CMN Weekly (24 Juli 2026) - Your Weekly CRISPR Medicine News

Top picks

• CRISPR-Cas9 kilobase-scale nickase-targeting (KNIT) editing couples a nickase to donor-DNA recruitment, enabling programmable 0.7 to 10 kb insertions without double-strand breaks across loci and cell types, with efficiencies up to 89% and fewer indels, translocations and off-target edits. The system restored gene expression in mutant cells and supported non-viral CAR-T engineering, producing antitumour activity in vitro and in mouse models.
• FDA has expanded approval of Vertex's CRISPR-Cas9 therapy, Casgevy, to children aged 2 and older with sickle-cell disease or transfusion-dependent β-thalassaemia. The decision follows strong results in children aged 5-11, while approval for ages 2–4 was based on FDA extrapolation from product characteristics and the available clinical evidence rather than direct trial data in that age group.

Clinical and preclinical

• The phase I TRAVERSE trial evaluated ALLO-316, a TALEN-edited, off-the-shelf CAR-T therapy targeting CD70. Among 51 patients with heavily pretreated clear-cell renal carcinoma, the phase Ib response rate was 25%, rising to 31% in highly CD70-positive tumours. Severe haematological toxicity was common, and three treatment-related deaths occurred.
• Epicrispr Biotechnologies has completed enrolment and dose escalation in the first-in-human trial of EPI-321, an epigenetic CRISPR-based therapy for facioscapulohumeral muscular dystrophy (FSHD). Interim results suggest the treatment was well tolerated and showed early signs of modifying disease biology, although the findings remain preliminary and derive from a small, open-label study.
• FDA granted RMAT designation to PM359, Prime Medicine’s investigational autologous prime-edited stem-cell therapy for p47phox-deficient chronic granulomatous disease. In an ongoing phase 1/2 trial, the two reported patients showed durable restoration of neutrophil function after treatment, with adverse effects consistent with busulfan conditioning. The designation provides enhanced FDA guidance and potential expedited review, but is not approval.
• FDA has cleared Prime Medicine’s IND application for PM577a, permitting a phase 1/2 trial of the lipid-nanoparticle-delivered in vivo prime editor in Wilson disease. The treatment targets the common ATP7B H1069Q variant and will initially be tested in clinically stable adults before possible adolescent enrolment. Trial initiation is planned for late 2026, with initial data expected in 2027.
• Preliminary Phase 1 data from Fate Therapeutics indicate that its off-the-shelf CAR T-cell therapy, FT819, can induce early clinical responses in patients with treatment-resistant systemic sclerosis (SSc), extending encouraging findings previously reported in systemic lupus erythematosus (SLE). The data also reinforce the feasibility of delivering the iPSC-derived therapy without fludarabine and, in some patients, in an outpatient setting.
• FDA has cleared Fate Therapeutics’ IND application for FT839, an off-the-shelf, multiplex gene-edited iPSC-derived CAR-T therapy carrying 13 genetic edits and targeting CD19 and CD38. A phase 1/2 basket trial will assess safety and preliminary activity across several autoimmune diseases, including treatment without conditioning chemotherapy. Enrolment is planned for late 2026; efficacy has so far been demonstrated only preclinically.
• FDA has cleared Beam Therapeutics’ IND application for BEAM-304, permitting clinical testing of lipid-nanoparticle-delivered in vivo base editors for phenylketonuria. The phase 1/2 trial will initially target the PAH R408W mutation before adding a second mutation-specific editor under the same programme. Preclinical treatment normalised blood phenylalanine in mouse models; efficacy in patients remains untested.

