CMN Weekly (20 June 2025) - Your Weekly CRISPR Medicine News

Top picks

• In an article published in Nucleic Acids Research, researchers in Denmark report the comprehensive mapping of 2.8 million RNA editing sites across 38 brain regions in the crab-eating macaque, a close human relative. The study, led by Professor Yonglun Luo (Aarhus University, Denmark) in collaboration with Associate Professor Jacob B. Hansen from the University of Copenhagen, found that brain regions with higher neuronal density exhibit increased RNA-editing activity, with edits concentrated in areas associated with cognition, emotion and motor function. The team identified almost 500,000 RNA editing sites shared between macaques and humans, especially in genes linked to memory and learning processes. These findings suggest that RNA editing plays a critical role in cognitive evolution and may contribute to the pathogenesis of neurological disorders such as autism and Alzheimer's disease.

Research

• In an article published this week in PNAS Nexus, researchers at Stanford University and University of Hawaiʻi at Mānoa report a novel gene-editing approach for glaucoma, which is a leading cause of irreversible blindness. The overall success of current treatments is hampered by poor compliance with eye drops, cardiovascular and kidney complications, and invasive surgeries with inconsistent durability. The study used CRISPR-Cas13d RNA editing to knock down two genes (AQP1 and CA2) involved in aqueous humour production, significantly reducing intraocular pressure in wild-type mice and in a corticosteroid-induced glaucoma mouse model. The treatment also reduced fluid production without affecting drainage and promoted retinal ganglion cell survival, offering potential advantages by eliminating daily medications and allowing flexible treatment adjustments.
• Researchers in China investigated the role of connexin43 (Cx43), which is extensively expressed in retinal macroglia, in glaucoma neurodegeneration. Using a high-fidelity CRISPR-Cas13X system to selectively knock down Cx43 expression in macroglia, they found that this protein promotes disease progression through ATP release that activates microglia and inflammation. Cx43 knockdown demonstrated significant neuroprotection in a mouse glaucoma model, promoting retinal ganglion cell survival, preserving optic nerve integrity, and improving visual function. This RNA-editing approach represents a potential therapeutic strategy for glaucoma and other neurodegenerative diseases. Their findings were published yesterday in Advanced Science.
• To address the difficulties in installing medium to large sized genomic modifications in therapeutically-relevant cells, researchers at various institutes in the United States developed a new method known as prime assembly. This approach permits DNA sequence assembly and integration in human cells by leveraging CRISPR-targeted dual flap synthesis and allows for RNA-programmable site-specific integration of single- or double-stranded DNA fragments. In contrast to homology-directed repair, prime assembly was similarly active in dividing and non-dividing cells. The team applied prime assembly to perform targeted exon recoding, transgene integration, and megabase-scale rearrangements, including at therapeutically-relevant loci in primary human cells. Their findings were shared in a manuscript on the pre-print server bioXriv.
• Researchers in China have developed an inhalable gene-editable nanoplatform (FePtR@HA) that combines CRISPR-Cas9 gene editing with a FePt diatomic catalyst to treat idiopathic pulmonary fibrosis (IPF). The rationale behind the approach is that the FePt catalyst efficiently clears reactive oxygen species while the CRISPR system knocks down the pro-aging gene KAT7 in alveolar type 2 cells, reversing cellular senescence. The team demonstrated antifibrotic efficacy in lung-on-a-chip models and IPF mouse studies, where the treatment reprogrammed the fibrotic microenvironment and alleviated fibrosis, presenting a promising therapeutic approach for IPF. Their findings were published this week in ACS Nano.
• In an article published in Cell & Bioscience, researchers in the United States and Taiwan report the development of a mouse model of human papillomavirus 16 (HPV16)+ head and neck cancer by modifying the CRISPR-SONIC system for precise integration of HPV oncogenes. The team demonstrated that CRISPR-SONIC-mediated knock-in of KrasG12D, HPV16 E6 and E7 could induce spontaneous buccal tumours under immunosuppression, with DNA vaccination reducing tumour growth through HPV16 E7-specific immune responses. Co-delivery of oncogenes AKT and c-Myc produced tumours that recapitulated the characteristic morphology of HPV+ head and neck cancer, offering a robust platform for evaluating new therapies and exploring HPV-related carcinogenesis.
• Researchers in the United States, Portugal, Netherlands and Switzerland have developed E-NoMi (engineered CD63 with mCherry and external FLAG tag), a system for enriching extracellular vesicles with desired therapeutic cargo. The method uses engineered CD63 transmembrane protein with mCherry inside the EV membrane and a FLAG tag outside, allowing cargo proteins such as EGFP, Cre recombinase and CRISPR-Cas nuclease to be loaded via high-affinity nanobody fusion during biogenesis. The team found that FLAG-tag-based immunocapture enables selection of cargo-loaded EVs, while incorporation of VSV-G fusogenic protein creates EVV vectors that are ten times more effective at cargo delivery than standard EVs. Functional delivery was validated in two in vivo mouse brain models. The findings were published in Journal of Extracellular Vesicles.
• In an article published yesterday in Clinical Epigenetics, researchers in the Netherlands and Italy report a dual-targeted cancer therapy approach that combines epigenetic editing with traditional drugs to enhance anti-cancer effects while reducing toxicity. Using CRISPRoff technology to silence KDM4A gene expression, the team demonstrated effective growth inhibition in colon, breast, and liver cancer cell lines. The researchers also discovered that conventional KDM4-inhibiting drugs paradoxically increase target gene expression, potentially promoting resistance. Their dual approach prevents this drug-induced upregulation while simultaneously targeting gene expression and protein activity, showing enhanced cancer cell growth inhibition compared to either treatment alone.
• A team of researchers in Japan, Germany, and the United Arab Emirates has developed a novel delivery system to target mitochondrial DNA mutations using CRISPR-Cas9 gene editing. They created RNP-MITO-Porter, a specialised lipid nanoparticle that delivers Cas9 ribonucleoproteins directly to mitochondria through membrane fusion, overcoming mitochondrial membrane barriers. The team demonstrated sequence-specific DNA breaks in isolated mitochondria and HeLa cells, successfully validating the system in cells carrying a disease-causing point mutation in the mitochondrial Atp8 gene. This system represents an advance toward clinical applications of mitochondrion-targeted gene therapy for treating mitochondrial diseases. Their findings were published yesterday in Scientific Reports.

