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  • 1.
    Cheng, Wing-Shing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Kraaij, Robert
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    van der Weel, Laura
    de Ridder, Corrina M.A.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    A novel TARP-promoter-based adenovirus against hormone-dependent and hormone-refractory prostate cancer2004In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 10, no 2, p. 355-364Article in journal (Refereed)
    Abstract [en]

    TARP (T cell receptor gamma-chain alternate reading frame protein) is a protein that in males is uniquely expressed in prostate epithelial cells and prostate cancer cells. We have previously shown that the transcriptional activity of a chimeric sequence comprising the TARP promoter (TARPp) and the PSA enhancer (PSAe) is strictly controlled by testosterone and highly restricted to cells of prostate origin. Here we report that a chimeric sequence comprising TARPp and the PSMA enhancer (PSMAe) is highly active in testosterone-deprived prostate cancer cells, while a regulatory sequence comprising PSAe, PSMAe, and TARPp (PPT) has high prostate-specific activity both in the presence and in the absence of testosterone. Therefore, the PPT sequence may, in a gene therapy setting, be beneficial to prostate cancer patients that have been treated with androgen withdrawal. A recombinant adenovirus vector with the PPT sequence, shielded from interfering adenoviral sequences by the mouse H19 insulator, yields high and prostate-specific transgene expression both in cell cultures and when prostate cancer, PC-346C, tumors were grown orthotopically in nude mice. Intravenous virus administration reveals both higher activity and higher selectivity for the insulator-shielded PPT sequence than for the immediate-early CMV promoter. Therefore, we believe that an adenovirus with therapeutic gene expression controlled by an insulator-shielded PPT sequence is a promising candidate for gene therapy of prostate cancer.

  • 2.
    Dassie, Justin P.
    et al.
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States.
    Hernandez, Luiza I.
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States.
    Thomas, Gregory S.
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States.
    Long, Matthew E.
    Molecular and Cellular Biology Program, University of of Iowa, Iowa City, IA, United States; Inflammation Program, University of of Iowa, Iowa City, IA, United States.
    Rockey, William M.
    Department of Radiation Oncology, University of of Iowa, Iowa City, IA, United States.
    Howell, Craig A.
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States.
    Chen, Yani
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States.
    Hernandez, Frank J
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States.
    Liu, Xiu Y.
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States.
    Wilson, Mary E.
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States; Department of Microbiology, University of of Iowa, Iowa City, IA, United States; Veterans Affairs Medical Center, University of of Iowa, Iowa City, IA, United States.
    Allen, Lee-Ann
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States; Molecular and Cellular Biology Program, University of of Iowa, Iowa City, IA, United States; Inflammation Program, University of of Iowa, Iowa City, IA, United States; Department of Microbiology, University of of Iowa, Iowa City, IA, United States; Veterans Affairs Medical Center, University of of Iowa, Iowa City, IA, United States.
    Vaena, Daniel A.
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States.
    Meyerholz, David K.
    Department of Pathology, University of of Iowa, Iowa City, IA, United States.
    Giangrande, Paloma H.
    Department of Internal Medicine, University of of Iowa, 375 Newton Rd, 5202 MERF, Iowa City, IA, United States; Molecular and Cellular Biology Program, University of of Iowa, Iowa City, IA, United States; Department of Radiation Oncology, University of of Iowa, Iowa City, IA, United States.
    Targeted inhibition of prostate cancer metastases with an RNA aptamer to prostate-specific membrane antigen2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, no 11, p. 1910-1922Article in journal (Refereed)
    Abstract [en]

    Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed to effectively treat some cancers. However, many cancers such as metastatic prostate cancer (PC) have yet to be treated with current smart drug technology. Here, we describe the thorough preclinical characterization of an RNA aptamer (A9g) that functions as a smart drug for PC by inhibiting the enzymatic activity of prostate-specific membrane antigen (PSMA). Treatment of PC cells with A9g results in reduced cell migration/invasion in culture and metastatic disease in vivo. Importantly, A9g is safe in vivo and is not immunogenic in human cells. Pharmacokinetic and biodistribution studies in mice confirm target specificity and absence of non-specific on/off-target effects. In conclusion, these studies provide new and important insights into the role of PSMA in driving carcinogenesis and demonstrate critical endpoints for the translation of a novel RNA smart drug for advanced stage PC. © The American Society of Gene amp; Cell Therapy.

