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Washington University School of Medicine, Department of Radiation Oncology, 4511 Forest Park, St. Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). Abstract: Oncolytic adenoviral vectors are a promising alternative for the treatment of glioblastoma. Abstract: Due to the fundamental progress in elucidating the molecular mechanisms of human diseases and the arrival of the post-genomic era, increasing numbers of therapeutic genes and cellular targets are available for gene therapy. Abstract: A long time has passed since the first clinical trial with adenoviral (Ad) vectors.
Today, there is only one class of antiviral medicines against herpesviruses - a family of viruses that cause mononucleosis, herpes, shingles, and meningitis among other illnesses - meaning options for treating these infections are limited. In a search for new drugs to treat viral infections, scientists at the University of Utah School of Medicine found that a medicine routinely used to treat heart failure, spironolactone, has an unexpected ability to block infection by Epstein-Barr virus (EBV), a herpesvirus that causes mono and is associated with several human cancers. Importantly, spironolactone’s ability to block viral infection appears to be independent from its ability to treat heart failure. But because all herpesviruses depend on SM-like proteins to spread infection, the work also has broader implications. Shop via one of these links and Phoenix Rising gets up to 8% of your spend at no cost to you! The material on this site has been compiled by laypeople and Phoenix Rising does not guarantee the accuracy or completeness of the content.
As disease mechanisms are elucidated, flexible gene delivery platforms incorporating transcriptional regulatory elements, therapeutic genes and targeted delivery are required for the safety and efficacy of these approaches. Recent publications have demonstrated the advantages of shielding viral particles within cellular vehicles (CVs), which can be targeted towards the tumor microenvironment. Meanwhile, the most important challenge is to develop gene delivery vectors with high efficiency through target cell selectivity, in particular under in situ conditions.
Despite being very promising, Ad vectors soon revealed their limitations in human clinical trials.
If viruses become resistant to these frontline treatments, a growing problem particularly in clinical settings, there are no alternative drugs to serve as backup.
They find that the drug’s antiviral properties stem from its ability to block a key step in viral infection that is common to all herpesviruses. Currently available drugs block a middle step of the viral infection cycle by inhibiting virus’ ability to replicate DNA.

Previous studies showed that the drug treats heart failure through a different, metabolic mechanism.
Spironolactone could be developed as a new medicine against EBV, a common and dangerous infection among transplant and other immunocompromised patients. Spironolactone could be a template for a new class of drug directed against all herpesviruses.
A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Adenovirus serotype 5 (Ad5)-based vectors can carry large genetic payloads to provide this flexibility, but do not transduce neuronal cells efficiently. Here, we studied T-cells, often having a natural capacity to target tumors, for their feasibility as a CV to deliver the oncolytic adenovirus, Delta24-RGD, to glioblastoma. The pre-existing immunity, the marked liver tropism and the high toxicity of first generation Ad (FG-Ad) vectors have been the main challenges for the development of new approaches. Spironolactone’s target is distinct from that of existing drugs, revealing that it could be developed into a new class of anti-herpesvirus drug. They found that like these drugs, spironolactone can block EBV replication in cells, but it does so by targeting the so-called SM protein, required for a late step in the infection cycle. This study demonstrates that a drug similar to spironolactone shares its ability to treat heart failure but not its antiviral properties.
Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website.
To address this, we have developed a tropism-modified Ad5 vector with neuron-selective targeting properties for evaluation in models of Parkinson disease therapy.
The Jurkat T-cell line was assessed in co-culture with the glioblastoma stem cell (GSC) line, MGG8, for the optimal transfer conditions of Delta24-RGD in vitro.
Recent endeavors in the development of selective Ad vectors that target cells or tissues of interest and spare the alteration of all others have focused on the modification of the virus broad natural tropism. Significant effort toward the development of genetically and chemically modified adenoviral vectors has enabled researchers to create more sophisticated vectors for gene therapy, with an improved safety profile and a higher transduction ability of different tissues. A panel of tropism-modified Ad5 vectors was screened for enhanced gene delivery in a neuroblastoma cell line model system.
The effect of intraparenchymal and tail vein injections on intratumoral virus distribution and overall survival was addressed in an orthotopic glioma stem cell (GSC)-based xenograft model. A popular way of Ad targeting is achieved by directing the vector towards distinct cellular receptors.

In this review, we will describe the latest findings in the high-speed, evolving field of genetic and chemical modifications of adenoviral vectors, a field in which different disciplines, such as biomaterial research, virology and immunology, co-operate synergistically to create better gene therapy tools for modern challenges. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
We used these observations to design and construct an unbiased Ad vector platform, consisting of an unmodified Ad5 and a tropism-modified Ad5 vector containing the fiber knob domain from canine Ad serotype 2 (Ad5-CGW-CK2).
Jurkat T-cells were demonstrated to facilitate the amplification and transfer of Delta24-RGD onto GSCs.
Redirecting can be accomplished by linking custom-made peptides with specific affinity to cellular surface proteins via genetic integration, chemical coupling or bridging with dual-specific adapter molecules. Delivery to the substantia nigra or striatum showed that this vector produced a neuronally-restricted pattern of gene expression. Delta24-RGD dosing and incubation time were found to influence the migratory ability of T-cells towards GSCs. Many of the transduced neurons were from regions with afferent projections to the injection site, implicating that the vector binds the presynaptic terminal resulting in presynaptic transduction. Injection of Delta24-RGD-loaded T-cells into the brains of GSC-bearing mice led to migration towards the tumor and dispersion of the virus within the tumor core and infiltrative zones.
Such altered vectors offer new opportunities to delineate functional genomics in a natural environment and may enable efficient systemic therapeutic approaches. We show that Ad5-CGW-CK2 can selectively transduce neurons in the brain and hypothesize that this modular platform is potentially adaptable to clinical use.
This occurred after injection into the ipsilateral hemisphere, as well as into the non-tumor-bearing hemisphere. This review provides a summary of current state-of-the-art techniques to specifically target adenovirus-based gene delivery vectors.
We found that T-cell-mediated delivery of Delta24-RGD led to the inhibition of tumor growth compared to non-treated controls, resulting in prolonged survival (p = 0.007).
Systemic administration of virus-loaded T-cells resulted in intratumoral viral delivery, albeit at low levels. Based on these findings, we conclude that T-cell-based CVs are a feasible approach to local Delta24-RGD delivery in glioblastoma, although efficient systemic targeting requires further improvement.

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