Targeted Adenoviral Vectors I : Transductional Targeting
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ABSTRACT:
SUBMITTER: Dmitriev I
PROVIDER: S-EPMC7149436 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
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Project description:Adenovirus serotype 5 remains one of the most promising vectors for delivering genetic material to cancer cells for imaging or therapy, but optimization of these agents to selectively promote tumor cell infection is needed to further their clinical development. Peptide sequences that bind to specific cell surface receptors have been inserted into adenoviral capsid proteins to improve tumor targeting, often in the background of mutations designed to ablate normal ligand:receptor interactions and thereby reduce off target effects and toxicities in non-target tissues. Different tumor types also express highly variable complements of cell surface receptors, so a customized targeting strategy using a particular peptide in the context of specific adenoviral mutations may be needed to achieve optimal efficacy. To further investigate peptide targeting strategies in adenoviral vectors, we used a set of peptide motifs originally isolated using phage display technology that evince tumor specificity in vivo. To demonstrate their abilities as targeting motifs, we genetically incorporated these peptides into a surface loop of the fiber capsid protein to construct targeted adenovirus vectors. We then systematically evaluated the ability of these peptide targeted vectors to infect several tumor cell types, both in vitro and in vivo, in a variety of mutational backgrounds designed to reduce CAR and/or HSG-mediated binding. Results from this study support previous observations that peptide insertions in the HI loop of the fiber knob domain are generally ineffective when used in combination with HSG detargeting mutations. The evidence also suggests that this strategy can attenuate other fiber knob interactions, such as CAR-mediated binding, and reduce overall viral infectivity. The insertion of peptides into fiber proved more effective for targeting tumor cell types expressing low levels of CAR receptor, as this strategy can partially compensate for the very low infectivity of wild-type adenovirus in those cells. Nevertheless, the incorporation of relatively low affinity peptide ligands into the fiber knob, while effective in vitro, has only minimal targeting efficacy in vivo and highlights the importance of high affinity ligand:receptor interactions to achieve tumor targeting.
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Project description:Many nonhuman adenoviruses (AdVs) of simian, bovine, porcine, canine, ovine, murine, and fowl origin are being developed as gene delivery systems for recombinant vaccines and gene therapy applications. In addition to circumventing preexisting human AdV (HAdV) immunity, nonhuman AdV vectors utilize coxsackievirus-adenovirus receptor or other receptors for vector internalization, thereby expanding the range of cell types that can be targeted. Nonhuman AdV vectors also provide excellent platforms for veterinary vaccines. A specific nonhuman AdV vector when used in its species of origin could provide an excellent animal model for evaluating the vector efficacy and pathogenesis. These vectors are useful in prime–boost approaches with other AdV vectors or with other gene delivery systems including DNA immunization and viral or bacterial vectors. When multiple vector inoculations are required, nonhuman AdV vectors could supplement HAdV or other viral vectors.
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Project description:The efficacy and safety of a new immunotherapy protocol for cancer were tested in a severe combined immunodeficient mouse model of human skin and metastatic lung melanoma. The protocol involves intratumoral injections of replication-incompetent adenoviral vectors encoding immunoconjugates composed of the Fc region of an IgG1 immunoglobulin conjugated to a tumor-targeting domain. One targeting domain is factor VII that binds to tissue factor expressed on endothelial cells lining the tumor neovasculature and on tumor cells; the active site of factor VII was mutated to inhibit the initiation of blood coagulation. Another targeting domain is a single-chain Fv antibody that binds to a cognate antigen expressed on human melanoma cells. The adenoviral vectors infect mainly the cells of the injected tumor, which synthesize and secrete the immunoconjugates. The bloodborne immunoconjugates induce a cytolytic immune response against the targeted neovasculature endothelial cells and tumor cells. The mouse model experiments showed that intratumoral delivery of the factor VII immunoconjugate, either alone or together with the single-chain Fv immunoconjugate, resulted in growth inhibition and regression of the injected tumor, and also of distant metastatic tumors, without evidence of damage to normal organs. There was extensive destruction of the tumor neovasculature, presumably mediated by the factor VII immunoconjugate bound to tissue factor on neovasculature endothelial cells. Because tissue factor is generally expressed on neovascular endothelial cells and tumor cells, a factor VII immunoconjugate could be used for immunotherapy against a broad range of human solid tumors.
