CMN Weekly (19 December 2025) - Your Weekly CRISPR Medicine News

Top picks

• The anti-CRISPR protein AcrIIA5 enhances prime editing activity by up to 8.2-fold while markedly reducing byproduct indels across various PE approaches (PE2–PE6), edit types and endogenous loci. Mechanistically, AcrIIA5 inhibits the re-nicking activity of the PE complex rather than enhancing core editing machinery, demonstrating that a known CRISPR-Cas inhibitor can unexpectedly optimise genome editing specificity and efficiency.
• Using engineered virus-like particles, researchers delivered CRISPR tools into primary human myeloid cells, enabling gene knockout, base editing, and precise DNA insertion without impairing immune function. This platform supported the first pooled CRISPR-Cas screens in human macrophages, identifying TNFAIP3 as a key inflammatory regulator. Its disruption enhanced pro-inflammatory responses and boosted HER2 CAR-macrophage cytotoxicity, advancing gene-target discovery for immunotherapy.

Research

• Using 3′-extended guide RNAs and phage-assisted evolution guided by protein-language models, researchers have developed adenine base editors that are two- to threefold more precise than ABE8e while maintaining high efficiency across thousands of human pathogenic contexts. This parallel engineering strategy optimises both guide RNAs and deaminase enzymes to minimise bystander editing – a major constraint in CRISPR-Cas base editing applications.
• Using CRISPR-Cas9, researchers inserted a designer cassette at the mouse REL locus to conditionally express human c-Rel cDNA in T cells for studying autoimmune diabetes. Despite successful genomic integration and T cell-specific deletion, the mice unexpectedly lacked c-Rel protein expression due to increased CpG methylation at the promoter – revealing a potential challenge in developing conditional knock-in models.
• Systematic analysis of late-onset Alzheimer's disease GWAS loci across 174 functional genomics datasets identified 41 candidate causal variant-effector gene pairs, revealing that the LOAD risk allele rs74504435 increases EGFR expression in microglia, astrocytes and neurons. CRISPR interference validated this enhancer–promoter interaction, suggesting EGFR as a potential therapeutic target in late-onset Alzheimer’s disease.

Industry

• Vor Bio has raised approximately $150 million in new funding through a private placement of 13.9 million common shares at $10.81 each to institutional healthcare investors. Proceeds will support Phase 3 development of telitacicept for myasthenia gravis and primary Sjögren’s disease, as well as general corporate use.
• Cellectis announced an arbitration ruling partially terminating its licence agreement with Servier for UCART19 V1 (ALLO-501), enabling potential direct licensing discussions with Allogene. UCART19 V1 is gene-edited using TALEN to disrupt endogenous T cell genes for allogeneic use. All other claims in the dispute were dismissed by the Tribunal.

Delivery

• A cell-free method called Plasmid2MC uses ΦC31 integrase to convert plasmids into highly pure, endotoxin-free minicircle DNA by excising bacterial backbones. The resulting mcDNA effectively delivered CRISPR-dCas9 for base editing in HEK293T cells and mouse embryonic stem cells, and enabled homology-independent targeted insertion genome editing.
• Non-replicative phage capsids (AB-Capsids) delivering CRISPR-Cas13a with guide RNA targeting blaIMP-1 specifically inhibited carbapenem-resistant Pseudomonas aeruginosa and significantly reduced imipenem minimum inhibitory concentrations. The programmable platform showed spacer-dependent and expression-level-dependent killing activity, demonstrating CRISPR-Cas13a delivery as a gene-specific antimicrobial strategy for reversing antibiotic resistance.

