CMN Weekly (13 March 2026) - Your Weekly CRISPR Medicine News

Top picks

• CRISPRa-mediated transcriptional activation of PPARGC1A increased cellular mitochondria in human cardiomyocytes by upregulating programmes driving mitochondrial biogenesis and cellular bioenergetics, boosting ATP production and reserve capacity. In an acute myocardial infarction mouse model, PPARGC1A activation recovered cardiac ejection fraction. Application to adult human hearts – both healthy and failing – elevated PPARGC1A protein, mitochondrial content, and mitochondrial function.
• Deep mutational scanning of a TnpB ribonucleoprotein – a small RNA-guided endonuclease evolutionarily related to CRISPR-Cas12 – identified activating mutations in both protein and RNA, enabling construction of two enhanced variants with improved editing activity in human cells and multiple plant species. Engineered variants achieved up to 55% indel frequencies in Nicotiana benthamiana – a 50-fold increase over wild type – outperforming other compact editors. These findings reveal latent endonuclease activity accessible through mutation and highlight TnpB as a promising compact genome-editing platform for human and agricultural applications.

Research

• A novel genome-editing platform addresses one of the field's most constant challenges – how to insert kilobase-scale DNA into living cells without triggering immune responses that have confined recombinase-based gene therapies largely to the laboratory. The work, published today in Nature, introduces INSTALL, a system that replaces toxic double-stranded DNA donors with engineered circular single-stranded molecules, thereby substantially reducing innate immune activation. Also, read our take on the study.
• Using the CRISPR-Cas9-based DOMINO strategy, researchers established a γC4 mutant mouse model recapitulating the human neurodevelopmental syndrome – including seizures, reduced brain size, and increased embryonic neuronal apoptosis – and generated mice retaining full-length γC4 whilst truncating all other 21 Pcdh-γ isoforms. These animals were viable and fertile, unlike Pcdh-γ cluster-deficient mice. The findings confirm that γC4 is a principal functional isoform required for neuronal survival and dendritic patterning within the Pcdh-γ cluster.
• Researchers have engineered inhalable lipid nanoparticles that selectively deliver CRISPR-Cas9 machinery to alveolar macrophages, allowing targeted knockout of Sting1 in the lung. In a murine model of pulmonary fibrosis, the approach lowered collagen deposition, remodelled the fibrotic immune microenvironment, and improved survival without evidence of general toxicity.
• Researchers developed INSCRIBE – a CRISPR editing recorder that mutates genomic targets at rates proportional to signalling activity, with edits read out via ratiometric dual-channel fluorescence imaging – to quantify WNT and BMP signal intensity and duration in single human cells. In BMP signalling, INSCRIBE uncovered a persistent cellular memory in which progeny of high-responding cells remained sensitised to BMP stimulation for up to three weeks. The platform offers a scalable approach for genetic recording of signalling activity during development and disease.
• Researchers developed ATTACH – a kill switch combining a CRISPR-repressed toxin–antitoxin (CreTA) module with type I-F CRISPR-Cas effector proteins – to create microbes addicted to Cas machinery, improving genetic stability and stringency of suicidal programmes. A single-plasmid, antibiotic-independent ATTACH device achieved robust microbial containment in the murine gut with negligible effects on growth or lycopene production. These results demonstrate that CreTA is an effective stabiliser of CRISPR-Cas-based kill switches, enabling safer deployment of engineered microbes.
• Structural and mechanistic analysis of an engineered AsCas12a variant revealed that reduced protein–DNA interactions facilitate more rapid R-loop formation – enhancing cleavage activity whilst retaining the high intrinsic specificity that distinguishes Cas12a from Cas9. These findings illuminate the mechanistic basis for the variant's superior potency without compromising specificity. The results offer broader strategies for designing genome-editing nucleases with an optimal balance between efficiency and off-target discrimination.
• Researchers engineered a CRISPR-Cas12a nanosystem gated by a subtly balanced dsDNA substrate that maintains Cas12a in an inert state until UDG-mediated uracil excision triggers crRNA invasion and amplified trans-cleavage – directly converting a single enzymatic event into a measurable signal without sequential processing steps. The system achieved a 1,840-fold discrimination ratio and detection limit of 5 × 10⁻⁷ U/mL, whilst a nuclear-localised variant enabled spatiotemporal imaging of endogenous UDG activity across cell cycle phases in living cells. This work establishes a generalised dsDNA-gating paradigm for precise molecular sensing using CRISPR-Cas12a.

