Gene editing to enhance the efficacy of cancer cell therapies

Murty, Surya; Mackall, Crystal L.

doi:10.1016/j.ymthe.2021.10.001

Cited by 8 publications

(8 citation statements)

References 121 publications

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“…Targeted epigenetic silencing may represent a promising solution to treat disorders that can benefit from permanent genetic inactivation, including diseases caused by gain-of-function mutations 1 , infectious diseases 2 and pathologies in which silencing of one gene may either compensate for an inherited defect in another one 3 or unleash the full potential of adoptive cell therapies 4,5 . One of the key, preliminary steps in any epigenetic silencing protocol is to identify the proper position on the target gene where to direct the ETRs that will deposit the repressive epigenetic marks necessary to turn off the transcriptional activity of the target.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in the last two decades, with the raise of gene therapy, it has been proposed as a potentially game-changing approach to treat diseases caused by gain-of-function mutations 1 , infectious diseases 2 or pathologies in which silencing of one gene may compensate for an inherited defect in another one 3 . Finally, genetic inactivation of key regulators of cell fitness and functional control has been proposed to enhance the efficiency of cell products for cancer immunotherapy 4 and regenerative medicine 5 .…”

Section: Introductionmentioning

confidence: 99%

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In vitro selection of Engineered Transcriptional Repressors for targeted epigenetic silencing and initial evaluation of their specificity profile

Migliara

Cappelluti

Valsoni

et al. 2022

Preprint

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Gene inactivation is instrumental to study gene function and represents a promising strategy for the treatment of a broad range of diseases. Among traditional technologies, RNA interference suffers from partial target abrogation and requirement for life-long treatments. On the other hand, artificial nucleases can impose stable gene inactivation through induction of DNA Double Strand Breaks, but recent studies are questioning the safety of this approach. Targeted epigenetic editing via Engineered Transcriptional Repressors (ETRs) may represent a solution, as a single administration of specific ETRs combinations can lead to durable silencing without DNA breaks induction. ETRs are proteins containing a programmable DNA Binding Domain (DBD) and effectors from naturally occurring transcriptional repressors. Specifically, a combination of three ETRs equipped with the KRAB domain of human ZNF10, the catalytic domain of human DNMT3A and human DNMT3L was shown to induce heritable repressive epigenetic states on the ETR-target gene. The hit-and-run nature of this platform, the lack of impact on the DNA sequence of the target, and the possibility to revert on-demand the repressive state by DNA demethylation, make epigenetic silencing a game-changing tool. A critical step is the identification of the proper position on the target gene where to tether the ETRs in order to maximize on target and minimizing off-target silencing. Performing this step in the final ex vivo or in vivo preclinical setting can be cumbersome. Taking CRISPR-Cas9 system as a paradigmatic DBD for ETRs, here we describe a protocol consisting in the in vitro screen of gRNAs coupled to the triple ETRs combination for efficient on-target silencing, followed by the evaluation of the genome-wide specificity profile of top hits. This allows reducing the initial repertoire of candidate gRNAs to a short list of promising ones, whose complexity is suitable for their final evaluation in the therapeutically relevant setting of interest.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vitro selection of Engineered Transcriptional Repressors for targeted epigenetic silencing and initial evaluation of their specificity profile

Migliara

Cappelluti

Valsoni

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Co-delivery of Cas9 and sgRNA targeting a genomic target holds promise for gene knockout strategies [ 9 , 138 ]. Researchers have demonstrated the possibility of using the CRISPR/Cas9 system to treat various diseases by repairing, deleting, or silencing certain genetic mutations associated with the disease in the body [ 139 , 140 , 141 ]. The following describes the delivery of CRISPR systems in the form of plasmids, RNAs, and ribonucleoprotein (RNP) using EV as a carrier.…”

Section: Nucleic Acid Drugs Delivered By Evs For Cancer Therapymentioning

confidence: 99%

Extracellular Vesicles as Delivery Vehicles for Therapeutic Nucleic Acids in Cancer Gene Therapy: Progress and Challenges

Wang

Zhu

et al. 2022

Pharmaceutics

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Extracellular vesicles (EVs) are nanoscale vesicles secreted by most types of cells as natural vehicles to transfer molecular information between cells. Due to their low toxicity and high biocompatibility, EVs have attracted increasing attention as drug delivery systems. Many studies have demonstrated that EV-loaded nucleic acids, including RNA-based nucleic acid drugs and CRISPR/Cas gene-editing systems, can alter gene expressions and functions of recipient cells for cancer gene therapy. Here in this review, we discuss the advantages and challenges of EV-based nucleic acid delivery systems in cancer therapy. We summarize the techniques and methods to increase EV yield, enhance nucleic acid loading efficiency, extend circulation time, and improve targeted delivery, as well as their applications in gene therapy and combination with other cancer therapies. Finally, we discuss the current status, challenges, and prospects of EVs as a therapeutic tool for the clinical application of nucleic acid drugs.

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“…Even since the concept of gene therapy was first put forward by Friedmann in 1972 [ 121 ], it has become an important modality for cancer therapy. This technology can treat cancer at its genetic root by editing a gene to enhance the efficacy of target cells, significantly improving the survival rate of cancer patients [ 122 ]. However, the major problem of this therapy is the accurate delivery of the gene expression vectors and the effective expression of target genes without affecting the cells’ normal regulatory activities [ 123 ].…”

Section: Cancer Treatments Combined With Thermal Therapymentioning

confidence: 99%

Synergetic Thermal Therapy for Cancer: State-of-the-Art and the Future

et al. 2022

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As a safe and minimal-invasive modality, thermal therapy has become an effective treatment in cancer treatment. Other than killing the tumor cells or destroying the tumor entirely, the thermal modality results in profound molecular, cellular and biological effects on both the targeted tissue, surrounding environments, and even the whole body, which has triggered the combination of the thermal therapy with other traditional therapies as chemotherapy and radiation therapy or new therapies like immunotherapy, gene therapy, etc. The combined treatments have shown encouraging therapeutic effects both in research and clinic. In this review, we have summarized the outcomes of the existing synergistic therapies, the underlying mechanisms that lead to these improvements, and the latest research in the past five years. Limitations and future directions of synergistic thermal therapy are also discussed.

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Gene editing to enhance the efficacy of cancer cell therapies

Cited by 8 publications

References 121 publications

In vitro selection of Engineered Transcriptional Repressors for targeted epigenetic silencing and initial evaluation of their specificity profile

In vitro selection of Engineered Transcriptional Repressors for targeted epigenetic silencing and initial evaluation of their specificity profile

Extracellular Vesicles as Delivery Vehicles for Therapeutic Nucleic Acids in Cancer Gene Therapy: Progress and Challenges

Synergetic Thermal Therapy for Cancer: State-of-the-Art and the Future

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