CMN Weekly (9 January 2026) - Your Weekly CRISPR Medicine News

Top picks

• HEAL, a compact dCas12f-based transcriptional activation system recruiting transactivators via MS2 aptamers, achieved over 100,000-fold activation of endogenous genes and outperformed existing CRISPRa systems. Red-light-inducible OptoHEAL and small-molecule-inducible ChemHEAL variants enabled remote transcriptional control, with AAV-delivered HEAL targeting IL10, alleviating acute kidney injury, and ChemHEAL-mediated TSLP activation reducing body weight in obese mice.
• Researchers have designed SpCas9-Mut5, an ultrahigh-fidelity variant for TTR gene editing to treat transthyretin amyloidosis, following structural analysis that revealed extensive off-target edits with wild-type SpCas9. SpCas9-Mut5 induced extremely low off-target edits and translocations whilst maintaining on-target activity, and proved compatible with adenine base editor systems, markedly reducing off-target edits and narrowing editing windows.

Research

• A first-in-human, phase I trial tested intrathecal delivery of CRISPR-Cas9-edited, allogeneic IL-13Rα2 CAR-T cells in five people with recurrent high-grade glioma. The single-centre study reports favourable safety as its primary endpoint and early antitumour activity as a secondary outcome, whilst preclinical characterisation shows how dual gene edits can limit alloreactivity without blunting cytotoxicity. Also, read our take on the story.
• Researchers at SNIPR Biome have characterised a type IV-A3 CRISPR-Cas system from Klebsiella pneumoniae and engineered it for genome editing in Escherichia coli. They created a nuclease-enabled variant by fusing the I-TevI endonuclease domain to Cas8 to introduce lethal double-stranded DNA breaks, and developed base editors with varying editing windows by fusing the PmCDA1 cytidine deaminase to Cas8, Cas5, or DinG subunits. Conjugative delivery of the Cas5–PmCDA1 base editor successfully deactivated the tryptophan repressor gene, boosting indole-3-acetic acid (IAA), and highlighting IV-A3’s potential for metabolic engineering production.
• Chinese researchers have designed SpCas9-Mut5, an ultrahigh-fidelity variant for TTR gene editing to treat amyloid transthyretin amyloidosis, following structural analysis revealing extensive off-target edits with wild-type SpCas9. SpCas9-Mut5 induced extremely low off-target edits and translocations whilst maintaining on-target activity, and proved compatible with adenine base editor systems, markedly reducing off-target edits and narrowing editing windows.
• CRISPR-Cas9-mediated knockdown of POLD4 sensitises prostate cancer cells to radiotherapy by disrupting DNA repair. Delivered via MRI-visible USPION-loaded liposomes (PIO@Lipo), the system enabled efficient gene editing, enhanced tumour apoptosis, and reversed immunosuppression. This study establishes POLD4 as a radiosensitisation target and showcases a dual-function nanoplatform for precise, image-guided prostate cancer therapy.
• CHANGE-seq-BE is a new unbiased method for detecting guide RNA-dependent off-target effects of adenine and cytosine base editors through selective sequencing of modified genomic DNA in vitro. The approach revealed that 98.8% of ABE8e off-target sites were unique compared to the Cas9 nuclease and was applied to support genotoxicity assessments for an investigational adenine base editor targeting CD40L-deficient X-linked hyper-IgM syndrome.
• Researchers have built a CRISPR-based screening system that directly reads RNA splicing outcomes, using it to uncover medically relevant regulators of the IRE1α–XBP1 stress pathway. The work not only advances how CRISPR can be used to interrogate RNA biology, but also points to a practical strategy for improving CAR-T cell immunotherapy. Also, read our take on the story.
• Cas12a3 is a new kind of effector nucleases from type V CRISPR-Cas systems that preferentially cleave tRNAs following target RNA recognition. Target RNA binding triggers Cas12a3 to cleave the conserved 5'-CCA-3' tail of diverse tRNAs, driving growth arrest and anti-phage defence. Synthetic reporters mimicking tRNA acceptor stems enabled multiplexed RNA detection, expanding CRISPR-based diagnostic capabilities.
• Japanese researchers have developed a CRISPR-Cas-based system to edit epigenetic marks in mouse sperm, enabling direct investigation of whether DNA methylation changes can be inherited across generations. The study reveals that while artificial removal of methylation at an imprinted gene locus causes growth defects in offspring, a histone modification acts downstream of epigenetic memory to partially restore the original methylation pattern during early embryonic development. Also, read our take on the story.
• CRISPR-Cas9-mediated knockout of lncRNA MEG3 in NRK-52E cells attenuated endoplasmic reticulum stress, apoptosis, and fibrotic progression during the transition from acute kidney injury to chronic kidney disease, with restoration of autophagy activity. MEG3 deletion reduced BiP, CHOP, ATF6, ATF4, fibronectin, and collagen I expression, whilst increasing Beclin-1 and LC3B levels. Combining MEG3 knockout with tauroursodeoxycholic acid further suppressed ER stress and fibrosis markers.
• Researchers in Japan have developed CRISPR-Cas3 genome editing to target the TTR gene in transthyretin amyloidosis, achieving substantial protein reduction without generating problematic in-frame mutations. A single lipid nanoparticle treatment reduced serum TTR levels by 80% in mice whilst eliminating cardiac protein deposits.

