CMN Weekly (23 January 2026) - Your Weekly CRISPR Medicine News

Top picks

• Scribe Therapeutics will enter clinical trials in mid-2026 with STX-1150, a CRISPR-based therapy that epigenetically silences PCSK9 to reduce LDL cholesterol without altering DNA. Using their ELXR platform, STX-1150 achieved durable LDL-C lowering in primates. The approach offers a reversible, long-lasting alternative to permanent gene editing for reducing cardiovascular risk. A new preprint outlines ELXR’s allosteric control, enhancing on-target activity and safety.
• CorriXR has presented new preclinical data showing that CRISPR-Cas9-mediated NRF2 disruption restores chemosensitivity in head and neck and oesophageal squamous cell carcinoma models—extending previous findings in lung cancer. These results highlight the durability of response and the importance of editing site selection. Crucially, CorriXR announces plans to file an IND for HNSCC, marking the first clinical application of its NRF2-targeting platform.

Research

• Researchers at Scribe Therapeutics have engineered allosterically gated CRISPR-CasX epigenetic editors (ELXRs) that incorporate DNMT3A's native regulatory ADD domain, substantially reducing off-target methylation whilst maintaining on-target silencing across multiple loci. The allosteric control mechanism, which activates methyltransferase activity only upon recognition of unmodified H3K4, reduced the expression of differentially expressed genes by 10–100-fold compared with non-allosteric editors. Lipid nanoparticle delivery in vivo achieved durable PCSK9 silencing with precise promoter methylation and minimal off-target effects.
• CRISPR-Cas9-generated Rasd2 knockout mice displayed normal hearing, but Rasd2 deletion exacerbated hearing loss in Tsc1-deficient mice through enhanced stereocilia defects and elevated mTORC1 signalling in hair cells. The findings suggest that RASD2 regulates stereocilia morphology and auditory transduction by modulating mTOR activity.
• Researchers have identified how the bacteriophage protein AcrIIA27 inhibits diverse Cas9 enzymes by binding solvent-exposed regions of the guide RNA rather than the protein itself. This structural insight enables the rational design of truncated guide RNAs that significantly enhance genome-editing efficiency across multiple platforms.
• A high-throughput platform for assessing DNA repair in Aedes aegypti embryos shows CRISPR-Cas9–induced double-strand breaks are predominantly repaired via microhomology-mediated end joining (MMEJ), not classical NHEJ. Single-strand annealing was also observed, with deletions up to 8.6 kb. These findings clarify the repair landscape in mosquitoes, informing gene drive design, transgene stability, and resistance management in vector control applications.
• CRISPR-Cas9 tethering of E. coli RecE markedly improves kilobase-scale homology-directed repair in mammalian cells, including hESCs. A domain-engineered dCas9-miniRecTE fusion enabled ∼20% knock-in efficiency without double-strand breaks, even in primary neurons. These findings identify RecE as a potent HDR enhancer and introduce a DSB-free editing strategy with broad relevance for therapeutic gene insertion.
• Cryo-electron microscopy revealed that anti-Cas9 protein AcrIIA27 binds the solvent-exposed phosphate backbone of single guide RNA near the PAM DNA-binding pocket on SpyCas9, preventing substrate DNA recognition through steric hindrance. This mechanism suggested that solvent-exposed sgRNA regions prone to nonspecific binding may compromise CRISPR-Cas editing efficiency – indeed, truncating these regions significantly enhanced genome-editing efficiency in human cells.
• Delivering LbuCas13a as ribonucleoprotein into human cells triggers robust collateral RNA cleavage activity within 50 minutes, targeting both exogenous and endogenous transcripts across different cell lines. Total RNA sequencing and Nanopore analysis revealed rapid, near-global depletion of cytoplasmic RNAs at specific nucleotide positions, triggering stress responses, upregulating innate immunity, and inducing apoptotic cell death. This enables target-RNA-specific cell elimination as a flexible, repeatable tool.
• A near-infrared light-inducible CRISPR-Cas12a system, integrated with upconversion nanoparticles and photocleavable DNA linkers, enables spatiotemporal control of mitochondrial DNA mutation imaging and editing. NIR irradiation triggers Cas12a trans-cleavage for amplified fluorescence detection (0.83 pM limit), whilst simultaneously inducing CRISPR-based mtDNA editing in living cells and tumour-bearing mice. This dual approach disrupts mitochondrial membrane potential, increases reactive oxygen species and promotes apoptosis, achieving effective tumour suppression.
• Systematically analysing functional genomics data from over 1,000 cancer cell lines with a CRISPR-enhanced framework, researchers identified more than 2,000 Dependency-Associated Mutations – somatic variants linked to increased viability dependency on their host gene. This uncovered over 1,000 genes not previously reported as cancer drivers, revealing hundreds of high-priority DAMs with clinical translation potential accessible through the CRISPR VUS Portal.
• Using CRISPR-Cas9, researchers knocked in c-JUN alongside a B7-H3 CAR into the TRAC locus of primary human T cells to overcome TGF-β1-mediated suppression in small cell lung cancer and thoracic SMARCA4-deficient undifferentiated tumours. The non-viral c-JUN+B7-H3 CAR T cells demonstrated enhanced killing of tumours with low antigen density, with good manufacturing practice clinical-scale production proving feasible for these engineered cells.