Research

• In a new study, ContactSeek combined AlphaFold3-predicted contact probabilities with genome-wide off-target data to identify specificity-determining residues in CRISPR-Cas base editors. Cas9 and TadA8e mutations selected using the framework produced an adenine base editor that outperformed several established high-fidelity variants in multiple specificity assays. Application to Cas12a cytosine base editors suggests the AI-driven approach may generalise across editing platforms.
• CRISPR-Cas9 nickase was coupled to an engineered ADAR and customised guide RNA to create snuABE, enabling single-nucleotide A-to-G DNA editing with minimal bystander or detectable DNA off-target activity. The editor corrected a pathogenic VHL variant in human cells and edited mouse liver DNA, although lower efficiency, sequence bias and substantial transient RNA off-target editing require further engineering.
• Researchers in Denmark have used CRISPR-Cas9 genome editing to generate T cells expressing a naturally occurring T-cell receptor (TCR) that recognises a PD-L1-derived peptide. In vitro, these engineered cells selectively targeted both PD-L1-expressing tumour cells and immunosuppressive myeloid cells, providing proof of concept for a TCR-based strategy directed against the tumour microenvironment.
• CRISPR-Cas correction of patient-derived LMNA-R541C – a highly penetrant cardiomyopathy variant – in iPSCs, alongside knock-in of the heterozygous variant, enabled isogenic analysis of derived cardiomyocytes. Across both models, the variant consistently altered 123 genes and disrupted G2/M checkpoint and oxidative phosphorylation pathways, corroborating earlier cellular and murine findings. Pathway-based informatics nominated several drug classes, including cardiac glycosides, as candidates for preclinical investigation.
• Adenine base editing or prime editing altered a KIT epitope in haematopoietic stem/progenitor cells, protecting them from anti-KIT antibodies while preserving receptor function. Combined disruption of the BCL11A enhancer increased fetal haemoglobin and prolonged antibody treatment progressively enriched multiplex-edited cells in vitro and in vivo without detectable clonal selection, supporting chemotherapy-free conditioning strategies for haemoglobinopathies.
• Researchers have used CRISPR base editing to identify a previously unknown regulatory mechanism in the WNT–β-catenin signalling pathway, revealing a potential therapeutic strategy for APC-mutant colorectal cancer. By systematically introducing targeted mutations into four key components of the β-catenin destruction complex, the team showed that strengthening the interaction between β-catenin and AXIN1 can restore destruction complex activity and suppress tumour cell growth.
• Y-linked genome editors encoding a nuclease that disrupts a female-essential gene were modelled for invasive-mouse control. Simulations predicted elimination of 10,000 mice within five years by releasing 350 males monthly, or within ten years with 150. These self-limiting editors outperformed comparable tools and showed minimal spillover, whereas gene drives required smaller releases but spread into non-target populations.
• Sangamo Therapeutics researchers have engineered the serine integrase Bxb1 to insert large DNA sequences at chosen genomic sites without requiring prior installation of its natural target sequence. The modular integrase (MINT) platform retargets Bxb1 to the therapeutically relevant AAVS1 and TRAC loci, achieving integration efficiencies of up to 35% in cell lines and 29% in primary human T cells.
• CRISPR-Cas9 editing was demonstrated for the first time in Culicoides sonorensis by injecting adult females with Cas9 and sgRNAs targeting the white gene. Heritable mutations produced white- and red-eye phenotypes, enabling establishment of a homozygous knockout line, with editing efficiencies reaching 12.3%. The protocol provides a foundation for functional genomics and potential vector-control research in biting midges.
• A new artificial intelligence–guided strategy can design highly divergent yet functional variants of TnpB, a compact RNA-guided nuclease that is evolutionarily related to CRISPR-Cas12 enzymes. By combining a structure-based inverse protein-folding model with evolutionary constraints, they generated synthetic nucleases that retained, and in some cases exceeded, the activity of the natural enzyme across bacterial, plant and human cells.
• CRISPR-Cas prime editing enabled precise, reversible and combinatorial mutation of histone H3 genes in their native genomic context. High-throughput screening in mouse embryonic stem cells identified several lysines required for cellular fitness, established a conserved role for H3K56 in mammalian genome stability, and revealed functional interactions between residues, providing a platform for systematically dissecting chromatin regulation.

