Inhibition of papilloma progression by antisense oligonucleotides targeted to HPV11 E6/E7 RNA
Abstract
Human papillomaviruses (HPVs) are recognized as important human pathogens, causing a spectrum of hyperproliferative lesions from benign warts to cervical dysplasias/carcinomas. HPV-associated lesions require continued production of the oncogenic E6/E7 proteins, which are encoded by either bicistronic or overlapping mRNAs. Here we targeted the E6/E7 mRNA of HPV11, a type implicated in causation of genital warts, using molecular reagents. Accessible sites in the HPV11(E6/E7) RNA were identified using library selection protocols, and nucleic acids (DNAzymes, antisense oligonucleotides) targeted to these sites were constructed, and tested in cell culture and on human foreskin grafts. While DNAzymes were at least equally effective in cell culture, antisense oligonucleotides targeted to the region surrounding one of the library-selected sites (ASO(407)) proved most effective in blocking progression of HPV11-induced papillomas in human foreskin grafts on immunodeficient mice. In total, 11 papillomas were treated with ASO(407). Of these, four of seven small papillomas treated with ASO(407) showed loss of detectable virus by in situ hybridization (ISH), and in all four of these, papillomas were no longer evident grossly or histologicall...Continue Reading
References
Detection of human serum antibodies that neutralize infectious human papillomavirus type 11 virions.
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