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Project description:The regulatory T cell master transcription factor, Forkhead box P3 (Foxp3), has been detected in cancer cells; however, its role in breast tumor pathogenesis remains controversial. Here we assessed Foxp3 tumor intrinsic effects in experimental breast cancer using a Foxp3 binder peptide (P60) that impairs Foxp3 nuclear translocation. Cisplatin upregulated Foxp3 expression in HER2+ and triple-negative breast cancer (TNBC) cells. Foxp3 inhibition with P60 enhanced chemosensitivity and reduced cell survival and migration in human and murine breast tumor cells. We also developed an adenoviral vector encoding P60 (Ad.P60) that efficiently transduced breast tumor cells, reduced cell viability and migration, and improved the cytotoxic response to cisplatin. Conditioned medium from transduced breast tumor cells contained lower levels of IL-10 and improved the activation of splenic lymphocytes. Intratumoral administration of Ad.P60 in breast-tumor-bearing mice significantly reduced tumor infiltration of Tregs, delayed tumor growth, and inhibited the development of spontaneous lung metastases. Our results suggest that Foxp3 exerts protumoral intrinsic effects in breast cancer cells and that gene-therapy-mediated blockade of Foxp3 could constitute a therapeutic strategy to improve the response of these tumors to standard treatment.
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Project description:Arterial endothelial cells (EC) are attractive targets for gene therapy of atherosclerosis because they are accessible to hematogenous and catheter-based vector delivery and overlie atherosclerotic plaques. Vector-mediated expression-in EC-of proteins that mediate cholesterol transfer out of the artery wall and decrease inflammation could prevent and reverse atherosclerosis. However, clinical application of this strategy is limited by lack of a suitable gene-transfer vector. First-generation adenovirus (FGAd) is useful for EC gene transfer in proof-of-concept studies, but is unsuitable for atheroprotective human gene therapy because of limited duration of expression and proinflammatory effects. Moreover, others have reported detrimental effects of FGAd on critical aspects of EC physiology including proliferation, migration, and apoptosis. Here, we investigated whether helper-dependent adenovirus (HDAd) either alone or expressing an atheroprotective gene [apolipoprotein A-I (apoA-I)] could circumvent these limitations. In contrast to control FGAd, HDAd did not alter any of several critical EC physiologic functions (including proliferation, migration, apoptosis, metabolic activity, and nitric oxide (NO) production) and did not stimulate proinflammatory pathways [including expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and interleukin-6 (IL-6)]. Expression of apoA-I by HDAd reduced EC VCAM-1 expression. HDAd is a promising vector and apoA-I is a promising gene for atheroprotective human gene therapy delivered via EC.
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Project description:Adenoviral vector has been employed as one of the most efficient means against infectious diseases and cancer. It can be genetically modified and armed with foreign antigens to elicit specific antibody responses and T cell responses in hosts as well as engineered to induce apoptosis in cancer cells. The chimpanzee adenovirus-based vector is one kind of novel vaccine carriers whose unique features and non-reactivity to pre-existing human adenovirus neutralizing antibodies makes it an outstanding candidate for vaccine research and development. Here, we review the different strategies for constructing chimpanzee adenoviral vectors and their applications in recent clinical trials and also discuss the oncolytic virotherapy and immunotherapy based on chimpanzee adenoviral vectors.
| S-EPMC6067905 | biostudies-literature
Project description:Adenoviral vectors have been widely used as vaccine candidates or potential vaccine candidates against infectious diseases due to the convenience of genome manipulation, their ability to accommodate large exogenous gene fragments, easy access of obtaining high-titer of virus, and high efficiency of transduction. At the same time, adenoviral vectors have also been used extensively in clinical research for cancer gene therapy and treatment of diseases caused by a single gene defect. However, application of adenovirus also faces a series of challenges such as poor targeting, strong immune response against the vector itself, and they cannot be used repeatedly. It is believed that these problems will be solved gradually with further research and technological development in related fields. Here, we review the construction methods of adenoviral vectors, including "gutless" adenovirus and discuss application of adenoviral vectors as prophylactic vaccines for infectious pathogens and their application prospects as therapeutic vaccines for cancer and other kinds of chronic infectious disease such as human papillomavirus, hepatitis B virus, and hepatitis C virus.