Clinical and preclinical

• A first-in-human, phase I trial tested intrathecal delivery of CRISPR-Cas9-edited, allogeneic IL-13Rα2 CAR-T cells in five people with recurrent high-grade glioma. The single-centre study reports favourable safety as its primary endpoint and early antitumour activity as a secondary outcome, whilst preclinical characterisation shows how dual gene edits can limit alloreactivity without blunting cytotoxicity. Also, read our take on the story.
• CRISPR Therapeutics’ allogeneic CAR T therapy, zugo-cel (CTX112), shows early promise in trials for autoimmune diseases and B-cell malignancies. In SLE and IMNM patients, a 100M-cell dose induced rapid B-cell depletion and clinical improvement, with no severe CRS or ICANS. In relapsed/refractory B-cell lymphoma, a 600M-cell dose achieved a complete response rate of 70%. Zugo-cel uses CRISPR-Cas9 for CD19-targeted CAR T editing without HLA matching.

Industry

• iECURE’s ECUR-506, an in vivo CRISPR-based gene insertion therapy for neonatal onset OTC deficiency, has received RMAT designation from the FDA and an Innovation Passport under the UK’s ILAP scheme. The therapy uses ARCUS nucleases to insert OTC transgenes at the PCSK9 locus. A complete response in the first treated infant supports its potential as a durable, variant-agnostic treatment.
• Tessera Therapeutics has issued a Worker Adjustment and Retraining Notification (WARN) Act notice of a mass layoff affecting 90 employees, around one-third of its workforce. The Somerville, MA-based company states the layoff is permanent but will not involve facility closures. In partnership with Regeneron, Tessera is advancing TSRA-196 – an in vivo gene editing therapy targeting the root cause of alpha-1 antitrypsin deficiency (AATD).
• Revvity and Profluent are opening access to next-generation base editing. Through the AI-enhanced Base Editing Access Program, selected researchers can receive complimentary evaluation services to assess the new AI-engineered adenine base editors integrated within Revvity’s modular Pin-point™ base editing platform. Our goal is simple: To empower therapeutic development teams to explore how modular, high-precision base editing can advance their programs - without the usual barriers to entry. Apply today! Deadline 6 February 2026.

Delivery

• Optimising lipid nanoparticle delivery of CRISPR-Cas9 for treating chronic hepatitis B, researchers tested ionizable lipid formulations in humanised chimeric mice with persistent HBV genotype C infection. The CL4F11_ζ-2 formulation, incorporating structural lipid optimisation and heat-treated WJ11 guide RNA, significantly reduced serum viral load, hepatic HBV DNA, covalently closed circular DNA, HBsAg, and HBcrAg levels compared to earlier candidates and controls.
• Researchers have developed G4F7-CRISPR, a fluoropolymer-based CRISPR-Cas9 delivery platform targeting TSHR and IGF1R for treating thyroid-associated ophthalmopathy. The method achieved high editing frequencies in orbital fibroblasts (37.2%, 42.8%), mature adipocytes, and orbital adipose tissue. Dual-gene editing significantly suppressed orbital adipogenesis, inflammation, and fibrosis in TAO mouse models and in 3D human orbital organoids, with minimal off-target activity, and outperformed teprotumumab in both efficacy and safety.
• CD44-specific peptide-modified lipid nanoparticles have been used to target the delivery of CRISPR-Cas9 mRNA and guide RNA against PLK1 to melanoma tumour cells. The system achieved enhanced gene editing efficacy and significant tumour growth inhibition in in vitro and in vivo skin melanoma models, whilst also demonstrating efficacy against brain metastatic melanoma and substantially suppressing tumour growth in brain metastasis models.
• Targeted-Antibacterial-Plasmids (TAPs) delivering CRISPR-Cas systems via conjugation eliminated extended-spectrum β-lactamase-producing Escherichia coli carrying blaCTX-M-15. Cas9-based TAPs caused bacterial death or plasmid loss, whilst dCas9-based TAPs restored cephalosporin susceptibility, with both substantially suppressing resistant E. coli in human faeces whilst sparing non-targeted species.

