Len Seymour

Publications of Len Seymour

• Virotherapy - cancer targeted pharmacology.

  Authors: Alison Tedcastle, Ryan Cawood, Ying Di, Kerry D Fisher, Len W Seymour

  Drug discovery today. 12/2011; 17(5-6):215-20.

  Building on their success in vaccination, many groups are now exploring the use of viruses as anticancer agents. In general, viral therapeutics provide the possibility to express anticancer proteinsBuilding on their success in vaccination, many groups are now exploring the use of viruses as anticancer agents. In general, viral therapeutics provide the possibility to express anticancer proteins directly at the tumour site, decreasing exposure to normal tissue during delivery and maximising therapeutic index. Some viruses are also 'oncolytic', either naturally or by design, and these agents function to kill cancer cells selectively before spreading to infect adjacent cells and repeat the process. This whole field of cancer 'virotherapy' is moving forward rapidly at the moment, with notable clinical successes demonstrated with a range of oncolytic agents developed as directly oncolytic and also as oncolytic cancer vaccines. Given the versatility of oncolytic viruses to express therapeutic proteins we anticipate this approach will provide the platform for useful application of a broad range of innovative biological therapies.

• Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1.

  Authors: Adel Benlahrech, Julian Harris, Andrea Meiser, Timos Papagatsias, Julia Hornig, Peter Hayes, Andre Lieber, Takis Athanasopoulos, Veronique Bachy, Eszter Csomor, Rod Daniels, Kerry Fisher, Frances Gotch, Len Seymour, Karen Logan, Romina Barbagallo, Linda Klavinskis, George Dickson, Steven Patterson

  Proceedings of the National Academy of Sciences of the United States of America. 11/2009;

  In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing alpha(4)beta(7) integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-gamma production in response to Ad stimulation correlated with Ad5 antibody titers. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with preexisting immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.

• Long-term Physiologically Regulated Expression of the Low-density Lipoprotein Receptor In Vivo Using Genomic DNA Mini-gene Constructs.

  Authors: Olivia C Hibbitt, Eileen McNeil, Michele Mp Lufino, Len Seymour, Keith Channon, Richard Wade-Martins

  Molecular therapy : the journal of the American Society of Gene Therapy. 10/2009;

  Familial hypercholesterolemia (FH) is a condition caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Expression of LDLR is highly regulated and excess receptor expression isFamilial hypercholesterolemia (FH) is a condition caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Expression of LDLR is highly regulated and excess receptor expression is cytotoxic. To incorporate essential gene regulation into a gene therapy vector for FH, we generated vectors in which the expression of therapeutic human LDLR gene, or luciferase reporter gene, is driven by 10 kb of human LDLR genomic DNA encompassing the promoter region including elements essential for physiologically regulated expression. Using luciferase expression and specific LDL binding and internalization assays, we have shown in vitro that the genomic promoter element confers long-term, physiologically regulated gene expression and complementation of receptor deficiency in culture for 240 cell-generations. This was demonstrated in the presence of sterols or statins, modifiers of LDLR promoter activity. In vivo, we demonstrate efficient liver-specific delivery and expression of luciferase following hydrodynamic tail-vein injection and confirm that expression from the LDLR promoter element is sensitive to statin administration. We also demonstrate long-term LDLR expression from the 10-kb promoter element up to 9 months following delivery. The vector system that we describe provides the efficient delivery, long-term expression, and physiological regulation required for a successful gene therapy intervention for FH.

• British Society for Gene Therapy annual conference 2008.

  Authors: Andrew H Baker, Chris Boyd, Len Seymour

  Human gene therapy. 07/2008; 19(6):659-60.

• Directed evolution generates a novel oncolytic virus for the treatment of colon cancer.

  Authors: Irene Kuhn, Paul Harden, Maxine Bauzon, Cecile Chartier, Julie Nye, Steve Thorne, Tony Reid, Shaoheng Ni, Andre Lieber, Kerry Fisher, Len Seymour, Gabor M Rubanyi, Richard N Harkins, Terry W Hermiston

  PLoS ONE. 01/2008; 3(6):e2409.

  BACKGROUND: Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth andBACKGROUND: Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term "Directed Evolution" for creating highly potent oncolytic viruses. METHODOLOGY/PRINCIPAL FINDINGS: Taking the "Directed Evolution" approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2-3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. CONCLUSIONS/SIGNIFICANCE: Using the "Directed Evolution" methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a >2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies.

• Fluorescence studies of the intra-cellular distribution of zinc bis(thiosemicarbazone) complexes in human cancer cells.

  Authors: Andrew R Cowley, Jason Davis, Jonathan R Dilworth, Paul S Donnelly, Rachel Dobson, Adrian Nightingale, Josephine M Peach, Ben Shore, David Kerr, Len Seymour

  Chemical communications (Cambridge, England). 03/2005;

  The uptake of zinc bis(thiosemicarbazone) complexes in human cancer cells has been studied by fluorescence microscopy and the cellular distribution established, including the degree of uptake in theThe uptake of zinc bis(thiosemicarbazone) complexes in human cancer cells has been studied by fluorescence microscopy and the cellular distribution established, including the degree of uptake in the nucleus.

• Hiroshi Maeda--defining the pathway to targeted cancer therapy.

  Authors: Ruth Duncan, Len Seymour

  Journal of drug targeting. 15(7-8):456.