The Experts below are selected from a list of 36 Experts worldwide ranked by ideXlab platform
Angela M. Belcher - One of the best experts on this subject based on the ideXlab platform.
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Cover Picture: Weaving Genetically Engineered Functionality into Mechanically Robust Virus Fibers (Adv. Mater. 6/2007)
Advanced Materials, 2007Co-Authors: Chung-yi Chiang, Charlene M. Mello, E. C. C. M. Silva, K. J. Van Vliet, Angela M. BelcherAbstract:The desired functionality of a Virus Fiber (such as gold-binding ability) can be programmed by manipulating the M13 Virus genome, report Angela Belcher, Krystyn Van Vliet, and co-workers on p. 826. The background picture is an illustration of a Virus Fiber that is conjugated with cadmium selenide quantum dots and emits red light when excited by UV irradiation. The genetically tunable functionality on the Virus Fiber offers a convenient designing process and will bring a variety of new applications to antimicrobial, catalytic, optical, medical, and electronic Fibers.
M Essand - One of the best experts on this subject based on the ideXlab platform.
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Oncolytic adenoVirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells
Gene Therapy, 2011Co-Authors: J Leja, B Nilsson, L Gedda, A Zieba, T Hakkarainen, G Åkerström, K Öberg, V Giandomenico, M EssandAbstract:We have previously described the oncolytic adenoVirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenoVirus serotype 5 (Ad5) and infects target cells by binding to the coxsackie-adenoVirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the Virus Fiber knob. We show that FWKT-modified Ad5 binds to SSTR_2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3–4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that Fiber knob modification may prolong the systemic circulation time. We conclude that modification of adenoVirus with the FWKT motif may be beneficial for NET therapy.
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Double-detargeted oncolytic adenoVirus shows replication arrest in liver cells and retains neuroendocrine cell killing ability.
PloS one, 2010Co-Authors: J Leja, B Nilsson, G Åkerström, K Öberg, V Giandomenico, Elisabet Gustafson, M EssandAbstract:Neuroendocrine tumors (NETs), originally described as carcinoids, represent a rare and heterogeneous group of neoplasms associated with intensive secretion of hormones, bioactive peptides and amines. Most of the patients are diagnosed at a late stage of disease, often with liver metastases. Surgery remains the main treatment to control metastatic disease, but is not curative. Oncolytic virotherapy represents a promising approach to treat cancer and different strategies have been exploited to restrict viral replication to tumor cells. We developed an oncolytic adenoVirus based on serotype 5, Ad5[CgA-E1A], where the chromogranin A (CgA) promoter controls expression of the E1A gene and thereby Virus replication. We found that Ad5[CgA-E1A], selectively replicates in NET cells and it is able to suppress fast-growing human BON carcinoid tumors in nude mice. The activity of Ad5[CgA-E1A] was not completely blocked in liver cells. We further repressed Virus replication in hepatocytes by targeting E1A with miR122, an miRNA specifically expressed in the liver. miRNAs bind to mRNA and induce its cleavage or translational blockage. By insertion of tandem repeats of miR122 target sequences in 3’UTR of E1A gene, we observed reduced E1A protein expression and replication arrest in miR122 expressing liver cells. The oncolytic potency of the miR122-targeted Virus was not affected in NET cells. Since some NET and neuroblastoma cells express high levels of somatostatin receptors (SSTRs), we introduced in the Virus Fiber knob cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site of somatostatin for SSTRs. The FWKT-modified Ad5 transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to a greater extent than Ad5, indicating that the Fiber knob modification may prolong the systemic circulation time. NETs represent a huge therapeutic challenge and novel diagnostic markers are needed for early detection and effective treatment of NETs. We have profiled primary tumors and liver metastases of ileocaceal NETs, using Affymetrix microarrays and advanced bioinformatics. We have identified six novel marker genes and show high similarity between primary lesions and liver metastases transcriptome by hierarchical clustering analysis.
Jerry L. Blackwell - One of the best experts on this subject based on the ideXlab platform.
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Substitution of the adenoVirus serotype 5 knob with a serotype 3 knob enhances multiple steps in Virus replication.
