David T Curiel

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (889)

  • [Show abstract] [Hide abstract] ABSTRACT: Contributing reviewers The editors of Journal of Ovarian Research would like to thank all of our reviewers who have contributed to the journal in Volume 8 (2015).
    Article · Dec 2016 · Journal of Ovarian Research
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    Full-text Article · Aug 2016 · Clinical and Translational Medicine
  • Article · Aug 2016 · Pancreatology
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    [Show abstract] [Hide abstract] ABSTRACT: Clostridium difficile infection (CDI), a leading cause of nosocomial infection, is a serious disease in North America, Europe and Asia. CDI varies greatly from asymptomatic carriage to life threatening diarrhea, toxic megacolon and toxemia. The incidence of community acquired infection has increased due to the emergence of hypervirulent antibiotic-resistant strains. These new strains contribute to the frequent occurrence of disease relapse; complicating treatment, increasing hospital stays, and increasing morbidity and mortality among patients. It is critical therefore to develop new therapeutic approaches that bypass the development of antimicrobial resistance and avoid disruption of gut microflora. Here we describe the construction of a single heteromultimeric V H H-based neutralizing agent (VNA) targeting the two primary virulence factors of Clostridium difficile , toxin A (TcdA) and B (TcdB). Designated VNA2-Tcd, this agent has sub-nanomolar toxin neutralization potencies for both C. difficile toxins in cell assays. When given systemically by parenteral administration, VNA2-Tcd protected against CDI in gnotobiotic piglets and mice, and to a lesser extent in hamsters. Protection from CDI was also observed in gnotobiotic piglets treated by gene therapy with an adenovirus promoting expression of VNA2-Tcd.
    Full-text Article · Jul 2016 · Clinical and Vaccine Immunology
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    [Show abstract] [Hide abstract] ABSTRACT: Rationale: Mutations in the ATP-binding cassette transporter A3 gene (ABCA3) result in severe neonatal respiratory distress syndrome (RDS) and childhood interstitial lung disease (chILD). As most ABCA3 mutations are rare or private, determination of mutation pathogenicity is often based on results from in silico prediction tools, identification in unrelated diseased individuals, statistical association studies, or expert opinion. Functional biologic studies of ABCA3 mutations are needed to confirm mutation pathogenicity and inform clinical decision making. Objective: To functionally characterize 2 ABCA3 mutations (p.R288K and p.R1474W) identified among term and late preterm infants with RDS with unclear pathogenicity in a genetically versatile model system. Methods: We performed transient transfection of HEK293T cells with wild-type or mutant ABCA3 alleles to assess protein processing with immunoblotting. We used transduction of A549 cells with adenoviral vectors which concurrently silenced endogenous ABCA3 and expressed either wild-type or mutant ABCA3 alleles (p.R288K and p.R1474W) to assess immunofluorescent localization, ATPase activity, and organelle ultrastructure. Measurements and main results: Both ABCA3 mutations (p.R288K and p.R1474W) encoded proteins with reduced ATPase activity, but with normal intracellular localization and protein processing. Ultrastructural phenotypes of lamellar body-like vesicles in A549 cells transduced with mutant alleles were similar to wild-type. Conclusions: Mutant proteins encoded by ABCA3 mutations p.R288K and p.R1474W had reduced ATPase activity, a biologically plausible explanation for disruption of surfactant metabolism by impaired phospholipid transport into the lamellar body. These results also demonstrate the usefulness of a genetically versatile, human model system for functional characterization of ABCA3 mutations with unclear pathogenicity.