  • 3.
    Davidsson, Marcus
    et al.
    Lund Univ, Mol Neuromodulat, Lund, Sweden..
    Aldrin-Kirk, Patrick
    Lund Univ, Mol Neuromodulat, Lund, Sweden..
    Cardoso, Tiago
    Lund Univ, Dev & Regenerat Neurobiol, Lund, Sweden..
    Hartnor, Morgan
    Lund Univ, Mol Neuromodulat, Lund, Sweden..
    Heuer, Andreas
    Lund Univ, Mol Neuromodulat, Lund, Sweden..
    Mollbrink, Annelie
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundeberg, Joakim
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Parmar, Malin
    Lund Univ, Dev & Regenerat Neurobiol, Lund, Sweden..
    Bjorklund, Tomas
    Lund Univ, Mol Neuromodulat, Lund, Sweden..
    Mapping the Connectome Using Novel AAV Vectors, DNA Barcoding and Spatial Transcriptomics2018In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 26, no 5, p. 319-319Article in journal (Other academic)
  • 4.
    EL Andaloussi, Samir
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Johansson, Henrik
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Holm, Tina
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    A novel cell-penetrating peptide, M918, for efficient delivery of proteins and peptide nucleic acids2007In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 15, no 10, p. 1820-1826Article in journal (Refereed)
    Abstract [en]

    Cell-penetrating peptides (CPPs) have attracted increasing attention in the past decade as a result of their high potential to convey various, otherwise impermeable, bioactive agents across cellular plasma membranes. Albeit different CPPs have proven potent in delivery of different cargoes, there is generally a correlation between high efficacy and cytotoxicity for these peptides. Hence, it is of great importance to find new, non-toxic CPPs with more widespread delivery properties. We present a novel CPP, M918, that efficiently translocates various cells in a non-toxic fashion. In line with most other CPPs, the peptide is internalized mainly via endocytosis, and in particular macropinocytosis, but independent of glycosaminoglycans on the cell surface. In addition, in a splice correction assay using antisense peptide nucleic acid (PNA) conjugated via a disulphide bridge to M918 (M918-PNA), we observed a dose-dependent increase in correct splicing, exceeding the effect of other CPPs. Our data demonstrate that M918 is a novel CPP that can be used to translocate different cargoes inside various cells efficiently.

