Past, present, and future of CRISPR genome editing technologies

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1076 - 1100

Published: Feb. 1, 2024

Genome editing has been a transformative force in the life sciences and human medicine, offering unprecedented opportunities to dissect complex biological processes treat underlying causes of many genetic diseases. CRISPR-based technologies, with their remarkable efficiency easy programmability, stand at forefront this revolution. In Review, we discuss current state CRISPR gene technologies both research therapy, highlighting limitations that constrain them technological innovations have developed recent years address them. Additionally, examine summarize landscape applications context health therapeutics. Finally, outline potential future developments could shape coming years.

Language: Английский

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CAR-T cell manufacturing: Major process parameters and next-generation strategies

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(2)

Published: Jan. 16, 2024

Chimeric antigen receptor (CAR)-T cell therapies have demonstrated strong curative potential and become a critical component in the array of B-cell malignancy treatments. Successful deployment CAR-T to treat hematologic solid cancers, as well other indications such autoimmune diseases, is dependent on effective manufacturing that impacts not only product safety efficacy but also overall accessibility patients need. In this review, we discuss major process parameters autologous manufacturing, regulatory considerations ongoing developments will enable next generation therapies.

Language: Английский

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A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1278 - 1295.e20

Published: Feb. 1, 2024

Language: Английский

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Revolutionizing cancer treatment: enhancing CAR-T cell therapy with CRISPR/Cas9 gene editing technology

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 21, 2024

CAR-T cell therapy, a novel immunotherapy, has made significant breakthroughs in clinical practice, particularly treating B-cell-associated leukemia and lymphoma. However, it still faces challenges such as poor persistence, limited proliferation capacity, high manufacturing costs, suboptimal efficacy. CRISPR/Cas system, an efficient simple method for precise gene editing, offers new possibilities optimizing cells. It can increase the function of cells reduce costs. The combination CRISPR/Cas9 technology therapy may promote development this provide more effective personalized treatment cancer patients. Meanwhile, safety issues surrounding application require further research evaluation. Future should focus on improving accuracy to facilitate better therapy. This review focuses including eliminating inhibitory effect immune checkpoints, enhancing ability resist exhaustion, assisting construction universal cells, reducing costs security problems faced. objective is show revolutionary role researchers.

Language: Английский

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Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met?

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 146 - 146

Published: Jan. 12, 2024

This last decade, chimeric antigen receptor (CAR) T-cell therapy has become a real treatment option for patients with B-cell malignancies, while multiple efforts are being made to extend this other malignancies and broader patient populations. However, several limitations remain, including those associated the time-consuming highly personalized manufacturing of autologous CAR-Ts. Technologies establish "off-the-shelf" allogeneic CAR-Ts low alloreactivity currently developed, strong focus on gene-editing technologies. Although these technologies have many advantages, they also limitations, double-strand breaks in DNA safety risks as well lack modulation. As an alternative, non-gene-editing provide interesting approach support development future, possibilities fine-tuning gene expression easy development. Here, we will review different ways can be manufactured discuss which used. The biggest hurdles successful summarized, finally, overview current clinical evidence comparison its counterpart given.

Language: Английский

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Targeted nonviral delivery of genome editors in vivo

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(11)

Published: March 4, 2024

Cell-type-specific in vivo delivery of genome editing molecules is the next breakthrough that will drive biological discovery and transform field cell gene therapy. Here, we discuss recent advances CRISPR-Cas editors either as preassembled ribonucleoproteins or encoded mRNA. Both strategies avoid pitfalls viral vector-mediated offer advantages including transient editor lifetime potentially streamlined manufacturing capability are already proving valuable for clinical use. We review current applications future opportunities these emerging approaches could make more efficacious accessible future.

Language: Английский

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High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR–Cas9 editing

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(7), P. 1482 - 1493

Published: May 29, 2024

Abstract Clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) is a powerful tool for introducing targeted mutations in DNA, but recent studies have shown that it can unintended effects such as structural changes. However, these not yet looked genome wide or across data types. Here we performed phenotypic CRISPR–Cas9 scan targeting 17,065 genes primary human cells, revealing ‘proximity bias’ which CRISPR knockouts show unexpected similarities to unrelated on the same chromosome arm. This bias was found be consistent cell types, laboratories, Cas9 delivery methods and assay modalities, suggest caused by telomeric truncations of arms, with cycle apoptotic pathways playing mediating role. Additionally, simple correction demonstrated mitigate this pervasive while preserving biological relationships. previously uncharacterized effect has implications functional genomic using CRISPR–Cas9, applications discovery biology, drug-target identification, therapies genetic therapeutics.

Language: Английский

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Epigenome editing technologies for discovery and medicine

Nature Biotechnology, Journal Year: 2024, Volume and Issue: 42(8), P. 1199 - 1217

Published: July 29, 2024

Language: Английский

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CRISPR–Cas9 applications in T cells and adoptive T cell therapies

Cellular & Molecular Biology Letters, Journal Year: 2024, Volume and Issue: 29(1)

Published: April 12, 2024

Abstract T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade adoptive therapies. Their diverse characteristics can be reprogrammed by different challenges dependent on antigen stimulation levels, metabolic conditions, the degree of inflammation. cell-based therapeutic strategies are gaining widespread adoption in oncology treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats–associated protein 9 (CRISPR–Cas9) genome editing has enabled cells more adaptable specific microenvironments, opening door advanced therapies preclinical clinical trials. CRISPR–Cas9 edit both primary engineered cells, including CAR-T TCR-T, vivo vitro regulate differentiation activation states. This review first provides a comprehensive summary role its applications studies for We also explore application CRISPR screen high-throughput technology anticipate current limitations CRISPR–Cas9, off-target effects delivery challenges, envisioned improvements related technologies disease screening, diagnosis, treatment.

Language: Английский

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Triple knockdown of CD11a , CD49d , and PSGL1 in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(782)

Published: Jan. 22, 2025

Chimeric antigen receptor (CAR)–T cell therapies have revolutionized the landscape of cancer treatment, in particular context hematologic malignancies. However, for solid tumors that lack tumor-specific antigens, CAR-T cells can infiltrate and attack nonmalignant tissues expressing CAR target antigen, leading to on-target, off-tumor toxicity. Severe toxicities been observed clinical trials therapy tumors, highlighting need address this issue. Here, we demonstrated targeting adhesion migration molecules lymphocyte function–associated 1 (LFA-1; CD11a/CD18) very late activation 4 (VLA-4; CD49d/CD29) with blocking antibodies reduced toxicity mice. To translate observation into improved therapy, either knocked out both CD11a CD49d or down along PSGL1 , another molecule, cells. We found these modified exhibited vivo without affecting efficacy. Furthermore, showed approach promoted T memory formation decreased tonic signaling. On basis data, engineered a human version low-toxicity further validated feasibility vitro vivo. Together, results provide potential solution challenge therapy.

Language: Английский

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