    Full-text Article · Jul 2016 · American Journal of Respiratory Cell and Molecular Biology
  • Ahmad Mohammad Ashshi · Adel Galal El-Shemi · Igor P. Dmitriev · [...] · David T. Curiel
    [Show abstract] [Hide abstract] ABSTRACT: Background A major hurdle incurrent to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy agents is their limited therapeutic efficacy. In this study we evaluated whether arming our previously reported Ad5/3Δ24 CRAd vector containing a 24-base pair deletion in the E1A conserved region 2, which allows selective replication within Rb-p16-deficient tumor cells, to express therapeutic genes could improve oncolytic virus potency in ovarian cancer cells. We choose to assess the therapeutic benefits achieved by virus-mediated expression of interleukin 24 (IL-24), a cytokine-like protein of the IL-10 family, and the inhibitor of growth 4 (ING4) tumor suppressor protein. Results The generated CRAd-IL24 and CRAd-ING4 vectors were tested in ovarian cancer cell lines in vitro to compare their replication, yield, and cytotoxic effects with control CRAd Ad5/3∆24 lacking the therapeutic gene. These studies showed that CRAd-IL24 infection resulted in significantly increased yield of infectious particles, which translated to a marked enhancement of virus-induced cytotoxic effects as compared to CRAd-ING4 and non-armed CRAd. Testing CRAd-IL24 and CRAd-ING4 vectors combined together did not revealed synergistic effects exceeding oncolytic potency of single CRAD-IL24 vector. Both CRAds were also tested along with anti-VEGF monoclonal antibody Avastin and showed no significant augmentation of viral cytolysis by anti-angiogenesis treatment in vitro. Conclusions Our studies validated that arming with these key immunomodulatory genes was not deleterious to virus-mediated oncolysis. These findings thus, warrant further preclinical studies of CRAd-IL24 tumoricidal efficacy in murine ovarian cancer models to establish its potential utility for the virotherapy of primary and advanced neoplastic diseases.
    Article · Jun 2016 · Journal of Ovarian Research
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    Full-text Article · May 2016 · Scientific Reports
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    Dataset: S2 Fig
    [Show abstract] [Hide abstract] ABSTRACT: Gating strategy for flow cytometry analysis, ICS. In this sample gating, cells were first gated for lymphocytes (SSC-A vs FSC-A) and then for singlets (FSC-H vs FSC-A). The singlets gate was further analyzed for their uptake of the Alexa 430 Live/Dead Stain. The samples were then analyzed by gating on the live population and CD3+ T cells selected for further characterization of CD4+ and CD8+ T cell subsets. IFN-γ, TNF-α and IL-2 producing CD4+ or CD8+ T cells were then quantified. (PDF)
    Full-text Dataset · Apr 2016
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    [Show abstract] [Hide abstract] ABSTRACT: A malaria vaccine is a public health priority. In order to produce an effective vaccine, a multistage approach targeting both the blood and the liver stage infection is desirable. The vaccine candidates also need to induce balanced immune responses including antibodies, CD4+ and CD8+ T cells. Protein-based subunit vaccines like RTS,S are able to induce strong antibody response but poor cellular reactivity. Adenoviral vectors have been effective inducing protective CD8+ T cell responses in several models including malaria; nonetheless this vaccine platform exhibits a limited induction of humoral immune responses. Two approaches have been used to improve the humoral immunogenicity of recombinant adenovirus vectors, the use of heterologous prime-boost regimens with recombinant proteins or the genetic modification of the hypervariable regions (HVR) of the capsid protein hexon to express B cell epitopes of interest. In this study, we describe the development of capsid modified Ad5 vectors that express a promiscuous Plasmodium yoelii T helper epitope denominated PyT53 within the hexon HVR2 region. Several regimens were tested in mice to determine the relevance of the hexon modification in enhancing protective immune responses induced by the previously described protein-based multi-stage experimental vaccine PyCMP. A heterologous prime-boost immunization regime that combines a hexon modified vector with transgenic expression of PyCMP followed by protein immunizations resulted in the induction of robust antibody and cellular immune responses in comparison to a similar regimen that includes a vector with unmodified hexon. These differences in immunogenicity translated into a better protective efficacy against both the hepatic and red blood cell stages of P. yoelii. To our knowledge, this is the first time that a hexon modification is used to deliver a promiscuous T cell epitope. Our data support the use of such modification to enhance the immunogenicity and protective efficacy of adenoviral based malaria vaccines.
    Full-text Article · Apr 2016 · PLoS ONE
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    Dataset: S1 Fig
    [Show abstract] [Hide abstract] ABSTRACT: Gating strategy for flow cytometry analysis, tetramer. In this sample gating, cells were first gated for lymphocytes (SSC-A vs FSC-A) and then for singlets (FSC-H vs FSC-A). The singlets gate was further analyzed for CD3 expression taking only the T cell population (CD3+). CD4 and CD8 surface expression was then determined and the CD8+ T cells were further analyzed to measure tetramer recognition. (PDF)
    Full-text Dataset · Apr 2016
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    [Show abstract] [Hide abstract] ABSTRACT: TRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL platform TR3 in efforts to improve the limitations associated with currently available drug variants. While in the process of characterizing mesothelin-targeted TR3 variants using a single chain antibody (scFv) delivery format (SS-TR3), we discovered that the membrane-tethered cytokine had a substantially increased activity profile compared to non-targeted TR3. However, cell death proceeded exclusively via a bystander mechanism and protected the mesothelin-positive targets from apoptosis rather than leading to their elimination. Incorporation of a spacer-into the mesothelin surface antigen or the cancer drug itself-converted SS-TR3 into a cis-acting phenotype. Further experiments with membrane-anchored TR3 variants and the native cytokine confirmed our hypothesis that membrane-proximal TRAIL species lack the capacity to physically engage their cognate receptors coexpressed on the same cell membrane. Our findings not only provide an explanation for the “peaceful” coexistence of ligand and receptor of a representative member of the TNF superfamily but give us vital clues for the design of activity-enhanced TR3-based cancer therapeutics.