  • 5.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlsson, Hannah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wikström, Kristina I.
    Karolinska Hosp, VECURA, Huddinge, Sweden..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Savoldo, Barbara
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Dotti, Gianpietro
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Brenner, Malcolm K.
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    A Clinical Trial Using Third Generation CD19 Targeting CAR T Cells for Relapsed Lymphoma and Leukemia2016In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 24, p. S295-S296Article in journal (Other academic)
  • 6.
    Eriksson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Milenova, Ioanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Moreno, Rafael
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alemany, Ramon
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Loskog, Angelica S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Activating CD40 While Inhibiting IL6R Induces Cytokine Production without PDL1 Upregulation in DCs2017In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 25, no 5 S1, p. 54-54Article in journal (Other academic)
  • 7.
    Essand, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ma, Jing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala Univ, Uppsala, Sweden..
    CAR T-Cells with Induced Secretion of Helicobacter Pylori Neutrophil-Activating Protein (HP-NAP) Yields Improved Anti-Tumor Activity and Reduced Immunosuppression2017In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 25, no 5 S1, p. 288-288Article in journal (Other academic)
  • 8.
    Gyorgy, Bence
    et al.
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lööv, Camilla
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    Takeda, Shuko
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    Lannfelt, Lars
    Uppsala Univ, Dept Geriatr, Uppsala, Sweden..
    Hyman, Bradley T.
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA..
    CRISPR-Cas9 Mediated Gene Editing in a Monogenic Form of Alzheimer's Disease2016In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 24, p. S226-S227Article in journal (Other academic)
  • 9.
    Gyorgy, Bence
    et al.
    Harvard Med Sch, Neurobiol, Boston, MA USA.
    Kleinstiver, Benjamin P.
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Garcia, Sara P.
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Zaborowski, Mikolaj
    Massachusetts Gen Hosp, Neurol, Boston, MA USA.
    Sousa, Alexander A.
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Tsai, Shengdar Q.
    St Jude Childrens Res Hosp, Expt Hematol, Memphis, TN USA.
    Bengtsson, Niclas E.
    Univ Washington, Neurol, Seattle, WA USA.
    Loov, Camilla
    Massachusetts Gen Hosp, MassGen Inst Neurodegenerat, Boston, MA USA.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Chamberlain, Jeffrey S.
    Univ Washington, Neurol, Seattle, WA USA.
    Corey, David P.
    Harvard Med Sch, Neurobiol, Boston, MA USA.
    Aryee, Martin J.
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Joung, J. Keith
    Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA USA.
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, Neurol, Boston, MA USA.
    Maguire, Casey A.
    Massachusetts Gen Hosp, Neurol, Boston, MA USA.
    AAV-Vector Integration into CRISPR-Induced Double-Stranded Breaks2018In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 26, no 5, p. 432-433Article in journal (Other academic)
  • 10.
    Hillerdal, Victoria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Boura, Vanessa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Engineering Regulatory Cells With a T Cell Receptor for Controlled Activation2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S180-S180Article in journal (Other academic)
  • 11.
    Jin, Chuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Allogeneic Lymphocyte-Licensed DCs Expand TCR/CAR-Engineered T Cells, Which Are Insensitive To Oxidative Stress and Immunosuppressive Factors2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S62-S62Article in journal (Other academic)
  • 12.
    Johansson, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    El-Andaloussi, Samir
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Holm, Tina
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Mäe, Maarja
    Jaak, Jänes
    Maimets, Toivo
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Characterization of a novel cytotoxic cell-penetrating peptide derived from p14ARF protein2008In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 16, no 1, p. 115-123Article in journal (Refereed)
  • 13.
    Johansson, Magnus
    et al.
    Örebro University, School of Medical Sciences.
    Frelin, Lars
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Maravelia, Panagiota
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Asghar, Naveed
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Caro-Perez, Noelia
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Pasetto, Anna
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlen, Gustaf
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sallberg, Matti
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Immunogenicity of a New Flaviviral-Based DNA Launched Suicidal Replicon for Protective Vaccination Against Hepatitis C2019In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 27, no 4, p. 139-139Article in journal (Other academic)
  • 14.
    Karlsson, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gigg, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Savoldo, Barbara
    Dotti, Gianpietro
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Antigen Signaling Enhances Proliferation and Cytotoxic Capacity of CD19-Targeting CD28/4-1BB CAR T Cells During Expansion Without Inducing Exhaustion2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S61-S61Article in journal (Other academic)
  • 15.
    Karlsson, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafsson, Wictor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Savoldo, Barbara
    Dotti, Gianpietro
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    CAR T Cells Express CD40L and Activates Human Dendritic Cells2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S61-S61Article in journal (Other academic)
  • 16.
    Lehto, Taavi
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Simonson, Oscar E.
    Mäger, Imre
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ezzat, Kariem
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sork, Helena
    Copolovici, Dana-Maria
    Viola, Joana R.
    Zaghloul, Eman M.
    Lundin, Per
    Moreno, Pedro M. D.
    Mäe, Maarja
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Oskolkov, Nikita
    Suhorutšenko, Julia
    Smith, C. I. Edvard
    EL Andaloussi, Samir
    A Peptide-based Vector for Efficient Gene Transfer In Vitro and In Vivo2011In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 19, no 8, p. 1457-1467Article in journal (Refereed)
    Abstract [en]

    Finding suitable nonviral delivery vehicles for nucleic acid-based therapeutics is a landmark goal in gene therapy. Cell-penetrating peptides (CPPs) are one class of delivery vectors that has been exploited for this purpose. However, since CPPs use endocytosis to enter cells, a large fraction of peptides remain trapped in endosomes. We have previously reported that stearylation of amphipathic CPPs, such as transportan 10 (TP10), dramatically increases transfection of oligonucleotides in vitro partially by promoting endosomal escape. Therefore, we aimed to evaluate whether stearyl-TP10 could be used for the delivery of plasmids as well. Our results demonstrate that stearyl-TP10 forms stable nanoparticles with plasmids that efficiently enter different cell-types in a ubiquitous manner, including primary cells, resulting in significantly higher gene expression levels than when using stearyl-Arg9 or unmodified CPPs. In fact, the transfection efficacy of stearyl-TP10 almost reached the levels of Lipofectamine 2000 (LF2000), however, without any of the observed lipofection-associated toxicities. Most importantly, stearyl-TP10/plasmid nanoparticles are nonimmunogenic, mediate efficient gene delivery in vivo, when administrated intramuscularly (i.m.) or intradermally (i.d.) without any associated toxicity in mice.

