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1615 Poydras Street - Suite 1000
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 Kate Ryman, PhD
Areas of Research: Cancer Virotherapy The resistance of cancers to conventional therapies has inspired the search for novel therapeutic strategies. Recently, the use of replicating oncolytic viruses for cancer therapy has gained favor. We have constructed a series of propagation-competent and incompetent virus vectors based on the alphavirus, Sindbis virus (SB). SB vectors offer several features advantageous to oncolytic virotherapy: i) efficient and targeted cell-type specific delivery; ii) high-level expression of a transgene; and iii) cytolytic activity in the targeted cell with minimal side-effects. As our understanding of the molecular events leading to the generation and evolution of malignancies increases, we are able to tailor and/or select virus vectors for their ability to replicate preferentially in tumor cells by altering virus tropism with modifications in viral surface antigens to refine cell targeting, by conditionally expressing toxic gene products with tissue-specific gene promoter elements, or by utilizing the ability of a virus to selectively kill tumor cells as a result of cancer-specific defects in the innate antiviral response. One of our projects uses SB replicated to high titers and triggers
apoptosis in many immortalized and transformed cell lines. We are
testing the premise that compromised interferons (IFNs) signaling
in tumors creates a cellular environment that supports SB infections
and replication, whereas normal cells. We believe that tumor-specific
targeting of SB vectors can be achieved by taking advantage of the
natural sensitivity of this virus to IFN-mediated antiviral pathways.
Another project studies the use of heparan sulfate (HS)-binding SB
vectors. When inoculated intratumorally, the infectivity of HS-binding
particles for cells in the local area will be optimized, while at
the same time the particles will be less likely to spread and replicated
beyond the site of inoculation, providing additional safety. We are
attempting to select tumor specific HS-binding mutations in the E2
protein. Ryman, K.D., Gardner, C.L., Meier, K.C., Biron, C.A., Johnston, R., and Klimstra, W.B. Early restriction of Alphavirus replication and dissemination contributes to age-dependent attenuation of systemic hyperinflammatory disease. Journal of General Virology, (2007) 88:518-529 Ryman, K.D., Gardner, C.L., Wyza, C.L., Meier, K.C., Thompson, J., and Klimstra. W.B. Heparan-sulfate binding can contribute to the neurovirulence of neuroadapted and non-neuroadapted Sindbis viruses. Journal of Virology, (2007) Ryman, K.D., Meier, K.C., Gardner, C.L., and Klimstra, W.B. Non-pathogenic Sindbis virus causes hemorrhagic fever in the absence of alpha/beta and gamma interferons. Virology, (2007) Klimstra, W.B., Williams, B.J., Ryman, K.D., and Heidner, H.W. Targeting Sindbis virus-based vectors to Fc receptor-positive cell types. Virology, (2005) July; 338(1): 9-21 Ryman, K.D., Meier, K.C., Nangle, E.M., Ragsdale, S.L., Korneeva, N.L., Rhoads, R.E., MacDonald, M.R., Klimstra, W.B. Sindbis virus translation is inhibited by a PKR/RNase L-independent effector induced by alpha/beta interferon priming of dendritic cells. Journal of Virology, (2005) February; 79(3): 1487-1499 |