Industry

• Sangamo Therapeutics has filed for Chapter 11 bankruptcy while agreeing provisional asset sales to Eli Lilly and Astellas. Lilly’s bid covers Sangamo’s capsid-delivery, zinc-finger and integrase platforms plus its prion programme, whereas Astellas seeks the Fabry gene therapy ST-920. Both agreements establish baseline bids, with Sangamo’s assets remaining subject to a court-supervised auction.
• Allotera Therapeutics (formerly Wugen) has raised $35 million to support the pivotal T-RRex trial of Sofi-cel in relapsed or refractory T-cell leukaemia and lymphoblastic lymphoma. The off-the-shelf, donor-derived CAR-T therapy uses CRISPR-Cas9 to delete CD7 and TRAC, aiming to prevent CAR-T-cell fratricide and reduce graft-versus-host disease risk.
• An arbitration tribunal ruled that Prime Medicine’s PM647 programme falls within the company’s licensed field under its agreement with Beam Therapeutics, finding no breach and awarding no damages. PM647 uses lipid-nanoparticle-delivered prime editing to correct the common SERPINA1 Pi*Z mutation underlying alpha-1 antitrypsin deficiency. Regulatory filing is planned for late 2026, following encouraging results in humanised mice.
• MaxCyte granted Genentech access to its ExPERT GTx electroporation platform and related technologies under a multi-program licensing partnership supporting ex vivo cell-therapy research, development and manufacturing. The agreement expands Genentech’s access to cell-engineering and gene-editing assessment capabilities, although the companies disclosed neither the therapeutic programmes involved nor the financial terms.

Delivery

• CRISPR-Cas prime-editing cargo was systematically optimised for lipid-nanoparticle delivery, achieving an average 49% editing in mouse liver after one dose. In a phenylketonuria model, correction of PAH R408W reduced serum phenylalanine to levels predicted to be therapeutic. The system supported repeat dosing, showed fewer off-target edits than DNA delivery and caused only transient liver-enzyme elevation.
• Researchers at Ghent University have engineered virus-like particles decorated with anti-CD4 nanobodies to deliver CRISPR-Cas machinery selectively into HIV's primary target cells. The resulting CD4-directed nanoblades disrupted the viral genome in infected T cells and reduced plasma viraemia in humanised mice, though clearing the virus from tissue reservoirs remained out of reach. Also, read our take on the story.

Screening

• Perturb-seq – single-cell CRISPR screening – within a 3D epidermal organoid model was shown to better mimic physiological skin differentiation than standard 2D cultures, capturing features like desmosome formation and barrier function. Perturbations significantly shifted diverse keratinocyte differentiation programs, notably revealing that non-canonical NF-κB signalling plays a bidirectional role in late-stage differentiation.
• A genome-wide CRISPR-Cas9 knockout screen in human melanoma cells identified lipid metabolism and inflammatory signalling as major determinants of ganoderic acid DM responses. Disrupting cholesterol-biosynthesis regulators conferred resistance, whereas loss of ubiquitin-mediated proteolysis and Hippo-pathway genes increased sensitivity. The findings suggest that delayed inflammatory responses and altered lipid regulation contribute to the compound’s cytotoxicity.
• A new CRISPR knockout- and activation-linked assay (CRISPR-KOALA) combined knockout and activation screens in immunocompetent mouse models to identify drivers within recurrent chromosome-arm alterations in basal-like breast cancer. Screening 3,752 genes revealed 90 candidate drivers spanning diverse signalling pathways, many previously uncharacterised. PLGRKT emerged as an oncogene associated with mitochondrial stress resistance, showing how broad aneuploidies can promote cancer by selecting specific dosage-sensitive genes.
• CRISPR-Cas interference profiling of 11,692 genes across more than 2.5 million human induced pluripotent stem cells generated a genome-scale atlas linking perturbations to transcriptional phenotypes. The resource recapitulated functional protein complexes and enabled validation of ZBTB41 and RNF7 as regulators of metabolism and pluripotency, respectively, while identifying DBR1 as a potent modulator of A-to-I RNA editing.