Clinical and preclinical

• Precision BioSciences reported progress with its CRISPR-Cas–based ARCUS gene editing therapy PBGENE-DMD, designed to excise dystrophin exons 45–55 and restore near full-length dystrophin expression. The programme received FDA Fast Track designation ahead of the Phase 1/2 FUNCTION-DMD trial. New preclinical data presented at the MDA conference showed reduced levels of muscle-damage biomarkers, increased dystrophin expression, and sustained functional improvements in a humanised Duchenne muscular dystrophy mouse model.
• Precision BioSciences also reported that its CRISPR-Cas–based ARCUS platform underpinning the PBGENE-HBV programme received two USPTO Notices of Allowance covering engineered meganucleases targeting the hepatitis B virus genome and a shortened polypeptide linker design. The patents, expected to run until 2044, provide composition-of-matter protection for the ARCUS nuclease used to disrupt viral cccDNA, the persistent template driving chronic hepatitis B infection.

Industry

• Korro Bio reported an $85 million PIPE financing to advance therapies derived from its RNA editing platform OPERA. The funding, led by Venrock Healthcare Capital Partners with participation from multiple investors, is expected to extend the company’s cash runway into the second half of 2028 and support clinical development of programmes including KRRO-121 and a GalNAc-conjugated alpha-1 antitrypsin deficiency candidate.

Q4 and full-year 2025 financial results

• Editas Medicine reports full-year net loss of $160 million and a cash deposit of $147 million. Q4 net loss was $6 million.

Screening

• Using a tetracycline-inducible CRISPR-Cas9 system enabling time-controllable mutagenesis, researchers performed FACS-based screens to map regulators of four major immunosuppressive surface molecules – PD-L1, CD47, CD276, and HLA-E – identifying the membrane-trafficking factor DNAJC13 as a prominent regulator of PD-L1 and CD276. Suppression of DNAJC13 strongly sensitised human cancer cells to T-cell attack in vitro and prolonged survival in a murine pancreatic tumour model. These findings establish regulatory maps of key immune-modulatory surface molecules and highlight DNAJC13 as a potential target for coordinated inhibition of multiple immunosuppressive signals.
• An in vivo genome-wide CRISPR-Cas9 screen identified GRIA2 – an AMPA-type glutamate receptor subunit – as a key driver of gastric cancer peritoneal metastasis, with cancer-associated fibroblasts supplying glutamate via a paracrine axis that activates GRIA2 and stabilises β-catenin through GSK-3β inhibition. Pharmacological blockade of AMPA receptors with NBQX and Selurampanel suppressed peritoneal metastasis in cell line and patient-derived organoid xenograft models. Clinically, high GRIA2 expression in peritoneal metastases correlated with Wnt pathway activation and poor prognosis.
• A genome-wide CRISPR activation screen – using sequential rounds of viral infection to enhance sensitivity – identified single genes sufficient for Ebola and rabies virus entry into normally non-permissive cells. This gain-of-function approach complements conventional loss-of-function screens by circumventing genetic redundancy. The strategy offers a broadly generalisable platform for accelerating the discovery of viral entry factors.

Detection

• Researchers developed CASTSA – a one-pot CRISPR-Cas12a diagnostic platform that couples sequence-specific cleavage with qPCR amplification, eliminating the need for a separate pre-amplification step and reducing cross-contamination risk. CASTSA, validated against clinical samples, distinguished HPV 16 from closely related subtypes, with a detection limit of 18 copies per reaction, using a laser-induced graphene electrochemical sensor. The platform offers a specific, sensitive, and streamlined alternative to standard nucleic acid diagnostic workflows.

Reviews

• CRISPR in Medicine: A Systematic Review of Clinical Trials and Therapeutic Applications. This review evaluates clinical trial evidence for CRISPR-Cas9 therapies across a range of diseases, assessing their safety, efficacy, and clinical potential while highlighting remaining challenges, including delivery optimisation, off-target effects, immunogenicity, and ethical considerations.
• Nano-Enabled CRISPR-Cas Gene Editing for Cancer Therapeutics. This review summarises current progress in nano-integrated CRISPR-Cas systems for cancer therapeutics, highlighting recent advancements in stimuli-responsive nanoplatforms for precise genome editing and their prospects for clinical application.

News from CRISPR Medicine News

• On Wednesday, we published an interview with Benjamin Kleinstiver and Connor Tou, PhD, at Harvard Medical School about INSTALL and its potential to make non-viral gene insertion work in vivo. INSTALL replaces toxic double-strand DNA donors, thereby substantially reducing innate immune activation. The original study was published in The Lancet Microbe.