[Weekly News]: High-Impact Nature Study—CRISPR Library Screening Unveils Synthetic Lethality Potential of PELO Gene in Two Cancer Subtypes

CRISPR/Cas technology is a revolutionary tool in modern biological sciences, with applications spanning medicine, agriculture, environmental conservation, and more. New findings and case studies continue to emerge across these fields. Our‘CRISPR Weekly News’column brings you the latest research and industry updates. Here's a brief summary of the past week's highlights:

I. Research Updates

i. CRISPR Screening

1. Article Title: SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO

Journal: Nature (IF: 50.5)

Original Link：https://doi.org/10.1038/s41586-024-08509-3

Summary:
Alterations in cancer genomes often cause cells to become dependent on certain genes, a characteristic that can be harnessed for targeted cancer therapies. This study leveraged large-scale CRISPR gene knockout screening data from the Cancer Dependency Map to identify synthetic lethal targets associated with biallelic deletion of the 9p21.3 chromosomal region or microsatellite instability-high (MSI-H) cancers. The findings revealed PELO as a synthetic lethal target in cancers with 9p21.3 deletions or high MSI. Loss of FOCAD or TTC37 destabilizes the SKI complex (SKIc), making PELO essential for rescuing ribosomes. Without PELO, the unfolded protein response is triggered, highlighting its therapeutic potential in these molecular cancer subtypes.

2. Article Title: SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation

Journal: Genome Biology (IF: 10.1)

Original Link：https://doi.org/10.1186/s13059-025-03483-z

Summary:
SETD2 mutations play a critical role in various cancers, especially in renal clear cell carcinoma where they are linked to poor prognosis. Recent research conducted with CRISPRi screening has identified NSD1 as a synthetic lethal target in SETD2-mutant cells. Inhibiting NSD1 (but not related methyltransferases) induces DNA damage and apoptosis, underscoring its unique function. Pharmacological inhibition with BT5 mimics these effects, demonstrating therapeutic potential. These findings offer a novel epigenetic strategy for targeting cancers deficient in SETD2, integrating genome-wide screening with genetic and pharmacological models.

3. Article Title: Functional screen identifies RBM42 as a mediator of oncogenic mRNA translation specificity

Journal: Nature Cell Biology (IF: 17.3)

Original Link：https://doi.org/10.1038/s41556-024-01604-7

Summary:
The dosage of oncogene proteins is tightly controlled to drive tumorigenesis, yet how this regulation occurs at the translational level remains unclear. Researchers conducting CRISPR interference screening in PDAC cells identified RBM42 as a critical regulator of MYC translation. RBM42 binds and reshapes the MYC 5′ UTR to promote translation initiation, co-regulating other oncogenic transcripts such as JUN and EGFR. RBM42 is vital for MYC-dependent tumor growth, making it a potential therapeutic target to disrupt oncogene expression in cancer.

ii. CRISPR Detection

1.Article Title: Room temperature CRISPR diagnostics for low-resource settings

Journal: Scientific Reports (IF: 3.8)

Original Link：https://doi.org/10.1038/s41598-025-86373-5

Summary:
Traditional diagnostic methods often require high reaction temperatures and complex, multi-step sample processing, increasing cost and complexity—barriers to widespread application in resource-limited settings. A research team developed a one-pot room-temperature RPA-Cas12a detection method using TsCas12a, an enzyme highly active at 25°C. Unlike other Cas12a homologs, TsCas12a can sensitively detect HPV-16 in crude cervical swab samples. This approach eliminates the need for complex sample preparation and heating, making CRISPR diagnostics more accessible in resource-limited environments.

2.Article Title: CRISPR/Cas13a-Programmed Cu NCs and Z-Scheme T-COF/Ag2S for Photoelectrochemical Biosensing of circRNA

Journal: ACS Sensors (IF: 8.2)

Original Link：https://doi.org/10.1021/acssensors.4c03180

Summary:
Researchers from China have developed a CRISPR-Cas13a photoelectrochemical biosensor for ultrasensitive detection of circular RNA in the blood of lung cancer patients. Using a Z-scheme T-COF/Ag₂S composite material combined with copper nanoclusters, the system achieved a detection limit of 0.5 fM. Signal amplification is provided by a hybridization chain reaction, and reusable magnetic beads help lower costs. This platform presents a promising tool for liquid biopsy-based lung cancer diagnostics.