    Full-text Article · Mar 2016 · Scientific Reports
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    Full-text Dataset · Mar 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and inhibiting proliferation of human leiomyoma cells in vitro while sparing normal myometrial cells. Study design: An in-vivo study, to compare efficacy and safety of modified adenovirus vector Ad-SSTR-RGD-TK/GCV versus untargeted vector for treatment of leiomyoma. Materials and methods: Female nude mice were implanted with rat leiomyoma cells subcutaneously. Then mice were randomized into three groups. Group 1 received Ad-LacZ (marker gene), Group 2 received untargeted Ad-TK, and Group 3 received the targeted Ad-SSTR-RGD-TK. Tumors were measured weekly for 4 weeks. Then mice were sacrificed and tissue samples were collected. Evaluation of markers of apoptosis, proliferation, extracellular matrix, and angiogenesis was performed using Western Blot & Immunohistochemistry. Statistical analysis was done using ANOVA. Dissemination of adenovirus was assessed by PCR. Results: In comparison with the untargeted vector, the targeted adenoviral vector significantly shrank leiomyoma size (P < 0.05), reduced expression of proliferation marker (PCNA) (P < 0.05), induced expression of apoptotic protein, c-PARP-1, (P < 0.05) and inhibited expression of extracellular matrix-related genes (TGF beta 3) and angiogenesis-related genes (VEGF & IGF-1) (P < 0.01). There were no detectable adenovirus in tested tissues other than leiomyoma lesions with both targeted and untargeted adenovirus. Conclusion: Targeted adenovirus, effectively reduces tumor size in leiomyoma without dissemination to other organs. Further evaluation of this localized targeted strategy for gene therapy is needed in appropriate preclinical humanoid animal models in preparation for a future pilot human trial.
    Article · Feb 2016 · Reproductive sciences (Thousand Oaks, Calif.)
  • Essam R Othman · David T Curiel · Mostafa Hussein · [...] · Ayman Al-Hendy
    [Show abstract] [Hide abstract] ABSTRACT: Objective: Our aim was to screen a panel of modified adenoviral gene transfer vectors to identify those which can sustain high gene expression in human endometrial cells. Methods: Normal endometrial stromal cell cultures were established from endometrial lining of hysterectomy specimens performed for benign gynecologic indications. Human endometrial stromal cells were transfected by modified adenoviruses expressing luciferase reporter gene. Luciferase activity mediated by each virus was expressed as a percentage of adenovirus serotype 5 (Ad5-CMV-luc) activity. The 2-tailed Student t test was used to compare data. Results: At a multiplicity of infection (MOI) of 10 pfu/cell, of the transductionally modified adenoviruses, adenovirus-RGD (Ad-RGD-luc) mediated highest level of endometrial cell transduction with transgene expression around 4 times higher when compared to Ad5 (P < .001). Of the transcriptionally targeted adenoviruses, adenovirus under secretory leukocyte protease inhibitor promoter (Ad-SLPI-luc) and adenovirus under heparanase promoter (Ad-heparanase-luc)-mediated luciferase activation were 5.8- and 4.3-folds higher than Ad5-CMV-luc, respectively (P = .02 and .03, respectively). At MOI of 50 pfu/cell, Ad-RGD-luc and AD-SLPI-luc mediated significantly higher gene transfer efficiency compared to Ad5-CMV-luc (P values < .001, for each virus). Ad-heparanase-luc achieved higher gene activity, but difference was not significant (P = .1). Ad-SLPI-luc, at low viral dose (10 pfu/ cell), mediated gene expression effect comparable to Ad5-CMV-luc at a high dose (50 pfu/cell), with no significant difference. Conclusions: We conclude that when compared to the wild-type adenovirus, Ad-RGD-luc, Ad-SLPI-luc, and Ad-heparanase-luc mediate higher reporter gene activity in endometrial cells and can work as effective gene transfer vectors in gene therapy applications to the endometrium.
