CMN Weekly (16 January 2026) - Your Weekly CRISPR Medicine News

Top picks

• A two-tiered CRISPR screening strategy using Cas12a, followed by domain-focused Cas9, interrogated all human coding genes for their impact on fetal globin regulation, identifying PTPA (a PP2A activator) as a key regulator whose loss elevates HBG1/2 expression whilst preserving erythroid differentiation through modulation of BCL11A. This comprehensive genome-wide screen represents the most extensive CRISPR dissection of fetal haemoglobin regulation to date, generating a valuable resource for haemoglobinopathy research.
• Using CRISPR-SpCas9, researchers precisely excised pathogenic GGC repeat expansions in the NOTCH2NLC gene, the cause of neuronal intranuclear inclusion disease (NIID), without affecting its near-identical paralogs. Validated in cell lines, patient-derived iPSCs, and transgenic mice, this targeted approach corrected NIID-linked neuropathology and behaviour. The study demonstrates a viable genome-editing strategy for repeat expansion disorders with minimal off-target risk.

Research

• Researchers have developed Adar-GPT, a framework that fine-tunes generative pre-trained transformer models to predict A-to-I RNA editing sites by ADAR enzymes using 201-nucleotide windows and liver tissue data at a clinically relevant 15% threshold. The approach outperformed established methods across precision, recall and specificity whilst remaining portable across model generations, providing immediate scoring to guide experimental validation and therapeutic RNA design.
• CRISPR-Cas has been used to delete SAMHD1 in human and mouse macrophages, revealing its role in suppressing NLRP3 inflammasome activation. SAMHD1 loss led to excess cytosolic dNTPs, fuelling mitochondrial DNA synthesis, oxidation, and release, which triggered inflammasome hyperactivation. Blocking mitochondrial dNTP import restored control, suggesting therapeutic potential for targeting this metabolic pathway in obesity-induced inflammation.
• Researchers at the University of Tokyo have developed a streamlined CRISPR-Cas9-based method that enables efficient replacement of entire mouse gene loci with their human counterparts, including all regulatory regions spanning over 200 kilobases. The approach, termed TECHNO, overcomes longstanding technical barriers to the creation of physiologically relevant humanised mouse models for biomedical research. Also, read our take on the study.
• Exome sequencing identified loss-of-function PGBD5 mutations causing intellectual disability, epilepsy and ataxia-dystonia in ten individuals from five families, with CRISPR-engineered Pgbd5-knockout and catalytic-mutant mice recapitulating these neurodevelopmental features. Mouse studies revealed that Pgbd5 mediates developmental DNA breaks and recurrent somatic genome rearrangements in postmitotic cortical neurons, whilst single-nucleus sequencing demonstrated disrupted gene expression in specific glutamatergic and GABAergic neuronal populations.
• CRISPR-Cas9 disruption of KLRC1 (encoding NKG2A) in anti-CD19 CAR NK cells enhanced their killing capacity against B-cell malignancies, particularly after repeated challenge. The edited cells showed significantly improved cytotoxicity against CD19-negative targets, including relapsed CD19-negative patient-derived xenograft cancer cells. Co-editing the death receptor FAS further increased CAR NK cell persistence both in vitro and in vivo.
• APOBEC3G base editor variants were engineered with optimised linkers, rational mutagenesis, and relaxed-PAM SpG and SpRY CRISPR-Cas9 effectors to enhance the precision of single-cytosine editing within CC motifs and broaden targeting scope. The improved editors precisely installed and corrected cystic fibrosis-causing mutations in HEK293T cells, then modulated CFTR mRNA levels, protein expression, and channel function in human bronchial epithelial cells.
• An optimised CRISPR-Cas9 system using safeguard single-guide RNAs with cytosine extensions enabled efficient editing of extrachromosomal DNA (ecDNA) whilst alleviating severe cytotoxicity and ecDNA copy number loss caused by conventional CRISPR-Cas9. The cytosine-length-dependent attenuation of Cas9 activity facilitated efficient knock-in into multiple ecDNA copies per cell, with computational simulations revealing how multiple cleavage events shape cell death and micronucleus formation.
• A new sensitive method detects large-scale chromosomal rearrangements caused by CRISPR-Cas9 genome editing in primary human cells. The approach reveals that palbociclib can prevent these unwanted genomic alterations, while rearranged cells disappear after long-term engraftment.
• CRISPR-Cas9 deletion of a single EGR1 binding motif within the CSF1R intronic FIRE enhancer abolished enhancer activity and reduced CSF1R expression by approximately 75% in HL-60 cells. The targeted deletion disrupted genome folding across the CSF1R super-enhancer, eliminating hundreds of chromosomal loops and downregulating neighbouring immune genes, including IRGM and TNIP1, that contact the locus during macrophage differentiation.
• Machine learning models trained on ENCODE data have predicted gene expression from histone post-translational modifications with correlations of approximately 0.70–0.79. Experimental validation using dCas9-p300 in HEK293T and K562 cells showed that models accurately ranked fold changes among genes but performed worse within individual genes, highlighting the need for comprehensive epigenome-editing datasets and improved causal models.

