Nanoparticles Based on Poly (β-Amino Ester) and HPV16-Targeting CRISPR/shRNA as Potential Drugs for HPV16-Related Cervical Malignancy

Zhu, Da; Shen, Hui; Tan, Songwei; Hu, Zheng; Wang, Liming; Yu, Lan; Tian, Xun; Ding, Wencheng; Ren, Chao; Gao, Chun; Cheng, Jing; Deng, Ming; Liu, Rong; Hu, Junbo; Liu, Xi; Wu, Peng; Zhang, Zhiping; Wang, Hui

doi:10.1016/j.ymthe.2018.07.019

Cited by 42 publications

(21 citation statements)

References 65 publications

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“…We and others have previously shown the effects of CRISPR/Cas in cancer models that use xenografts in immunodeficient mice [ 6 , 18 , 19 ]. This misses an important aspect of responses to treatment, namely the immune response itself.…”

Section: Resultsmentioning

confidence: 99%

CRISPR/Cas9-loaded stealth liposomes effectively cleared established HPV16-driven tumours in syngeneic mice

et al. 2021

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Gene-editing has raised the possibility of being able to treat or cure cancers, but key challenges remain, including efficient delivery, in vivo efficacy, and its safety profile. Ideal targets for cancer therapy are oncogenes, that when edited, cause cell death. Here, we show, using the human papillomavirus (HPV) type 16 cancer cell line TC1, that CRISPR/Cas9 targeting the E7 oncogene and packaged in PEGylated liposomes cleared established tumours in immunocompetent mice. Treatment caused no significant toxicity in the spleen or liver. An ideal therapeutic outcome would be the induction of an immunogenic cell death (ICD), such that recurrent tumours would be eliminated by the host immune system. We show here for the first time that CRISPR/Cas9-mediated cell death via targeting E7 did not result in ICD. Overall, our data show that in vivo CRISPR/Cas targeting of oncogenes is an effective treatment approach for cancer.

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Section: Resultsmentioning

confidence: 99%

CRISPR/Cas9-loaded stealth liposomes effectively cleared established HPV16-driven tumours in syngeneic mice

et al. 2021

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“…Several pathogenic viruses, including hepatitis B virus, human papilloma virus (HPV), herpes virus, and human immunodeficiency virus type I have shown promising results in action with the CRISPR system and also some of these CRISPR-based treatments have entered into the clinical trials [ 52 – 56 ]. For instance, Zhu et al introduced a safe method to target E7 in HPV-induced cervical cancer cells in vaginal context using poly ß-amino ester-based nanoparticles for delivery of CRISPR modules into xenograft tumor models, resulted in the knockout of E7 and thereby suppression of tumor progression [ 57 ]. Moreover, among all CRISPR-based therapeutic advancements, the utmost consideration has been given to the treatment of cancers.…”

Section: Crispr the Treasure Trove Of Gene-editing Technologiesmentioning

confidence: 99%

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

et al. 2020

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Cancer immunotherapy has been emerged as a promising strategy for treatment of a broad spectrum of malignancies ranging from hematological to solid tumors. One of the principal approaches of cancer immunotherapy is transfer of natural or engineered tumor-specific T-cells into patients, a so called “adoptive cell transfer”, or ACT, process. Construction of allogeneic T-cells is dependent on the employment of a gene-editing tool to modify donor-extracted T-cells and prepare them to specifically act against tumor cells with enhanced function and durability and least side-effects. In this context, CRISPR technology can be used to produce universal T-cells, equipped with recombinant T cell receptor (TCR) or chimeric antigen receptor (CAR), through multiplex genome engineering using Cas nucleases. The robust potential of CRISPR-Cas in preparing the building blocks of ACT immunotherapy has broaden the application of such therapies and some of them have gotten FDA approvals. Here, we have collected the last investigations in the field of immuno-oncology conducted in partnership with CRISPR technology. In addition, studies that have addressed the challenges in the path of CRISPR-mediated cancer immunotherapy, as well as pre-treatment applications of CRISPR-Cas have been mentioned in detail.

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“…safer gene therapies for HPV-related diseases (14,15). Previous studies have indicated that systemic delivery of CRISPR/Cas9 targeting HPV oncogenes is effective at eliminating established tumors (16)(17)(18)(19). However, Cas9 may cause many unexpected off-target effects.…”

Section: Discussionmentioning

confidence: 99%

“…These results demonstrated the efficacy of CRISPR-Cas13a in regulating the deregulated phenotypes induced by HPV 16/18. Because the E6 HPV genes share no sequence homology to any human genes, knockdown of this gene will not induce death of healthy cells (16).…”

Section: Discussionmentioning

confidence: 99%

Reprogrammed CRISPR‑Cas13a targeting the HPV16/18 E6 gene inhibits proliferation and induces apoptosis in E6‑transformed keratinocytes

Guo

Liu

et al. 2020

Exp Ther Med

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The long-lasting infection of high-risk type (type 16 or type 18) human papillomavirus (HPV) is the main cause of gynecological and urinary malignancies. Given the high mortality rate after surgery, the development of a new molecular therapy would be of value to clinicians. The aim of the present study was to achieve targeted inactivation of the viral E6 gene in keratinocytes using the reprogrammed CRISPR-Cas13a system. To accomplish this, a reprogrammed CRISPR-Cas13a system, targeting both the HPV16/18 E6 genes was constructed using a guide RNA expressing vector. The expression levels of E6 protein were measured using western blot analysis after transfection of the vector into E6-transformed keratin oocytes. Cell proliferation was analyzed using CCK-8 assays and cell apoptosis was evaluated using Hoechst 33258 staining and ELISAs examining caspase-3 levels. The results indicated that both the HPV16/18 E6 genes can be inactivated using the CRISPR-Cas13a system. Furthermore, silencing E6 inhibited cell proliferation (14±1.8% on average) and induced apoptosis (80.2±3.2% on average) in E6-transformed keratinocytes but not in normal keratinocytes. In conclusion, results of the present study demonstrate that the reprogrammed CRISPR-Cas13a system has the potential for inactivating HPV E6 gene functions.

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Nanoparticles Based on Poly (β-Amino Ester) and HPV16-Targeting CRISPR/shRNA as Potential Drugs for HPV16-Related Cervical Malignancy

Cited by 42 publications

References 65 publications

CRISPR/Cas9-loaded stealth liposomes effectively cleared established HPV16-driven tumours in syngeneic mice

CRISPR/Cas9-loaded stealth liposomes effectively cleared established HPV16-driven tumours in syngeneic mice

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

Reprogrammed CRISPR‑Cas13a targeting the HPV16/18 E6 gene inhibits proliferation and induces apoptosis in E6‑transformed keratinocytes

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