Screening

• CRISPR-Cas9 screens have identified the lysosomal protein SPNS1 as essential for enterovirus A71 (EV-A71) infection, where it acts as a transporter releasing viral pocket factor to enable genome uncoating and replication. SPNS1 deficiency protected mice from EV-A71 pathogenesis and proved critical for infection by 9 of 11 examined enteroviruses, suggesting SPNS1 as a potential broad-spectrum antiviral target.
• Over 150 regulatory interactions controlling key astrocyte functions and Alzheimer's disease-related genes have been identified using CRISPR inhibition (CRISPRi) screening combined with single-cell RNA-seq in human primary astrocytes. The screen data trained EGrf, a random forest model that predicts enhancer–gene interactions genome-wide, creating AstroREG – a comprehensive functional map of enhancer-mediated regulation in astrocytes.
• An optical pooled screening platform combining CRISPR with Cell Painting enables hypothesis-free reverse genetic screening through multiplexed morphological profiling. Validation using morphological gene sets and mechanism-of-action libraries demonstrated that deep learning analysis of rich morphological data reveals gene networks without target-specific biomarkers, facilitating unbiased discovery in druggable genome screens.

Detection

• A CRISPR-Cas12a diagnostic platform exploits the hydrophobic adhesion of gold nanoparticles functionalized with Cy5-labelled ssDNA probes, in which Cas12a cleavage triggers surface adhesion rather than the conventional aggregation-dispersion. Combined with recombinase polymerase amplification, the visual colourimetric assay achieved 10 aM sensitivity for HPV DNA detection in cervical swab samples, offering a simple, instrument-free approach for point-of-care diagnostics.
• Combined experimental and theoretical analysis of 480 CRISPR-Cas12a lateral flow test configurations identified critical factors affecting diagnostic performance, revealing that 5-minute pre-incubation of conjugate with reporter eliminated false positives. Optimising reporter concentration to 20 nM and using smaller gold nanoparticles with multivalent fluorescent reporters improved sensitivity by over 50-fold, enabling amplification-free detection of 20 pM Erwinia amylovora DNA.

Perspectives and opinions

• In an interview with Inside Precision Medicine, Prime Medicine CEO Allan Reine discusses the first clinical use of prime editing in two patients with CGD treated with PM359, an autologous HSC therapy that avoids double-strand DNA breaks. Despite promising early results, the programme is paused due to market size, with the company prioritising broader indications such as Wilson’s disease and AATD.
• A perspective piece in Trends in Biotechnology calls for integrating whole-genome sequencing into the Athlete Biological Passport to detect CRISPR-based gene doping. The proposal highlights how edits to genes like EPO or ACTN3 could evade detection, and advocates blockchain to ensure data integrity and athlete privacy, framing genomic surveillance as essential for fairness in post-CRISPR sport.

Reviews

• Emerging trends in gene and cell therapy: CRISPR in DNA editing and beyond. This review highlights how advances in genome-editing technologies, ranging from CRISPR-Cas nucleases to base and prime editors, are expanding the therapeutic landscape beyond traditional gene-knockout approaches, with a special focus on their clinical translation.
• Recent advances in CRISPR- and RCA-based biosensing chips and devices for POCT and in situ detection. This review summarises recent advances over the past five years in CRISPR- and rolling circle amplification-based biosensing chips and devices, focusing on their performance, technological features, and prospects for point-of-care testing, in situ applications, and commercialisation.
• Overcoming barriers in CAR-NK immunotherapy: CRISPR-Driven advances in checkpoint editing and allogeneic design. This review discusses how CRISPR/Cas9 genome editing is being integrated into CAR-engineered natural killer cell development to enhance antitumour efficacy, persistence, tumour targeting, and off-the-shelf potential for next-generation cancer immunotherapies.
• CRISPR-Cas9: A comprehensive review of gene editing for inherited blood disorders. This review examines the principles and clinical applications of CRISPR-Cas9 genome editing in inherited blood disorders, synthesising recent experimental, preclinical, and clinical evidence to assess its diagnostic, therapeutic, and future potential in haematology.
• CRISPR-Based Biosensing for Genetically Modified Organism Detection: Current Applications and Future Perspectives. This review explores the use of CRISPR-Cas-based diagnostic technologies for rapid, decentralised detection of genetically modified organisms in agriculture and food supply chains, detailing underlying mechanisms, detection platforms, readout strategies, and future challenges.