Clinical and preclinical

• The FDA has announced a more flexible approach to chemistry, manufacturing and control (CMC) requirements for cell and gene therapies to expedite development and better support Biologics Licence Application preparation. The Center for Biologics Evaluation and Research has applied regulatory flexibilities tailored to complex, often patient‑specific biologics while maintaining quality standards. Broader communication of these flexibilities aims to reduce barriers and foster innovation across the field.

Industry

• Synthego has expanded into molecular and clinical diagnostics, applying its CRISPR-Cas expertise to develop high-quality reagents for nucleic acid-based assays. Partnering with biotechrabbit, it offers ISO-certified components for disease detection and personalised medicine. This strategic shift supports rapid diagnostic development and global accessibility, while marking Synthego’s evolution post-Chapter 11 into a broader biotech platform with sustained growth ambitions.

Delivery

• Researchers have developed gold-polymer hybrid nanoparticles (CRISPR-AuNPs) for non-viral delivery of CRISPR ribonucleoproteins into primary CD34+ haematopoietic stem and progenitor cells, achieving efficient editing with Cas9, Cas12a and Cas12a-M29-1 systems without compromising viability. The nanoformulation can be assembled in under two hours for less than $70 per million cells treated, establishing a scalable, cost-effective gene-editing platform.

Screening

• Using customised CRISPR libraries and a split-toxin selection system, researchers screened human myoblasts to identify genes essential for muscle cell fusion. The screen revealed numerous hits clustering into 23 protein complexes, 41 of which are linked to muscle-related diseases. Single-cell CRISPR and RNA-seq showed these genes also regulate early myogenic differentiation, providing a scalable method to dissect cell-autonomous control of human muscle development.

Detection

• Raising the reaction temperature enables Cas12a to robustly use non-canonical PAMs for trans-cleavage while limiting cis-cleavage. Exploiting this, researchers developed POP-CRISPR, a one-pot, poikilothermal Cas12a diagnostic platform with superior sensitivity and specificity. Validated on HPV and Mycoplasma samples, including drug-resistant strains, POP-CRISPR enables accurate, on-site pathogen detection in under 20 minutes using a portable device.
• Researchers developed a Cas13a autocatalytic biosensing system assisted by RNA-nanocircles, exploiting the discovery that double-stranded RNA activates Cas13a trans-cleavage whilst being slowly cleaved itself. The approach achieved ultrasensitive detection of 1 attomolar synthetic RNA targets without preamplification within 15 minutes, with clinical validation demonstrated through monitoring miRNA-21 levels in plasma samples from colorectal cancer patients.
• A steric-regulation framework using rationally engineered extensions on split activators enabled predictable control of CRISPR-Cas12a trans-cleavage kinetics for molecular diagnostics. Integration with an entropy-driven DNA circuit suppressed premature activation and enabled precise kinetic matching, creating a one-pot detection system with 1.24 pM sensitivity for microRNA-21 and high fidelity.

Perspectives and comments

• In a guest post on CRISPR Medicine News, researchers from the Middle East reflect on a rare visit to a pharmaceutical R&D facility and what direct industry exposure reveals about drug discovery, CRISPR-enabled therapies and translational science. Drawing on this experience, the article argues for stronger and more systematic collaboration between pharma companies and academic researchers, particularly in the Middle East and Africa.

Reviews

• Monitoring biological effects of somatic cell genome editing. This review outlines emerging tools for evaluating CRISPR-based therapeutics, spanning DNA-level edits to whole-organism imaging, and highlights their role in bridging preclinical safety and efficacy assessments with clinical translation.
• Chronic In Vivo CRISPR-Cas Genome Editing: Challenges, Long-Term Safety, and Outlook. This review aims to define when sustained CRISPR-Cas activity is therapeutically justified, examining its efficacy, off-target risks, and safety across platforms, and proposes control strategies to separate durable editing from prolonged nuclease exposure.
• CRISPR-Cas9 technology: a breakthrough in cancer gene therapy. This review explores the application of CRISPR-Cas9 in cancer therapy, highlighting its role in modelling tumour biology, validating oncogenes, and advancing precision genome editing for malignancy research.
• Illuminating the genome: emerging approaches in CRISPR-Cas live-cell imaging. This review summarises recent advances in CRISPR live-cell imaging and highlights key design trade-offs and biological constraints.
• Targeted delivery of genome editors in vivo. This review discusses preclinical and clinical advances in delivering genome editors with both established and emerging delivery mechanisms.