  • 17. Lindholm, L
    et al.
    Andersson, K
    Boulanger, P
    Frykholm, K
    Henning, P
    Hoeben, R
    Hong, S S
    Johannisson, J
    Magnusson, M
    Myhre, S
    Nygren, Per-Åke
    KTH, Superseded Departments, Biotechnology.
    Pettersson, E
    Stahl, Stefan
    KTH, Superseded Departments, Biotechnology.
    Vellinga, J
    Wikman, Maria
    KTH, Superseded Departments, Biotechnology.
    Genetic re-targeting of adenovirus using a hyperstable scFv domain and an affibody (R) molecule against Her2/neu2004In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 9, p. S250-S250Article in journal (Refereed)
    Abstract [en]

    One important goal in gene therapy is to develop adenovirus (Ad) vectors that are genetically de-targeted as well as re-targeted. Genetic re-targeting of Ad using complex cell-binding ligands has previously not been possible. We have previously demonstrated that ligands for genetic re-targeting of adenoviruses must be able to fold correctly in the cytoplasm of virus producing cells, a milieu that is not conducive to the formation of disulphide bonds.

    Here, we describe functional Ad5 viruses with fibers and pIX capsid proteins genetically modified to contain two types of complex ligands. One is affibody® molecules, corresponding to small (6 kDa) binding proteins developed by combinatorial protein engineering using a single three-helix bundle staphylococcal protein A domain. The other type is hyperstable antibody scFv domains.

    The affibody molecule used here (ZH2N) is directed against Her2/neu. Recombinant viruses were constructed with ZH2N in three different positions: (i) at the C-terminus of shaft repeat 7 of de-knobbed fibers; (ii) at the C-terminus of pIX; and (iii) in the HI-loop of the fiber knob. Each of the viruses exhibited a characteristic phenotype regarding fiber content, growth and ability to infect Her2/neu expressing cells.

    In order to test the potentials of scFv liganded Ad vectors, a hyperstable antibody scFv against b-galactosidase was genetically incorporated into knobless fibers, in tandem with a mutated protein A domain reactive with IgG1 Fc that targeted the virus to Fc-expressing 293 cells. These fibers could be rescued into viable virions that retained the original antigen binding specificity of the scFv, demonstrating the basic potential of hyperstable scFvs for genetic re-targeting of Ad. Quite unexpectedly, the fiber content of Ad with knobless, scFv containing fibers was close to normal in contrast to other Ad with knobless fibers that generally has a much reduced fiber content. The hyperstable scFv was further fused to the C-terminus of the capsid protein pIX. The recombinant molecules could be rescued into viable viruses with wt fibers. The scFv retained its binding-specificity on the recombinant virions.

    The results demonstrate that, contrary to current beliefs, it is possible to construct Ad that genetically incorporates functional scFvs and other complex ligands into the virus fiber and pIX. The feasibility is demonstrated by the creation of different viruses that are re-targeted to Her2/neu. These viruses are currently in pre-clinical development.

  • 18.
    Lindqvist, Johan M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The Cardiac Alkali Myosin Light Chain Can Restore Skeletal Muscle Function in a Mouse Model of Nemaline Myopathy2013In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, p. S68-S68Article in journal (Other academic)
  • 19.
    Loskog, Angelica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Maleka, Aglaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Krause, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Agnarsdottir, Margret
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    AdCD40L Immunostimulatory Gene Therapy in Combination with Cyclophosphamide Prolongs 6-Months Survival in a Phase I/II Trial for Malignant Melanoma2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S247-S247Article in journal (Other academic)
  • 20.
    Magnusson, Maria K.
    et al.
    Univ Gothenburg, Inst Biomed, Gothenburg, Sweden.;Got A Gene AB, Kullavik, Sweden..
    Frejd, Fredrik Y.
    Affibody AB, Bromma, Sweden..
    Friedman, Mikaela
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lindholm, Leif
    Got A Gene AB, Kullavik, Sweden..
    Reproducible Genetic Re-Targeting of Adenovirus Using Affibody Molecules2009In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 17, p. S320-S321Article in journal (Other academic)
  • 21. Maguire, Casey A.
    et al.
    Balaj, Leonora
    Sivaraman, Sarada
    Crommentuijn, Matheus H. W.
    Ericsson, Maria
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Gianni, Davide
    Tannous, Bakhos A.
    Sena-Esteves, Miguel
    Breakefield, Xandra O.
    Skog, Johan
    Microvesicle-associated AAV Vector as a Novel Gene Delivery System2012In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 20, no 5, p. 960-971Article in journal (Refereed)
    Abstract [en]

