Study of Molecular-targeted Therapy Using Zinc Finger Nuclease in Cervical Precancerous Lesions

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Safety Study of Zinc Finger Nucleases ZFN-602 and ZFN-758 in HPV-infected Subjects

Conditions
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Human Papillomavirus-Related Malignant Neoplasm

Intervention / Treatment
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* Biological: ZFN-603 and ZFN-758


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HPV16 or HPV18 infection. Married and fertile, no fertility requirements. Without administration of hormone in the last six months Subjects must be meet the ethical requirements and have signed informed consent Exclusion Criteria: Pregnancy and breast feeding Any bacterial vaginitis Any Fungal vaginitis Any sexually transmitted diseases Active drug or alcohol abuse Any HPV medications within the past 12 weeks Allergy to active or non active ingredients in the study of drugs Cardiac insufficiency Liver and renal insufficiency Hypertension and severe complications Serious illness in past 30 days Currently participating in another clinical trail or any prior gene therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZFN-603 and ZFN-758<br>Subjects will receive suppository with ZFN-603 or ZFN-758 | Biological: ZFN-603 and ZFN-758<br>* Each suppository contain 500 µg of ZFN-603 or ZFN-758<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Treatment related adverse events of ZFN-603 in HPV16-positive subjects, related adverse events of ZFN-758 in HPV18-positive subjects | Number of participants who report adverse events as a measure of safety | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate persistence of HPV16 and HPV18 as measured by HPV DNA | Reduce the virus titers after using ZFN-603 and ZFN-758 | 6 months | 
| Change in the number of dysplastic cells as mearsured by ThinPrep Pap Test | From high-grade squamous intraepithelial lesion (HSIL) to Low-grade Squamous Intraepithelial Lesion (LSIL), or from LSIL to negative. | 6 months | 
| Number of participants with Regain health or without progress |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human papillomavirus, cervical intraepithelial neoplasia, zinc finger nuclease