Screening

• Single-cell profiling of inflammatory bowel disease tissues has identified inflammation-associated fibroblasts induced by proinflammatory macrophages that produce profibrotic cytokine IL-11. Genome-wide CRISPR knockout and activation screens identified transcription factor GLIS3 as a key regulator of inflammatory and fibrotic gene networks, with fibroblast-specific Glis3 deletion alleviating chronic colitis in mice and GLIS3 expression levels stratifying ulcerative colitis patients by disease severity.
• Genome-wide CRISPR-Cas9 knockout screening in A549 lung cancer cells identified CLDN1 (claudin-1) as a critical modulator of berberine sensitivity. CLDN1 knockout markedly increased sensitivity to berberine, enhancing G1-phase arrest and reducing proliferation, suggesting CLDN1 serves a dual role promoting resistance under selective pressure whilst representing a therapeutic vulnerability when directly inhibited.
• A genome-wide screen in Escherichia coli identified 15 host factors affecting Vibrio cholerae CRISPR-associated transposase activity (VchCAST), with seven enhancing and two inhibiting transposition. Guided by the identification of homologous recombination effectors RecD and RecA, the incorporation of the λ-Red recombineering system increased editing efficiency 55.2-fold in E. coli, 5.6-fold in Pseudomonas putida, and 10.8-fold in Klebsiella michiganensis, whilst maintaining high target specificity.
• Genome-wide CRISPR knockout screens in differentiating mouse embryonic stem cells identified hundreds of essential genes for neural development, with mouse models of eight genes (Eml1, Dusp26, Dynlrb2, Mta3, Peds1, Sgms1, Slitrk4, Vamp3) revealing neuroanatomical abnormalities, including microcephaly. Peds1 deficiency impaired plasmalogen biosynthesis, caused accelerated cell-cycle exit and disrupted neuronal differentiation and migration, with a bi-allelic PEDS1 variant identified in individuals with microcephaly, global developmental delay, and congenital cataracts.

Webinars and conferences

• RAVYN, a biotech intelligence tool that curbs $100M/year in wasted executive time, will debut at a live event today, Friday, January 9, at 6:00 PM CET. Designed to end unproductive news-scanning, it delivers only the updates that matter – tailored to your role, company, and goals. Attendees will see it in action, hear from early users, and receive an exclusive one-time launch offer. This is a must-attend for biotech leaders.

Reviews

• Plant-Based Oral Vaccines: Molecular Biotechnology Approaches Toward Functional Food-Based Immunization. This review discusses how plant-based oral vaccines use bioencapsulation to deliver stable antigens that elicit mucosal and systemic immunity, with advances in chloroplast engineering, CRISPR-Cas9 editing, and AI design supporting low-cost immunisation strategies.
• CRISPR/Cas strategies to enhance CAR T-cell function and persistence via metabolic reprogramming. This review examines the application of CRISPR-Cas to improve CAR T-cell function and persistence, addressing issues of exhaustion and dysfunction, with a focus on metabolic reprogramming.
• Prime Editing, CRISPR-Cas9, and NanoCas Genome Editing for Cancer Treatment. This review evaluates how successive genome-editing platforms – from CRISPR-Cas9 to base, prime, and nanoCas editors – are reshaping cancer research and therapy, comparing their mechanisms, delivery challenges, and translational potential for precise and safer oncological interventions.