3.Article Title: DNAzyme-Triggered Equilibrium Transfer with Self-Activated CRISPR-Cas12a Biosensor Enables One-Pot Diagnosis of Nucleic Acids

Journal: Analytical Chemistry (IF: 6.7)

Original Link：https://doi.org/10.1021/acs.analchem.4c06066

Summary:

While combining recombinase polymerase amplification (RPA) with CRISPR-Cas12a holds great potential for nucleic acid detection, existing methods are often complex, less efficient, and hindered by limitations in Cas12a activity. Researchers from China introduced the DESCRIBER platform, which integrates RPA with CRISPR-Cas12a for sensitive, single-step nucleic acid detection. A DNAzyme-triggered equilibrium transfer minimizes interference, ensuring sequential activation of RPA and Cas12a. This approach can detect 500 copies/mL of HIV-1 within an hour, achieving accuracy comparable to qRT-PCR.

iii. Other CRISPR-Related Research

1. Article Title: Implantation of engineered adipocytes suppresses tumor progression in cancer models

Journal: Nature Biotechnology (IF: 33.1)

Original Link：https://doi.org/10.1038/s41587-024-02551-2

Summary:
A study demonstrates that CRISPRa-modified adipocytes can inhibit cancer growth by altering tumor metabolism, indicating the potential of adipocyte modification as a cancer metabolic therapy. Upregulation of UCP1 in adipocytes boosts glucose and fatty acid metabolism, reducing cancer proliferation in vitro and in xenograft models. Adipose organ tissues expressing UPP1 consume uridine from the tumor microenvironment, thereby suppressing pancreatic cancer growth.

2. Article Title: Single-AAV CRISPR editing of skeletal muscle in non-human primates with NanoCas, an ultracompact nuclease

Journal: BioRxiv

Original Link：https://doi.org/10.1101/2025.01.29.635576

Summary:
NanoCas, an ultracompact CRISPR nuclease, enables efficient in vivo gene editing beyond liver-targeted therapies. Derived from metagenomic data, NanoCas is only a third the size of traditional nucleases while maintaining strong activity. In mouse and non-human primate models, NanoCas achieved over 30% editing in muscle tissue, showcasing its potential for single-AAV delivery in gene therapy, including base and epigenetic editing.

3. Article Title: BCL11A +58/+55 enhancer-editing facilitates HSPC engraftment and HbF induction in rhesus macaques conditioned with a CD45 antibody-drug conjugate

Journal: Cell Stem Cell (IF: 19.8)

Original Link：https://doi.org/10.1016/j.stem.2024.10.014

Summary:
Two new related studies show that CRISPR-Cas9 editing of the BCL11A +58 and +55 enhancers induces sustained reactivation of fetal hemoglobin (HbF). Demirci et al. demonstrated persistent HbF expression (>4 years) in rhesus macaques conditioned with an antibody-drug conjugate. Zeng et al. found that editing quiescent hematopoietic stem/progenitor cells (HSPCs) allowed for sustained engraftment while minimizing genotoxicity. Together, these findings support safer, more effective gene editing strategies for β-hemoglobinopathy therapies.

II. Industry News

1. Vertex’s CASGEVY Receives NHS Reimbursement

Vertex Pharmaceuticals’ CRISPR-Cas9 gene-editing therapy, CASGEVY, has received reimbursement approval from the UK’s National Health Service (NHS). The therapy will now be available for treating sickle cell disease and transfusion-dependent beta thalassemia. CASGEVY, a one-time treatment administered at specialized centers, is part of Vertex’s plan to establish a network of authorized treatment sites to ensure efficient delivery.

2. FDA Designations for Arbor Biotech’s ABO-101
Arbor Biotechnologies’ CRISPR-Cas12i2-based therapy, ABO-101, has received both orphan drug and rare pediatric disease designations from the U.S. Food and Drug Administration (FDA) for the treatment of primary hyperoxaluria type 1 (PH1). ABO-101 utilizes lipid nanoparticle delivery of gene-editing technology to disable the HAO1 gene, thereby reducing excessive oxalate production. An upcoming Phase 1/2 trial will assess its safety and efficacy. These FDA designations provide regulatory incentives, bolstering ABO-101’s potential as a first-in-class, long-lasting therapy for PH1.

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