Novel Genetic Activation Screening in Liver Repopulation and Cancer: Now CRISPR Than Ever!

Preziosi, Morgan; Monga, Satdarshan P.

doi:10.1002/hep.30084

Cited by 3 publications

(3 citation statements)

References 13 publications

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“…Patients with prior HCV treatment experience will still require both genotyping and more comprehensive cirrhosis testing to determine G/P treatment duration. Thus, 8-week G/P regimen for these treatment-naïve patients with APRI ≤ 1 and no prior evidence of cirrhosis provides a simplified and shortened treatment program which may improve health benefits and save costs for healthcare systems [30]. Further simplification may be possible on the basis of preliminary results from EXPEDITION-8 that show high SVR12 rates with 8-week G/P treatment in patients with chronic HCV GT1, 2, 4, 5, or 6 infection and compensated cirrhosis; however, 8-week G/P treatment is currently not a recommended regimen for patients with prior evidence of cirrhosis [31].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve, HCV-Infected Patients with APRI ≤ 1 in a Single-Arm, Open-Label, Multicenter Study

et al. 2019

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Introduction: The presence or absence of cirrhosis in patients with chronic hepatitis C virus (HCV) infection influences the type and duration of antiviral therapy. Non-invasive markers, like serum aspartate aminotransferase (AST) to platelet ratio index (APRI), may help identify appropriate HCV treatment-naive patients for 8-week treatment with the pangenotypic regimen of glecaprevir/pibrentasvir. Methods: This single-arm, open-label, international, prospective study (NCT03212521) evaluated the efficacy and safety of 8-week glecaprevir/pibrentasvir regimen in HCV treatment-naïve adults with chronic HCV genotypes 1-6 infection, APRI B 1, and no prior evidence of cirrhosis. The primary and secondary outcomes were sustained virologic response at 12 weeks post-treatment (SVR12) by modified intent-to-treat (mITT) and intent-to-treat (ITT) analyses, respectively. Additional endpoints included virologic failures, treatment adherence, and genotype-specific SVR12 rates. Results: Among the 230 patients enrolled, most were less than 65 years old (90%); 37% and 43% had a history of injection drug use or psychiatric disorders, respectively. SVR12 rates were 100% (222/222; 95% CI 98.3-100%) and 96.5% (222/230; 95% CI 94.2-98.9%) by mITT Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.9924842.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve, HCV-Infected Patients with APRI ≤ 1 in a Single-Arm, Open-Label, Multicenter Study

et al. 2019

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“…Clustered regularly interspaced short palindromic repeat (CRISPR) sequences and their associated proteins (Cas) were first identified in the immune system of bacteria and archaea, 15 CRISPR/Cas technology has become a major tool in the field of biological medicine research, 16 for gene editing, 17 for regulating gene signal networks 18,19 and in synthetic biology research. 20,21 The CRISPR Cas9 system is composed of single-guide RNA (sgRNA) and Cas9 protein with endonuclease activity.…”

Section: Crispr/cas Technologymentioning

confidence: 99%

“…CRISPR technology provides a robust and multiplex genome editing tool, enabling researchers to precisely manipulate specific genomic elements, to facilitate the elucidation of target gene functions in cells and disease states. CRISPR/Cas technology has become a major tool in the field of biological medicine research, for gene editing, for regulating gene signal networks and in synthetic biology research …”

Section: Introductionmentioning

confidence: 99%

A revolutionary tool: CRISPR technology plays an important role in construction of intelligentized gene circuits

et al. 2018

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With the development of synthetic biology, synthetic gene circuits have shown great applied potential in medicine, biology, and as commodity chemicals. An ultimate challenge in the construction of gene circuits is the lack of effective, programmable, secure and sequence-specific gene editing tools. The clustered regularly interspaced short palindromic repeat (CRISPR) system, a CRISPR-associated RNA-guided endonuclease Cas9 (CRISPR-associated protein 9)-targeted genome editing tool, has recently been applied in engineering gene circuits for its unique properties-operability, high efficiency and programmability. The traditional single-targeted therapy cannot effectively distinguish tumour cells from normal cells, and gene therapy for single targets has poor anti-tumour effects, which severely limits the application of gene therapy. Currently, the design of gene circuits using tumour-specific targets based on CRISPR/Cas systems provides a new way for precision cancer therapy. Hence, the application of intelligentized gene circuits based on CRISPR technology effectively guarantees the safety, efficiency and specificity of cancer therapy. Here, we assessed the use of synthetic gene circuits and if the CRISPR system could be used, especially artificial switch-inducible Cas9, to more effectively target and treat tumour cells.Moreover, we also discussed recent advances, prospectives and underlying challenges in CRISPR-based gene circuit development.protein, in order to reduce the non-specific binding of dCas9 to DNA (with a negative charge). 69 In addition, a truncated sgRNA with only 17-19 nucleotides was constructed for targeted DNA sequences. 70 Another major problem is that CRISPR systems are difficult to package using AAVs. Therefore, novel transcriptional activators (TFs) and transcriptional inhibitors were used, such as the dCpf1 system, a miniaturized CRISPR dCas9 system. With the development of these technologies, the CRISPR/Cas system may become more sophisticated and efficient for use in the future.In conclusion, with the continuous development of genome editing and gene circuit technology, the abovementioned deficiencies will eventually be resolved. This will provide a method for its application in clinical treatment. Intelligentized gene circuits based on CRISPR technology will be an important research direction in the field of tumour gene therapy in the future.

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Efficient activation of hundreds of LTR12C elements reveals cis-regulatory function determined by distinct epigenetic mechanisms

Ohtani,

Liu,

Liang

et al. 2024

Nucleic Acids Research

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Long terminal repeats (LTRs), which often contain promoter and enhancer sequences of intact endogenous retroviruses (ERVs), are known to be co-opted as cis-regulatory elements for fine-tuning host-coding gene expression. Since LTRs are mainly silenced by the deposition of repressive epigenetic marks, substantial activation of LTRs has been found in human cells after treatment with epigenetic inhibitors. Although the LTR12C family makes up the majority of ERVs activated by epigenetic inhibitors, how these epigenetically and transcriptionally activated LTR12C elements can regulate the host-coding gene expression remains unclear due to genome-wide alteration of transcriptional changes after epigenetic inhibitor treatments. Here, we specifically transactivated >600 LTR12C elements by using single guide RNA-based dCas9-SunTag-VP64, a site-specific targeting CRISPR activation (CRISPRa) system, with minimal off-target events. Interestingly, most of the transactivated LTR12C elements acquired the H3K27ac-marked enhancer feature, while only 20% were co-marked with promoter-associated H3K4me3 modifications. The enrichment of the H3K4me3 signal was intricately associated with downstream regions of LTR12C, such as internal regions of intact ERV9 or other types of retrotransposons. Here, we leverage an optimized CRISPRa system to identify two distinct epigenetic signatures that define LTR12C transcriptional activation, which modulate the expression of proximal protein-coding genes.

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Novel Genetic Activation Screening in Liver Repopulation and Cancer: Now CRISPR Than Ever!

Cited by 3 publications

References 13 publications

Efficacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve, HCV-Infected Patients with APRI ≤ 1 in a Single-Arm, Open-Label, Multicenter Study

Efficacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve, HCV-Infected Patients with APRI ≤ 1 in a Single-Arm, Open-Label, Multicenter Study

A revolutionary tool: CRISPR technology plays an important role in construction of intelligentized gene circuits

Efficient activation of hundreds of LTR12C elements reveals cis-regulatory function determined by distinct epigenetic mechanisms

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