    Article · Feb 2016 · Reproductive Sciences
  • Maurizio Buggio · Christopher Towe · Anand Annan · [...] · David T. Curiel
    [Show abstract] [Hide abstract] ABSTRACT: Background: Gene therapy for inherited serum deficiency disorders has previously been limited by the balance between obtaining adequate expression and causing hepatic toxicity. Our group has previously described modifications of a replication deficient human Adenovirus serotype 5 that increase pulmonary vasculature transgene expression. Methods: Herein, we use a modified pulmonary targeted Adenovirus to express human Alpha-1 Antitrypsin (A1AT) in C57BL/6J mice. Results: By using the targeted Adenovirus, we are able to achieve similar increases in serum A1AT levels with less liver viral uptake. We also increased pulmonary epithelial lining fluid A1AT levels more than an order of magnitude compared to that of untargeted Adenovirus expressing A1AT in a mouse model. These gains are achieved with evidence of decreased systemic inflammation and no evidence for increased inflammation within the vector-targeted end organ. Conclusions: In addition to advancing us closer to clinically viable gene therapy for A1AT, by maximizing protein production at the site of action, this represents a significant technical advancement in the field of systemically delivered pulmonary targeted gene therapy. It also provides an alternative to the previous limitations of hepatic viral transduction and associated toxicities.
    Article · Jan 2016 · The Journal of Gene Medicine
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    Full-text Dataset · Jan 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Bacillus anthracis , the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH-based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 μg/ml, with some as high as 10 mg/ml. The levels were 10- to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 μg/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 μg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors.
    Article · Jan 2016 · Clinical and vaccine Immunology: CVI
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    Dataset: S1 Table
    [Show abstract] [Hide abstract] ABSTRACT: VP/ml titers of CRAds used in this study. * indicate novel oncolytic viruses generated in this study. (TIF)
    Full-text Dataset · Dec 2015
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    [Show abstract] [Hide abstract] ABSTRACT: Studies have demonstrated that oncolytic adenoviruses based on a 24 base pair deletion in the viral E1A gene (D24) may be promising therapeutics for treating a number of cancer types. In order to increase the therapeutic potential of these oncolytic viruses, a novel conditionally replicating adenovirus targeting multiple receptors upregulated on tumors was generated by incorporating an Ad5/3 fiber with a carboxyl terminus RGD ligand. The virus displayed full cytopathic effect in all tumor lines assayed at low titers with improved cytotoxicity over Ad5-RGD D24, Ad5/3 D24 and an HSV oncolytic virus. The virus was then engineered to deliver immunotherapeutic agents such as GM-CSF while maintaining enhanced heterogenic oncolysis.
    Full-text Article · Dec 2015 · PLoS ONE
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    Dataset: S5 Fig
    [Show abstract] [Hide abstract] ABSTRACT: Phase contrast images of neuroblastoma lines treated with multiple OVs. SK-N-As and Be cells were infected with the indicated OVs at an MOI of 0.1 or 1.0 PFUs/cell. Live images at 60 hpi in a 96 well plate prior to MTS assays (100 × magnification). (TIF)
    Full-text Dataset · Dec 2015

Publication Stats

32k Citations


  • 2015
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2008-2009
    • Virginia Commonwealth University
      • Department of Biochemistry and Molecular Biology
      Richmond, VA, United States
  • 2007
    • University of Alabama at Birmingham
      • Department of Surgery
      Birmingham, Alabama, United States
    • Royal Adelaide Hospital
      • Department of Thoracic Medicine
      Tarndarnya, South Australia, Australia
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
  • 2004-2007
    • Columbia University
      New York, New York, United States
    • VU University Medical Center
      • Department of Orthopedic Surgery
      Amsterdam, North Holland, Netherlands
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 2006
    • University of Chicago
      Chicago, Illinois, United States
  • 2002-2004
    • VU University Amsterdam
      • Department of Orthopaedic Surgery
      Amsterdamo, North Holland, Netherlands
  • 2003
    • University of Helsinki
      Helsinki, Uusimaa, Finland
  • 2002-2003
    • Tulane University
      • Section of Hematology and Medical Oncology
      New Orleans, Louisiana, United States
  • 2000
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 1997
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1996-1997
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany