TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy

Hu, Zheng; Ding, Wencheng; Zhu, Da; Yu, Lan; Jiang, Xiaohui; Wang, Xiaoli; Zhang, Changlin; Wang, Liming; Ji, Tiantian; Liú, Dan; He, Dan; Xia, Xi; Zhu, Τao; Wei, Juncheng; Wu, Peng; Wang, Changyu; Liu, Xi; Gao, Qinglei; Chen, Gang; Liu, Rong; Li, Kezhen; Li, Shuang; Wang, Shixuan; Zhou, Jianfeng; Ma, Ding; Wang, Hui

doi:10.1172/jci78206

Cited by 105 publications

(83 citation statements)

References 48 publications

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“…Our previous data indicated that knockdown of HPV16 E7 could induce apoptosis in HPV16 E7-positive cells [22, 23]. To determine whether downregulation of VDAC1 would induce apoptosis in cervical cell lines, we used CRISPR-VDAC1 to block the expression of endogenous VDAC1 in human cervical cancer S12 and SiHa cells.…”

Section: Resultsmentioning

confidence: 99%

Proteomics-based identification of VDAC1 as a tumor promoter in cervical carcinoma

et al. 2016

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We used oxidative isotope-coded affinity tags (OxICAT) to investigate the global redox status of proteins in human papillomavirus (HPV)-related cervical cancer cells, in order to identify a potential target for gene therapy. Voltage-dependent anion channel 1 (VDAC1) was found to be highly oxidized in HPV-positive cervical cancer cells. VDAC1 expression correlated significantly with the invasion of cervical cancer, the grade of cervical intraepithelial neoplasia (CIN) and the expression of HPV16 E7 in CIN. Knockdown of VDAC1 in cell lines increased the rate of apoptosis, while overexpression of the VDAC1 (respectively) partly reversed the effect. Thus, VDAC1 may promote the malignant progression of HPV-related disease, and treatments designed to suppress VDAC1 could prevent the progression of HPV-induced cervical disease.

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Section: Resultsmentioning

confidence: 99%

Proteomics-based identification of VDAC1 as a tumor promoter in cervical carcinoma

et al. 2016

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“…Importantly, one of these studies also showed that ZFNs could be used to inhibit growth of HPV-positive tumor xenografts (Ding et al 2014), demonstrating their potential uses as anti-cancer therapeutics. In another comprehensive study, it was demonstrated that TALENs could also be used as anti-HPV therapeutics (Hu et al 2014a). TALENs targeting the E6 and E7 genes of HPV-16 and HPV-18 showed efficacy in several HPV in vitro models, and importantly were able to reverse the HPV-driven malignant phenotype of K14-HPV16 transgenic mice that are immune competent.…”

Section: The Current Status Of Gene-editing Antiviral Therapiesmentioning

confidence: 99%

“…No ZFN-related in vivo toxicity or immunogenicity was seen in human clinical trials, where patients who received ZFN-treated T cells retained gene modified cells for at least 252 days post-transplant (Tebas et al 2014), although T-cell expansion prior to infusion likely limited ongoing levels of ZFN expression. Similarly, no in vivo toxicity was observed when TALENs were used as therapeutics in mouse models of HBV and HPV (Bloom et al 2013; Chen et al 2014; Hu et al 2014a). For CRISPR/Cas9 no associated toxicity was seen in CRISPR knock-in mice (Platt et al 2014), or when saCas9 (Ran et al 2015) or spCas9 (Swiech et al 2015) were delivered to the liver and brain, respectively.…”

Section: Hurdles To Human Applicationmentioning

confidence: 99%

Genome editing and the next generation of antiviral therapy

2016

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Engineered endonucleases such as homing endonucleases (HEs), zinc finger nucleases (ZFNs), Tal-effector nucleases (TALENS) and the RNA-guided engineered nucleases (RGENs or CRISPR/Cas9) can target specific DNA sequences for cleavage, and are proving to be valuable tools for gene editing. Recently engineered endonucleases have shown great promise as therapeutics for the treatment of genetic disease and infectious pathogens. In this review, we discuss recent efforts to use the HE, ZFN, TALEN and CRISPR/Cas9 gene-editing platforms as antiviral therapeutics. We also discuss the obstacles facing gene-editing antiviral therapeutics as they are tested in animal models of disease and transition towards human application.

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“…A recent study showed that a transfection reagent could be used to deliver DNA encoding transcription activator-like effector nucleases (TALENs) to target cells after topical administration in a murine model of HPV-induced cervical cancer [33]. Currently, using NVVs to transduce cells with DNA expression cassettes is limited.…”

Section: Antiviral Nucleic Acids That May Be Delivered With Nvvsmentioning

confidence: 99%