    Adeno-associated virus (AAV) vectors have shown remarkable efficiency for gene delivery to cultured cells and in animal models of human disease. However, limitations to AAV vectored gene transfer exist after intravenous transfer, including off-target gene delivery (e.g., liver) and low transduction of target tissue. Here, we show that during production, a fraction of AAV vectors are associated with microvesicles/exosomes, termed vexosomes (vector-exosomes). AAV capsids associated with the surface and in the interior of microvesicles were visualized using electron microscopy. In cultured cells, vexosomes outperformed conventionally purified AAV vectors in transduction efficiency. We found that purified vexosomes were more resistant to a neutralizing anti-AAV antibody compared to conventionally purified AAV. Finally, we show that vexosomes bound to magnetic beads can be attracted to a magnetized area in cultured cells. Vexosomes represent a unique entity which offers a promising strategy to improve gene delivery.

  • 22.
    Milenova, Ioanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Moreno, Rafael
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Alemany, Ramon
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Lokon Pharma AB, Uppsala, Sweden..
    An Oncolytic Adenovirus Gene Therapy Targeting Both Tumor Cell Survival and Desmoplasia in Pancreatic Cancer2016In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 24, p. S262-S262Article in journal (Other academic)
  • 23. Nikravesh, Abbas
    et al.
    Dryselius, Rikard
    Faridani, Omid R
    Goh, Shan
    Sadeghizadeh, Majid
    Behmanesh, Mehrdad
    Ganyu, Anita
    Klok, Erik Jan
    Zain, Rula
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Good, Liam
    Antisense PNA Accumulates in Escheria coli and mediates a Long Post-antibiotic Effect2008In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 15, no 8, p. 1537-1542Article in journal (Refereed)
    Abstract [en]

    Antisense agents that target growth-essential genes display surprisingly potent bactericidal properties. In particular, peptide nucleic acid (PNA) and phosphorodiamidate morpholino oligomers linked to cationic carrier peptides are effective in time kill assays and as inhibitors of bacterial peritonitis in mice. It is unclear how these relatively large antimicrobials overcome stringent bacterial barriers and mediate killing. Here we determined the transit kinetics of peptide–PNAs and observed an accumulation of cell-associated PNA in Escherichia coli and slow efflux. An inhibitor of drug efflux pumps did not alter peptide–PNA potency, indicating a lack of active efflux from cells. Consistent with cell retention, the post-antibiotic effect (PAE) of the anti-acyl carrier protein (acpP) peptide–PNA was greater than 11 hours. Bacterial cell accumulation and a long PAE are properties of significant interest for antimicrobial development.

  • 24.
    Ramachandran, Mohanraj
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Adenovirus Encoded Helicobacter pylori Neutrophil Activating Protein Promotes Maturation of DCs with Th-1 Polarization, Improved Antigen Presentation and Migration2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S242-S243Article in journal (Other academic)
  • 25.
    Ramachandran, Mohanraj
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors2013In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, no 11, p. 2008-2018Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylori Neutrophil Activating Protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate anti-tumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Δ24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as TNF-α and MIP2-α in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours post-virus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting anti-tumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus.

  • 26.
    Roche, Francis P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ohlin, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Histidine-Rich Glycoprotein (HRG): A Novel Gene-Therapy Effector for the Treatment of Cancer2013In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, p. S241-S241Article in journal (Other academic)
  • 27.
    Roche, Francis P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ohlin, Elisabet K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Histidine-Rich Glycoprotein (HRG): A Novel Gene-Therapy Effector for the Treatment of Cancer2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S243-S244Article in journal (Other academic)
  • 28.
    Skog, Johan
    et al.
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Adenoviruses 16 and CV23 efficiently transduce human low-passage brain tumor and cancer stem cells2007In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 15, no 12, p. 2140-5Article in journal (Refereed)
    Abstract [en]

    Most clinical protocols involving adenovirus (Ad) vectors for gene therapy use a vector based on serotype 5 (Ad5). We believe that this serotype is not suitable for all gene therapy applications and that alternative vectors based on other serotypes should be developed. We have compared the ability of Ad5, Ad11p, Ad16p, and a chimpanzee Ad (CV23) to infect human low-passage brain tumor cells as well as primary glioma cells sorted into a CD133(+) and CD133(-) population. Cancer stem cells have been shown to reside in the CD133(+) population of cells in human glioma tumors and they are of considerable interest in glioma therapy. Ad16p and CV23 infected the low-passage brain tumor cell lines and also the CD133(+) and CD133(-) primary tumor cells most efficiently. Interestingly, as the passage number of the cells increased, the infection capacity of Ad5 increased significantly, whereas this was not seen for CV23. To ensure the therapeutic effect of Ad vectors on brain tumors, the vector must be capable of addressing both the CD133(+) cancer stem cells and the CD133(-) cells of the tumor. In particular, Ad16 and CV23 are meeting this challenge.