Cancer research, 2003Co-Authors: Yosuke Kawakami, John T. Lam, Victor Krasnykh, David T. Curiel, Jerry L. BlackwellAbstract:AdenoVirus (Ad) serotype 5 (Ad5) continues to be the predominant vector used for cancer gene therapy. However, many tumor types are reported to be relatively refractory to Ad5 infection because of low surface expression of the native Ad5 receptor, CAR. The observation that many tumor cells are CAR deficient has necessitated the development of CAR-independent infection strategies, including the introduction of heterologous ligand sequences into the Virus Fiber gene and immunological or chemical modifications of the capsid proteins. Alternatively, native Ad5 tropism can be modified by substituting the knob region from other Ad serotypes such as Ad type 3 (Ad3) into the Ad5 knob region. To date, the effect(s) of tropism modification on the replication and oncolytic capacity of these chimeric Ad vectors has not been fully evaluated. To address this issue, Ad5 vectors and isogenically matched chimeric vectors with Ad3 tropism (Ad5/3) were compared in this study. Various parameters of Virus infection were compared, including binding, nuclear translocation, E1A transcription, transgene expression, de novo Virus production, and oncolysis. Overall, the chimeric Ad5/3 Virus was progressively more efficient at each step of the replication cycle compared with its Ad5 counterpart. The higher replication efficiency of the chimeric Ad5/3 vector translated into improved therapeutic efficacy in a murine in vivo tumor rejection model. These findings suggest that in addition to the initial target cell interaction, multiple mechanisms contribute to the enhanced replication of the chimeric Ad5/3 vector. Furthermore, the data demonstrate that alternative Ad serotype receptors can be used to improve infection and subsequent oncolytic replication, which is particularly relevant in gene therapy applications for tumors that are inefficiently infected with Ad5.
Chung-yi Chiang - One of the best experts on this subject based on the ideXlab platform.
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Cover Picture: Weaving Genetically Engineered Functionality into Mechanically Robust Virus Fibers (Adv. Mater. 6/2007)
Advanced Materials, 2007Co-Authors: Chung-yi Chiang, Charlene M. Mello, E. C. C. M. Silva, K. J. Van Vliet, Angela M. BelcherAbstract:The desired functionality of a Virus Fiber (such as gold-binding ability) can be programmed by manipulating the M13 Virus genome, report Angela Belcher, Krystyn Van Vliet, and co-workers on p. 826. The background picture is an illustration of a Virus Fiber that is conjugated with cadmium selenide quantum dots and emits red light when excited by UV irradiation. The genetically tunable functionality on the Virus Fiber offers a convenient designing process and will bring a variety of new applications to antimicrobial, catalytic, optical, medical, and electronic Fibers.
J Leja - One of the best experts on this subject based on the ideXlab platform.
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Oncolytic adenoVirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells
Gene Therapy, 2011Co-Authors: J Leja, B Nilsson, L Gedda, A Zieba, T Hakkarainen, G Åkerström, K Öberg, V Giandomenico, M EssandAbstract:We have previously described the oncolytic adenoVirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenoVirus serotype 5 (Ad5) and infects target cells by binding to the coxsackie-adenoVirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the Virus Fiber knob. We show that FWKT-modified Ad5 binds to SSTR_2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3–4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that Fiber knob modification may prolong the systemic circulation time. We conclude that modification of adenoVirus with the FWKT motif may be beneficial for NET therapy.
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Double-detargeted oncolytic adenoVirus shows replication arrest in liver cells and retains neuroendocrine cell killing ability.
PloS one, 2010Co-Authors: J Leja, B Nilsson, G Åkerström, K Öberg, V Giandomenico, Elisabet Gustafson, M EssandAbstract:Neuroendocrine tumors (NETs), originally described as carcinoids, represent a rare and heterogeneous group of neoplasms associated with intensive secretion of hormones, bioactive peptides and amines. Most of the patients are diagnosed at a late stage of disease, often with liver metastases. Surgery remains the main treatment to control metastatic disease, but is not curative. Oncolytic virotherapy represents a promising approach to treat cancer and different strategies have been exploited to restrict viral replication to tumor cells. We developed an oncolytic adenoVirus based on serotype 5, Ad5[CgA-E1A], where the chromogranin A (CgA) promoter controls expression of the E1A gene and thereby Virus replication. We found that Ad5[CgA-E1A], selectively replicates in NET cells and it is able to suppress fast-growing human BON carcinoid tumors in nude mice. The activity of Ad5[CgA-E1A] was not completely blocked in liver cells. We further repressed Virus replication in hepatocytes by targeting E1A with miR122, an miRNA specifically expressed in the liver. miRNAs bind to mRNA and induce its cleavage or translational blockage. By insertion of tandem repeats of miR122 target sequences in 3’UTR of E1A gene, we observed reduced E1A protein expression and replication arrest in miR122 expressing liver cells. The oncolytic potency of the miR122-targeted Virus was not affected in NET cells. Since some NET and neuroblastoma cells express high levels of somatostatin receptors (SSTRs), we introduced in the Virus Fiber knob cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site of somatostatin for SSTRs. The FWKT-modified Ad5 transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to a greater extent than Ad5, indicating that the Fiber knob modification may prolong the systemic circulation time. NETs represent a huge therapeutic challenge and novel diagnostic markers are needed for early detection and effective treatment of NETs. We have profiled primary tumors and liver metastases of ileocaceal NETs, using Affymetrix microarrays and advanced bioinformatics. We have identified six novel marker genes and show high similarity between primary lesions and liver metastases transcriptome by hierarchical clustering analysis.