| S-EPMC10556817 | biostudies-literature
Project description:Adenoviruses are a commonly utilized virus for gene therapy platforms worldwide. Since adenovirus components are characterized as highly immunogenic, their immunogenicity inhibits the widespread use of adenoviral vectors to treat genetic disorders. However, stimulation of the immune response can be exploited for cancer immunotherapy platforms, and thus adenoviral vectors are used for therapeutic gene transfer, vaccines, and oncolytic agents in the cancer gene therapy field. It is now accepted that the generation of anti-tumor immune responses induced by oncolytic adenovirus treatments is critical for their anti-tumor efficacy. As such, in cancer immunotherapy with adenoviral vectors, a balance must be struck between induction of anti-adenoviral and anti-tumor immune responses. The recent trend in adenoviral-based cancer gene therapy is the development of adenoviral vectors to enhance immune responses and redirect them toward tumors. This review focuses on anti-adenoviral immunity and how adenovirotherapies skew the immune response toward an anti-tumor response.
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Project description:IntroductionCurrently available medications for neuropathic pain are of limited efficacy. Moreover, they are administered systemically and are associated with significant side effects. Ideally, one can circumvent systemic side effects if such treatment can be administered by delivery of the therapeutic agent directly to the diseased neurons. Towards this end, we previously reported the production of a recombinant helper-dependent adenovirus (HDAd) armed with a tissue-specific homing peptide to deliver transgenes targeting sensory neurons with high efficacy.ObjectivesTo develop an effective gene therapy for neuropathic pain by producing a dorsal root ganglion (DRG)-targeted HDAd vector that specifically expresses glutamic acid decarboxylase (GAD) 67 (HDAd-DRG-GAD67).MethodsWe produced spinal nerve transection (SNT) mice as a neuropathic pain model and delivered HDAd-DRG-GAD67 by injection into spinal nerve or intrathecally to these animals. We evaluated the therapeutic efficacy by measuring ion channel gene expression and quantifying mechanical allodynia, a representative symptom of neuropathic pain, in treated animals.ResultsGlutamic acid decarboxylase expression by HDAd-DRG-GAD67 reduced allodynia significantly in SNT mice. In addition, HDAd-DRG-GAD67 had a much greater transduction efficacy and expressed the therapeutic gene for a much longer time and at a lower dose of viral particles than wild-type HDAd. We found that SNT induced the upregulation of Cav3.2 mRNA in the DRG and GAD67 overexpression suppressed the elevation. Furthermore, the HDAd-DRG-GAD67-induced allodynia amelioration occurred even when we delayed intrathecal delivery of the therapeutic vector to day 7 after SNT.ConclusionHDAd-mediated DRG-targeted gene therapy delivering GAD67 is an efficacious treatment for neuropathic pain in SNT mice.
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Project description:Adenovirus binds to mammalian cells via interaction of fiber with the coxsackie-adenovirus receptor (CAR). Redirecting adenoviral vectors to enter target cells via new receptors has the advantage of increasing the efficiency of gene delivery and reducing nonspecific transduction of untargeted tissues. In an attempt to reach this goal, we have produced bifunctional molecules with soluble CAR (sCAR), which is the extracellular domain of CAR fused to peptide-targeting ligands. Two peptide-targeting ligands have been evaluated: a cyclic RGD peptide (cRGD) and the receptor-binding domain of apolipoprotein E (ApoE). Human diploid fibroblasts (HDF) are poorly transduced by adenovirus due to a lack of CAR on the surface. Addition of the sCAR-cRGD or sCAR-ApoE targeting protein to adenovirus redirected binding to the appropriate receptor on HDF. However, a large excess of the monomeric protein was needed for maximal transduction, indicating a suboptimal interaction. To improve interaction of sCAR with the fiber knob, an isoleucine GCN4 trimerization domain was introduced, and trimerization was verified by cross-linking analysis. Trimerized sCAR proteins were significantly better at interacting with fiber and inhibiting binding to HeLa cells. Trimeric sCAR proteins containing cRGD and ApoE were more efficient at transducing HDF in vitro than the monomeric proteins. In addition, the trimerized sCAR protein without targeting ligands efficiently blocked liver gene transfer in normal C57BL/6 mice. However, addition of either ligand failed to retarget the liver in vivo. One explanation may be the large complex size, which serves to decrease the bioavailability of the trimeric sCAR-adenovirus complexes. In summary, we have demonstrated that trimerization of sCAR proteins can significantly improve the potency of this targeting approach in altering vector tropism in vitro and allow the efficient blocking of liver gene transfer in vivo.
| S-EPMC135917 | biostudies-literature