Detection

• CRISPR-Cas12a trans-cleavage was integrated with dual-antibody recognition and multistage nucleic-acid amplification to detect MRSA across 10–10⁶ CFU/mL. The assay distinguished common interfering pathogens and correlated strongly with culture-based measurements in spiked serum samples. These laboratory findings support further evaluation of the platform for rapid postoperative infection monitoring in clinical specimens.
• CRISPR-Cas12a was integrated into a pump-free microfluidic chip for simultaneous fluorescence detection of four foodborne bacterial pathogens, with replicate channels and internal controls. Detection limits were 10² CFU/mL for Listeria monocytogenes and 10³ CFU/mL for Staphylococcus aureus, Escherichia coli O157:H7 and Cronobacter sakazakii, supporting further development for rapid on-site food-safety testing.
• CRISPR-Cas12a was combined with catalytic hairpin assembly, hybridisation chain reaction and gold-nanoparticle probes to create an amplified biosensor for microRNA detection. The platform achieved a 37-fM detection limit, distinguished single-nucleotide mismatches and performed reliably in serum and tumour-cell lysates, supporting further development for sensitive biomarker analysis and potential early cancer screening.
• CRISPR-Cas12a was coupled with multiplex RT-RPA and lateral-flow readout to detect hepatitis A virus and two human norovirus genogroups within 50 minutes. Detection limits ranged from 20 to 2,000 copies per reaction, with no cross-reactivity against other foodborne viruses. Tests using RNA-spiked shellfish extracts provided preliminary laboratory evidence for portable, simultaneous pathogen detection.

Perspectives

• A Nature Medicine feature reports that several ex vivo CRISPR-Cas therapies consistently reactivated fetal haemoglobin and reduced transfusions or severe pain crises in early-stage trials for sickle-cell disease and β-thalassaemia. The convergence of nuclease and base-editing results suggests increasing platform reliability, although toxic conditioning, high costs and limited accessibility remain major barriers to broader treatment.
• A perspective article in Nature Reviews Bioengineering outlines how CRISPR-based RNA silencing could be integrated into ex vivo machine perfusion of donor organs before transplantation. Drawing on early proof-of-concept work, the authors argue that transient gene silencing could improve organ quality and reduce pathogen burden without directly editing patients.
• A Technology Feature in Nature explores how CRISPR-Cas-based epigenetic editors can durably activate or silence genes without changing DNA sequences, highlighting emerging research, therapeutic and agricultural applications. Although early clinical studies and animal experiments show promise, limited understanding of epigenetic rules, unpredictable outcomes and delivery challenges remain major obstacles to precise, safe and reproducible editing.

Reviews

• CRISPR in clinical oncology: translational advances from molecular diagnostics to therapeutics. This review examines the expanding role of CRISPR-Cas technologies in cancer research, diagnosis and treatment, assessing their early clinical translation alongside the delivery, safety and regulatory barriers that will determine their clinical utility.
• The future of pediatric gene therapy: CRISPR-Cas9, AI, and personalised medicine. This review examines how CRISPR-Cas9, AI and personalised medicine could advance paediatric gene therapy, highlighting mutation correction, AI-assisted edit design, and viral and non-viral delivery.
• Analytical dissection of CRISPR-Cas9-mediated gene editing fidelity: integrating next-generation bioanalytical platforms for precision immunotherapeutics and rare disease correction. This review provides a balanced foundation for advancing genome editing toward safer and more reliable therapeutic applications.
• Gene editing of hematopoietic stem cells: applications and advances. This review examines the development of CRISPR-Cas9 and related tools for ex vivo editing of autologous haematopoietic stem cells as an alternative to allogeneic transplantation for inherited blood disorders, tracing progress from mechanistic studies to clinical trials.
• CRISPR/cas-based biosensors for point-of-care testing: a comprehensive review of signal readout strategies. This review aims to provide actionable insights for researchers developing next‑generation CRISPR diagnostics and to accelerate the transition from laboratory prototypes to deployable POCT devices.
• CRISPR-Cas9-based therapies for Huntington’s disease and Friedreich’s ataxia: mechanisms, advances, and future perspectives. This review examines the development and translational prospects of CRISPR-Cas therapies targeting the distinct repeat-expansion mechanisms underlying Huntington’s disease and Friedreich’s ataxia, highlighting encouraging preclinical findings alongside persistent delivery, safety, ethical and regulatory barriers.
• Epigenome editing: a dimension of genome editing beyond DNA sequence. This review provides a comprehensive and integrated perspective on epigenome editing by linking molecular mechanisms, advanced editing tools, and practical applications in plant systems, thereby offering a foundation for future research and the development of climate-resilient and sustainable crop improvement strategies.
• Decoding and Overcoming Temozolomide Resistance Through CRISPR/Cas Technologies. This review examines how CRISPR-Cas technologies are being used to investigate and potentially overcome temozolomide resistance in glioblastoma, while supporting the development of more informative disease models and rational therapeutic strategies.