Clinical and preclinical

• iECURE's ECUR-506 has secured both the US FDA Regenerative Medicine Advanced Therapy designation and a UK Innovation Passport, positioning the investigational in vivo gene insertion therapy for accelerated development as a treatment for neonatal-onset ornithine transcarbamylase deficiency. The dual regulatory recognition follows encouraging clinical responses in the ongoing OTC-HOPE study, in which the first treated infant achieved complete discontinuation of ammonia-scavenging medications within three months. Also, read our take on the story.
• Wugen’s allogeneic anti-CD7 CAR-T therapy Sofi-cel has received FDA Breakthrough Therapy Designation for relapsed/refractory T-ALL/T-LBL. Sofi-cel uses CRISPR-Cas9 to delete CD7 and TRAC, preventing fratricide and GvHD. Sofi-cel, now in a pivotal Phase 2 trial, is an off-the-shelf therapy that uses healthy donor T cells to avoid malignant contamination.

Delivery

• A CRISPR-dCas9 bacterial delivery platform induces targeted pyroptosis in tumours by upregulating GSDMD via Salmonella typhimurium VNP20009 encapsulated in Fe³⁺-tannic acid nanofilms. Upon reaching acidic tumour microenvironments, the system releases CRISPR machinery and generates ROS, while bacterial flagella activate caspase-1 to cleave GSDMD. This synergistically amplifies pyroptosis, enhancing anti-tumour immune responses and offering a multi-modal strategy for tumour-selective immunotherapy.

