Human Papillomavirus-Related Malignant Neoplasm Clinical Trial
Official title:
Safety Study of Zinc Finger Nucleases ZFN-602 and ZFN-758 in HPV-infected Subjects
This research study is being carried out to study a new way to possibly treat human cervical
intraepithelial neoplasia (CIN) without invasion.
Persistent infection with specific types of human papillomavirus (HPV, most frequently types
16 and 18) may lead to precancerous lesions(CIN). If untreated, these lesions may progress to
cervical cancer within many years. In the infected cells, HPV expresses the oncoproteins E6
and E7, both of which play key roles in maintaining viral infection and promoting
carcinogenesis. Previous studies has demonstrated that E7 alone, but not E6, is sufficient to
immortalize human keratinocytes in vitro and induce high-grade cervical dysplasia in a
transgenic mouse model. These data indicated that E7 may dominate the malignant progress in
HPV-infected cells.
The agents zinc finger nucleases (ZFNs), called ZFN-603 and ZFN-758, which can cleave the
HPV16 and HPV18 E7 oncogene specifically. ZFN-mediated disruption of HPV16 and HPV18 E7 DNA
directly decreased the expression of E7, induced type-specific apoptosis in HPV16- and
HPV18-positive cells, and inhibited cell growth.
The purpose of this study is to determine whether ZFN-603 and ZFN-758 are effective in the
treatment of HPV16- and HPV18-positive cervical intraepithelial neoplasia.
Laboratory studies have shown that ZFN-603 and ZFN-758 could induce significant cleavage of
E7 DNA in HPV16- and HPV18-positive cells. The disruption to viral DNA directly led to
downregulation of E7 expression and restoration of the tumor suppressor genes retinoblastoma
1 (RB1), resulting in apoptosis and growth inhibition of ZFN-treated HPV16- and HPV18-
positive cell lines. On the basis of these laboratory results, there is the potential that
this may work in humans infected with high-risk HPV (especially HPV16 and HPV18) and block
the progression of CIN The new treatment to be studied will involve transfecting ZFNs into
HPV-infected cervical epithelials. Cells modified by ZFN-603 and ZFN-758 will lose the
ability of immortalization and progress to apoptosis.
Researchers hope that these agents will be able to block the malignant progression of CIN and
reduce the incidence of cervical cancer
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