, remarkable efficacy of in vivo transduction, and production at high titers. More importantly, the lack of viral coding sequences in the genomes of HC-AdVs extends the cloning capacity up to 37 Kb, and allows long-term episomal persistence of transgenes in non-dividing cells. These properties open a wide repertoire of therapeutic opportunities in the fields of gene supplementation and gene correction, which have been explored at the preclinical level over the past two decades. During this time, production methods have been optimized to obtain the yield, purity, and reliability required for clinical implementation. Better understanding of inflammatory responses and the implementation of methods to control them have increased the safety of these vectors. We will review the most significant achievements that are turning an interesting research tool into a sound vector platform, which could contribute to overcome current limitations in the gene therapy field.

show abstract

Is Viral Vector Gene Delivery More Effective Using Biomaterials?

Wang

Bruggeman

Franks

et al. 2020

Adv Healthcare Materials

View full text Add to dashboard Cite

Gene delivery has been extensively investigated for introducing foreign genetic material into cells to promote expression of therapeutic proteins or to silence relevant genes. This approach can regulate genetic or epigenetic disorders, offering an attractive alternative to pharmacological therapy or invasive protein delivery options. However, the exciting potential of viral gene therapy has yet to be fully realized, with a number of clinical trials failing to deliver optimal therapeutic outcomes. Reasons for this include difficulty in achieving localized delivery, and subsequently lower efficacy at the target site, as well as poor or inconsistent transduction efficiency. Thus, ongoing efforts are focused on improving local viral delivery and enhancing its efficiency. Recently, biomaterials have been exploited as an option for more controlled, targeted and programmable gene delivery. There is a growing body of literature demonstrating the efficacy of biomaterials and their potential advantages over other delivery strategies. This review explores current limitations of gene delivery and the progress of biomaterial‐mediated gene delivery. The combination of biomaterials and gene vectors holds the potential to surmount major challenges, including the uncontrolled release of viral vectors with random delivery duration, poorly localized viral delivery with associated off‐target effects, limited viral tropism, and immune safety concerns.

show abstract

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

Cited by 8 publications

References 45 publications

Modulated expression of the HIV-1 2LTR zinc finger efficiently interferes with the HIV integration process

Modulated expression of the HIV-1 2LTR zinc finger efficiently interferes with the HIV integration process

High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy

Is Viral Vector Gene Delivery More Effective Using Biomaterials?

Contact Info

Product

Resources

About