Screening

• Whole-genome CRISPR-Cas9 knockout screens in tumoroid-T cell co-cultures identified CHD1 and MAP3K7 loss as sensitisers to anti-tumour immunity by potentiating IFN-γ transcriptional responses. Syngeneic mouse models deficient in these genes showed enhanced checkpoint blockade efficacy, with increased intra-tumoural CD8+ T cells, whilst reduced expression in patient tumours correlated with immunotherapy response, suggesting they are potential biomarkers.
• Genome-wide CRISPR screenings in hepatobiliary cancers identified BAP1 as a driver of adaptive resistance to CDK4/6 inhibitors through chromatin remodelling that induces a stem cell-like state. BAP1 removes H2AK119ub at the TCF4 promoter, activating WNT and EMT signalling to enhance cellular plasticity during therapy. Genetic and pharmacological BAP1 inhibition markedly improved abemaciclib efficacy in mouse models and patient-derived organoids.
• Pooled CRISPR knockout and inhibition screens in MCF7 breast cancer cells co-cultured with cytotoxic T lymphocytes identified 33 genes at breast cancer risk loci that modulate immune killing, of which 6 were validated, including PRMT7. Pharmacological PRMT7 inhibition sensitised breast cells to CTL killing in vitro, whilst Prmt7-deficient tumours showed reduced growth and increased CD8+ T cell infiltration in immunocompetent mice, implicating PRMT7 in immune evasion.
• Using CRISPR-Cas9 screening in head and neck squamous cell carcinoma organoids from cell lines and patient tissues, researchers identified SREBP1 as a critical lipid metabolism regulator whose expression correlates with patient survival and chemotherapy response. Functional validation showed that SREBP1 downregulation conferred cisplatin resistance and reduced cell death in both organoid and xenograft models, establishing SREBP1-mediated lipid rewiring as a key determinant of treatment outcomes.
• Genome-wide CRISPR-Cas9 knockout screens in prion-infectible CAD5 neuronal cells identified 46 positive and 21 negative regulators of cell-surface PrPC expression in the undifferentiated state, with the GPI anchor and N-glycosylation biosynthetic pathways overrepresented. Comparing undifferentiated and differentiated states revealed 23 core shared regulators alongside unique state-dependent mechanisms, offering potential therapeutic targets for prion and neurodegenerative diseases.
• Researchers have developed PORTAL, which encodes CRISPR perturbation effects in expressed transcripts for single-molecule quantitative RNA phenotyping, alongside CAP cloning that bypasses bacterial transformation for ultrahigh-complexity lentiviral library construction. Combining these technologies, they generated a genetic interaction map spanning 665,856 pairwise perturbations across 46 million clonal lineages – the largest exhaustive map in human cells using a non-fitness phenotype.

Detection

• A new one-pot isothermal assay combines recombinase polymerase amplification with CRISPR-Cas13a collateral cleavage to detect Treponema pallidum subspecies pallidum, the causative agent of syphilis. Testing 186 clinical specimens showed sensitivities of 58.97% in whole blood, 84.21% in lesion exudate and 57.14% in cerebrospinal fluid, with 100% specificity across all sample types. The rapid, field-friendly format offers promise for point-of-care syphilis diagnostics.
• A CRISPR-Cas12a–based iontronic sensing platform enables ultra-sensitive detection of methylated septin9 DNA, a key colorectal cancer biomarker. Combining AciI digestion, CHA amplification, Ag-DNAzyme generation, and nanoparticle-based ion modulation, the system achieves a 34 aM detection limit and distinguishes cancer from normal samples. This non-destructive, high-specificity approach offers strong potential for early, site-specific methylation diagnostics.

Perspectives and comments

• A Berkeley Voices podcast episode recounts how Victoria Gray became the first person treated with CRISPR‑Cas for sickle cell disease. Her haemoglobin gene was edited in 2019 using UC Berkeley–developed technology. The therapy ended decades of severe pain and transfusions, highlighting the transformative clinical potential of CRISPR‑Cas for inherited blood disorders.
• An Opinion Article in Frontiers in Microbiology establishes a four-element stewardship framework for translating CRISPR-Cas antimicrobial resistance interventions into clinical practice, comprising minimal diagnostics, standardised dose-at-site reporting, escape surveillance with adaptive responses, and equity-by-design considerations. The framework addresses engineered bacteriophage delivery of CRISPR systems targeting carbapenem resistance genes to enable antibiotic-sparing strategies whilst emphasising platform-agnostic reporting standards. Regional carbapenemase target panels should enable modular customisation within a globally interoperable platform.

Reviews

• Genetically Encoded Near-Infrared Fluorescent Proteins for Viral Imaging and Detection: A Mini-Review. This review synthesises the design principles, viral imaging/detection use cases, and translational prospects of bacteriophytochrome-derived NIR FPs, highlighting their potential to advance viral surveillance, therapeutic evaluation, and precision diagnostics.
• Research progress of Class 2 CRISPR-Cas system in nucleic acid detection of animal pathogens. This review explores CRISPR-Cas-based nucleic acid detection technologies and their application in diagnosing animal diseases, highlighting their potential for rapid, sensitive, and on-site pathogen detection in livestock.