The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: July 29, 2011

TK/GCV Suicide Gene Therapy: Connecting the Dots

Laval University ♦ Published in Cancer Gene Therapy (npg), July 22, 2011

Glioblastoma is an aggressive form of brain cancer requiring intensive therapy. Even with surgery, chemotherapy, and radiation, the mean survival time is approximately one year. A new therapeutic paradigm is currently being investigated in clinical trials, wherein a lentivirus delivers the herpes simplex virus thymidine kinase (TK) gene to the tumour bed following surgery. Tumour cells that are infected with the TK gene produce the TK protein, which in turn sensitizes tumour cells to the chemotherapeutic ganciclovir. After ganciclovir enters tumour cells it is phosphorylated by TK and then broken down into various toxic compounds that lead to cell death. In a nutshell the cell is altered genetically such that it commits suicide in the presence of the chemotherapeutic. One aspect critical to the success of this approach, however, is the degree to which tumour cells are connected; the therapy relies on something known as the “bystander effect”.

Researchers at the University of Laval have recently completed a comprehensive investigation on gap junctions in human glioblastomas. Gap junctions form between cells to allow intercellular communication through the migration of small molecules and peptides. They can be leveraged, therapeutically speaking, to amplify the efficiency of cancer therapies because they connect multiple cells into larger units. In the case of the suicide gene therapy described above, TK protein can migrate from cells that were successfully infected with the lentivirus into untransformed cells such that they are also eradicated in the presence of ganciclovir. In this study researchers found that connexin 43 (Cx43), the unit that assembles to form gap junctions in astrocytes, has heterogenous expression across glioblastoma cell lines. Analysis of 74 glioblastoma cell lines shows that Cx43 expression can be unaltered, reduced, or lost entirely. Cx43 expression was observed in 77% of cell lines, and its presence was adequate to provide a bystander effect regardless of whether its localization was considered normal or aberrant. Previous studies of smaller sets of glioblastoma cell lines had contradicting results, with some linking disease progression to loss of Cx43, while others supported the notion that high levels of Cx43 expression exacerbate disease conditions by promoting tumour cell infiltration into healthy tissue. This study provides the first comprehensive look at Cx43 in glioblastoma and should provide valuable information to companies in industry developing therapies that require a bystander effect for their success.

Structure of AMA1/RON2 Complex Elucidated

University of Victoria ♦ Published in Science, July 22, 2011

Apicomplexan parasites, including the Plasmodium species that cause malaria, have a very interesting mechanism that allows for host cell invasion. Upon contact with a host cell, these parasites release a structure known as a rhoptry neck (RON) complex that implants itself in the host cell membrane. A domain on RON2 then acts as a binding site for the apical membrane antigen 1 (AMA 1) displayed on the parasites cell surface. Essentially, apicomplexan parasites have evolved a means to provide both receptor and ligand to dock themselves on host cells. Once formed, the complex organizes itself into a structure known as a moving junction (MJ), a ring-like structure deeply embedded in the host cell membrane.  As this structure migrates from the anterior to the posterior of the parasite, the parasite becomes enveloped in a vacuole that is then internalized into the cell. Now researchers have elucidated the structure of the MJ complex at 1.95 angstrom resolution, providing valuable insight into its machinery. It is hoped that the structure can be used to develop therapies that prevent host cell invasion by apicomplexan parasites.

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