  • 29.
    Svensson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Moreno, Rafael
    Milenova, Ioanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Alemany, Ramon
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Immunostimulating Gene Therapy Using an Oncolytic Adenovirus Armed with CD40 Ligand Potently Kill Tumor Cells, Activates Dendritic Cells and Induces T Cell Responses2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S253-S254Article in journal (Other academic)
  • 30. van Rijn, Sjoerd
    et al.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Noske, David P.
    Vandertop, W. Peter
    Tannous, Bakhos A.
    Wuerdinger, Thomas
    Transcription Factor Activity Analysis Using a Functional Multiplex Gaussia Luciferase-Based Reporter Assay2013In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, p. S123-S124Article in journal (Refereed)
  • 31. Wein, Nicolas
    et al.
    Vulin, Adeline
    Falzanaro, Maria S.
    Szigyarto, Cristina Al-Khalili
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Maiti, Baijayanta
    Findlay, Andrew
    Heller, Kristin N.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Bakthavachalu, Baskar
    Messina, Sonia
    Vita, Giuseppe L.
    Gualandi, Francesca
    Wilton, Steve D.
    Yang, Lin
    Dunn, Diane M.
    Schoenberg, Daniel
    Weiss, Robert B.
    Howard, Michael T.
    Ferlini, Alessandra
    Flanigan, Kevin M.
    Successful Use of Out-of-Frame Exon 2 Skipping Induces IRES-Driven Expression of the N-Truncated Dystrophin Isoform: Promising Approach for Treating Other 5 ' Dystrophin Mutations2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S294-S295Article in journal (Other academic)
  • 32.
    Wenthe, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Milenova, Ioanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Moreno, Rafael
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Alemany, Ramon
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Lokon Pharma AB, Uppsala, Sweden..
    A Novel Oncolytic Adenovirus Expressing Tumor Microenvironment Stimulators to Evoke and Facilitate Anti-Tumor Immune Responses2016In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 24, p. S206-S206Article in journal (Other academic)
  • 33. Wettergren, E E
    et al.
    Gussing, F
    Sest, Maike
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Graslund, T
    Lundberg, Cecilia
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Regulation of Endogenous GAD67 Expression Using Artificial Transcription Factors2011In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 19, no 7Article in journal (Other academic)
  • 34.
    Whilding, Lynsey M.
    et al.
    Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England..
    Archibald, Kyra M.
    Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England..
    Kulbe, Hagen
    Queen Mary Univ London, Barts Canc Inst, Ctr Canc & Inflammat, London, England..
    Balkwill, Frances R.
    Queen Mary Univ London, Barts Canc Inst, Ctr Canc & Inflammat, London, England..
    Öberg, Daniel
    Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England..
    McNeish, Iain A.
    Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England.;Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland..
    Vaccinia Virus Induces Programmed Necrosis in Ovarian Cancer Cells2013In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, no 11, p. 2074-2086Article in journal (Refereed)
    Abstract [en]

    The mechanisms by which oncolytic vaccinia virus induces tumor cell death are poorly understood. We have evaluated cell death pathways following infection of ovarian cancer cells with both wild-type and thymidine kinase-deleted (dTK) Lister strain vaccinia. We show that death does not rely upon classical apoptosis despite the appearances of some limited apoptotic features, including phosphatidylserine externalization and appearance of sub-G1 DNA populations. Vaccinia infection induces marked lipidation of LC3 proteins, but there is no general activation of the autophagic process and cell death does not rely upon autophagy induction. We show that vaccinia induces necrotic morphology on transmission electron microscopy, accompanied by marked by reductions in intracellular adenosine triphosphate, altered mitochondrial metabolism, and release of high mobility group box 1 (HMGB1) protein. This necrotic cell death appears regulated, as infection induces formation of a receptor interacting protein (RIP1)/caspase-8 complex. In addition, pharmacological inhibition of both RIP1 and substrates downstream of RIP1, including MLKL, significantly attenuate cell death. Blockade of TNF-alpha, however, does not alter virus efficacy, suggesting that necrosis does not result from autocrine cytokine release. Overall, these results show that, in ovarian cancer cells, vaccinia virus causes necrotic cell death that is mediated through a programmed series of events.

1 - 34 of 34
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