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HPV Treatment Aims at Destroying Virus, Genital Warts

Human papillomavirus (HPV), now considered the most prevalent sexually transmitted disease agent, causes genital warts and persistent infections that can lead to cancer of the cervix. To combat the virus and the medical problems it leads to, researchers in Canada are evaluating a series of synthetic antisense oligonucleotides aimed at interfering with HPV replication, several of which appear safe and effective enough in preclinical studies to warrant follow-up clinical studies. In July, Origenix submitted an investigational new drug application to the U.S. Food and Drug Administration, seeking to test a topical formulation containing one of those candidate drugs on patients with genital warts.

Each year in the United States, patients with genital warts make about 2 million visits to physicians, and about 750,000 new cases routinely arise. Although effective in blocking the spread of other sexually transmitted pathogens, condoms are not effective against HPV because the virus is disseminated in cells of the outer skin in the genital and anal areas. Moreover, widely used therapies for genital warts, including surgical removal and cryotherapy with liquid nitrogen, are not particularly effective.

"The warts come back, and the virus stays in the body," explains virologist Samir Mounir, director of biology at Origenix Technologies, Inc., in Quebec, Canada. He and his colleagues have been focusing on one of the more promising drug candidates, called ORI-1001, that is intended to block viral replication and thereby also eradicate genital warts. This drug is an antisense compound containing 20 nucleotides that targets the E1 region of the HPV genome, which is required for its DNA to replicate—a necessary step for the virus to infect cells persistently and form warts. The E1 region is highly conserved across a number of HPV strains.

Because HPV is difficult to grow in cell culture for in vitro testing of ORI-1001 or other agents that target this virus, Mounir and his collaborators had to devise an indirect assay for measuring their antiviral effectiveness. To do so, they fused the E1 region of HPV to a luciferase reporter gene, and inserted the construct into a mammalian cell line. A fluorescent signal from luciferase reflects HPV levels and, hence, agents that block E1 gene expression can be quickly screened for their relative potency at the cellular level. In this system, so far ORI-1001 is the most potent inhibitor of E1 expression.

ORI-1001 also inhibits wart formation in animals. For example, when HPV-infected human foreskin is implanted in the flanks of nude mice with severe combined immunodeficiency (SCID) to tolerate the graft, a wart-like growth typically forms within 6 weeks of implant. However, administering ORI-1001 twice per week for these 6 weeks leads to dose-dependent shrinkage of the warts. In another series of experiments in nude mice, subcutaneously administered ORI-1001 reduces warts that arise from HPV-infected human foreskin that was implanted into the kidney capsules of the animals. In both sets of experiments, the researchers report no signs of toxicity when the drug is administered within its effective dose range.

A major category of antiviral drugs consists of nucleoside analogs that, when added to growing viral DNA chains, can block further growth and prematurely end their replication. However, such drugs often prove nonspecific and may also inhibit cellular DNA synthesis, damaging mitochondria and causing bone marrow toxicity. Until recently, nucleotide analogs were presumed to have little therapeutic potential, in part because nucleotides themselves are unable to move across membranes into virus-infected cells. However, Origenix researchers find that some of their nucleotide analogs not only show potent antiviral activity, but also selectively inhibit viral DNA at early steps of replication pathways, thereby making them not only potentially effective antiviral agents but also less toxic than ordinary nucleotides and nucleoside analogs.

In addition to pursuing development of the antisense drug ORI-1001, Origenix researchers also produced and are testing a library of nucleotide analogs containing one, two, or three nucleotides that mimic interactions between nucleic acids and proteins, thus interfering with viral replication cycles. These compounds are being tested against a number of important human viruses. At the 14th International Conference on Antiviral Research, held last April in Seattle, Wash., Mounir reported that another proprietary nucleotide analog inhibits hepatitis B virus in cell culture at an early step in the replication process. "This confirms the strength of our technology," says Mounir.

Carol Potera
Carol Potera is a freelance writer based in Great Falls, Mont.