Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy.

Biopharmaceutical Research Laboratories ofDong-A Pharmaceutical Co., Ltd.Kyunggi-Do, Korea.
Experimental and Molecular Medicine (Impact Factor: 2.46). 08/2011; 43(10):580-6. DOI: 10.3858/emm.2011.43.10.065
Source: PubMed

ABSTRACT Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The IGF-I receptor (IGF-IR) has an important role in malignant disease and is the target of several drugs presently in clinical trials. Gene therapy has been explored as cancer treatment, mainly for delivery of genes that induce cell death or enhance the immunological response to cancer. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here, we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. We constructed a third generation gutless adenovirus expressing sIGFIR and found that HEK-293 cells transduced by this, but not control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival in vitro. Following virus injection in vivo, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective anticancer strategy.Cancer Gene Therapy advance online publication, 8 March 2013; doi:10.1038/cgt.2013.10.
    Cancer gene therapy 03/2013; 73(8 Supplement). DOI:10.1038/cgt.2013.10 · 2.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Reactive oxygen species (ROS) and signaling events are involved in the pathogenesis of endothelial dysfunction and represent a major contribution to vascular regulation. Molecular signaling is highly dependent on ROS. But depending on the amount of ROS production it might have toxic or protective effects. Despite a large number of negative outcomes in large clinical trials (e.g., HOPE, HOPE-TOO), antioxidant molecules and agents are important players to influence the critical balance between production and elimination of reactive oxygen and nitrogen species. However, chronic systemic antioxidant therapy lacks clinical efficacy, probably by interfering with important physiological redox signaling pathways. Therefore, it may be a much more promising attempt to induce intrinsic antioxidant pathways in order to increase the antioxidants not systemically but at the place of oxidative stress and complications. Among others, heme oxygenase (HO) has been shown to be important for attenuating the overall production of ROS in a broad range of disease states through its ability to degrade heme and to produce carbon monoxide and biliverdin/bilirubin. With the present review we would like to highlight the important antioxidant role of the HO system and especially discuss the contribution of the biliverdin, bilirubin, and biliverdin reductase (BVR) to these beneficial effects. The BVR was reported to confer an antioxidant redox amplification cycle by which low, physiological bilirubin concentrations confer potent antioxidant protection via recycling of biliverdin from oxidized bilirubin by the BVR, linking this sink for oxidants to the NADPH pool. To date the existence and role of this antioxidant redox cycle is still under debate and we present and discuss the pros and cons as well as our own findings on this topic.
    Frontiers in Pharmacology 03/2012; 3:30. DOI:10.3389/fphar.2012.00030
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma is the most aggressive primary brain tumor and its prognosis remains poor despite different treatment modalities including surgery, radiotherapy and chemotherapy. Therefore, more useful treatments for glioblastoma patients are required. Human interleukin 15 (hIL15) is an immunomodulator that has antitumor activities. hIL15 combined with gene therapy method is also currently under cosideration as a treatment option. Since recombinant adeno-associated virus serotype 2 (rAAV2) with low immunogenicity and long-term gene expression in human clinical trials has been demonstrated, rAAV2 encoding hIL15 (rAAV2-hIL15) were used to inhibit human glioblastoma growth in the present study. rAAV2-hIL15, which is able to express IL15 protein with bioactivity, was successfully produced and purified. Data of this study demonstrated that the long-term expression of rAAV2-hIL15 enhances immunoglobulin (Ig) production and the cytotoxic activity of lymphokine-activated killer (LAK) cells. In addition, results of the present study showed that rAAV2-hIL15 delays tumor growth on a xenografted human glioblastoma mice model. Taken together, these results indicated that rAAV2-hIL15 constitutes a powerful and potent gene immunotherapy method for human glioblastoma treatment.
    Molecular and Clinical Oncology 01/2013; 1(2):321-325. DOI:10.3892/mco.2013.60


Available from