Advances in CRISPR/Cas-based Gene Therapy in Human Genetic Diseases

Wu, Shaoshuai; Li, Qing-Cui; Yin, Changqing; Xue, Wen; Song, Chun‐Qing

doi:10.7150/thno.43360

Cited by 102 publications

(79 citation statements)

References 97 publications

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“…Compared to the siRNA-mediated knockdown or CRISPR-Cas9-based knockout strategy 28 , 29 , this CRISPR-CasRx system owns several advantages. First, unlike CRISPR-Cas9 which directly alters the sequence in genomic DNA, CasRx is an RNA-level editing protein that specifically binds and cleaves target RNA transcripts 14 .…”

Section: Discussionmentioning

confidence: 99%

Precise and efficient silencing of mutant Kras^G12D by CRISPR-CasRx controls pancreatic cancer progression

Jiang

Liu

et al. 2020

Theranostics

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Rationale: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with few therapeutic targets and rare effective treatments. Over 90% of PDAC tumors bear a Kras mutation, and the single-site mutation G12D (Kras G12D ) is most prevalent. Methods: Here, we applied the CRISPR-CasRx system to silence the mutant Kras G12D transcript in PDAC cells. We also used a capsid-optimized adenovirus-associated virus 8 vector (AAV8) to deliver the CRISPR-CasRx system into PDAC orthotopic tumors and patient-derived tumor xenografts (PDX). Results: Our data showed that guided by a KrasG12D-specific gRNA, CasRx is able to precisely and efficiently silence the mutant KrasG12D expression in PDAC cells. The knockdown of mutant KrasG12D by CasRx abolishes the aberrant activation of downstream signaling induced by mutant KrasG12D and subsequently suppresses the tumor growth and improves the sensitivity of gemcitabine in PDAC. Additionally, delivering CasRx-gRNA via AAV8 into the orthotopic KrasG12D PDAC tumors substantially improves the survival of mice without obvious toxicity. Furthermore, targeting KrasG12D through CasRx suppresses the growth of PDAC PDXs. In conclusion, our study provides a proof-of-concept that CRISPR-CasRx can be utilized to target and silence mutant KrasG12D transcripts and therefore inhibit PDAC malignancy.

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Section: Discussionmentioning

confidence: 99%

Precise and efficient silencing of mutant Kras^G12D by CRISPR-CasRx controls pancreatic cancer progression

Jiang

Liu

et al. 2020

Theranostics

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“…Genome editing has entered a blooming period of development in recent years due to its extensive and effective application promise for scientific researches and disease treatment 282 , 283 . The widely-used CRPSPR/Cas9 system is by far the most flexible and convenient genome-editing tool.…”

Section: Discussionmentioning

confidence: 99%

Strategies in the delivery of Cas9 ribonucleoprotein for CRISPR/Cas9 genome editing

Song¹,

Shen²,

Li³

et al. 2021

Theranostics

274

184

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CRISPR/Cas9 genome editing has gained rapidly increasing attentions in recent years, however, the translation of this biotechnology into therapy has been hindered by efficient delivery of CRISPR/Cas9 materials into target cells. Direct delivery of CRISPR/Cas9 system as a ribonucleoprotein (RNP) complex consisting of Cas9 protein and single guide RNA (sgRNA) has emerged as a powerful and widespread method for genome editing due to its advantages of transient genome editing and reduced off-target effects. In this review, we summarized the current Cas9 RNP delivery systems including physical approaches and synthetic carriers. The mechanisms and beneficial roles of these strategies in intracellular Cas9 RNP delivery were reviewed. Examples in the development of stimuli-responsive and targeted carriers for RNP delivery are highlighted. Finally, the challenges of current Cas9 RNP delivery systems and perspectives in rational design of next generation materials for this promising field will be discussed.

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“…However, it was reported that these DNA base editors can cause substantial off-target editing in both genomic DNA and RNA, and thus further studies will be performed to improve the selectivity of DNA base editors [82]. Despite system deficiencies that still need to be improved, it is likely that the CRISPR/Cas9 systems will be incorporated into the therapeutic strategy for the treatment of monogenically inherited disorders and malignancies whose pathological features can be attributed to a single genetic event, such as gene fusion [83,84].…”

Section: Overview Of the Crispr/cas9 Systemmentioning

confidence: 99%

Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy

Vuelta

García‐Tuñón

Hernández‐Carabias

et al. 2021

Biology

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The constitutively active tyrosine-kinase BCR/ABL1 oncogene plays a key role in human chronic myeloid leukemia development and disease maintenance, and determines most of the features of this leukemia. For this reason, tyrosine-kinase inhibitors are the first-line treatment, offering most patients a life expectancy like that of an equivalent healthy person. However, since the oncogene stays intact, lifelong oral medication is essential, even though this triggers adverse effects in many patients. Furthermore, leukemic stem cells remain quiescent and resistance is observed in approximately 25% of patients. Thus, new therapeutic alternatives are still needed. In this scenario, the interruption/deletion of the oncogenic sequence might be an effective therapeutic option. The emergence of CRISPR (clustered regularly interspaced short palindromic repeats) technology can offer a definitive treatment based on its capacity to induce a specific DNA double strand break. Besides, it has the advantage of providing complete and permanent oncogene knockout, while tyrosine kinase inhibitors (TKIs) only ensure that BCR-ABL1 oncoprotein is inactivated during treatment. CRISPR/Cas9 cuts DNA in a sequence-specific manner making it possible to turn oncogenes off in a way that was not previously feasible in humans. This review describes chronic myeloid leukemia (CML) disease and the main advances in the genome-editing field by which it may be treated in the future.

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Advances in CRISPR/Cas-based Gene Therapy in Human Genetic Diseases

Cited by 102 publications

References 97 publications

Precise and efficient silencing of mutant Kras^G12D by CRISPR-CasRx controls pancreatic cancer progression

Precise and efficient silencing of mutant Kras^G12D by CRISPR-CasRx controls pancreatic cancer progression

Strategies in the delivery of Cas9 ribonucleoprotein for CRISPR/Cas9 genome editing

Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy

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Advances in CRISPR/Cas-based Gene Therapy in Human Genetic Diseases

Cited by 102 publications

References 97 publications

Precise and efficient silencing of mutant KrasG12D by CRISPR-CasRx controls pancreatic cancer progression

Precise and efficient silencing of mutant KrasG12D by CRISPR-CasRx controls pancreatic cancer progression

Strategies in the delivery of Cas9 ribonucleoprotein for CRISPR/Cas9 genome editing

Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy

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Product

Resources

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Precise and efficient silencing of mutant Kras^G12D by CRISPR-CasRx controls pancreatic cancer progression

Precise and efficient silencing of mutant Kras^G12D by CRISPR-CasRx controls pancreatic cancer progression