Recurrence of laryngeal papillomas often results from activation of latent HPV. Latent HPV is maintained as a low copy episome in the host keratinocyte. In this proposal an antisense therapy is developed to eliminate or reduce the latent infection by suppressing replication of latent HPV11 virus. Two advances made during the current grant will be utilized: (l) An in vitro model with human keratinocytes was shown to stably maintain episomal HPV11 DNA at low copy number; (2) An antisense oligonucleotide targeted to the start codon of the E1 open reading frame was shown to specifically reduce HPV11 DNA copy number. The experiments put forth here assess the potential of this antisense oligonucleotide to treat latent HPV Il infections of the larynx.
Three specific aims are advanced: (1) To quantify suppression using competitive PCR of low copy HPV11 DNA during sustained exposure to the antisense oligonucleotide. (2) To determine the mechanism of action of the El antisense oligonucleotide in suppressing HPV11 DNA replication. (3) To monitor uptake and effectiveness of the antisense oligonucleotide in organotypic cultures that will provide a realistic model of intact laryngeal epithelium. The information gained in this study will provide a basis to proceed on to drug delivery studies in animals and clinical trials in humans. An effective therapy for latent HPV infection of the larynx would have relevance for treating HPV disease at other sites.
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