Industry and clinical

• Eli Lilly and Verve Therapeutics announced earlier this week that Lilly will acquire Verve for up to $1.3 billion to develop single-dose base-editing treatments for people with high cardiovascular risk. The transaction is expected to close in Q3 of 2025, subject to customary closing conditions. See the official press release for further details.
• Scope Biosciences, a deep tech spin-off from Wageningen University & Research, announced this week that it has secured follow-on investment from SHIFT Invest and Oost NL to scale up its CRISPR diagnostics platform. The funding brings Scope's total seed-stage funding to €6 million. The company's scopeDx® platform delivers ultra-precise, single-nucleotide detection in a portable, field-ready format for agricultural crop disease detection and healthcare applications in areas lacking centralised laboratories. See the press release for further details.
• Intellia Therapeutics has reported positive three-year follow-data from the ongoing Phase 1/2 trial of lonvo-z (formerly known as NTLA-2002) in patients with hereditary angioedema. The data show that a single dose of the in vivo CRISPR-based therapeutic candidate eliminated severe inflammatory attacks in all patients with a favourable safety profile. A Phase 3 trial is ongoing. See the press release for further details.

Reviews

• Current perspectives on gene therapy and its involvement in curing genetic disorders. This review highlights the impact of genomics, including gene-editing technology, on public health and its potential to reshape healthcare through innovative treatment strategies for rare genetic diseases.
• Progress and Criteria in Public Health Applications of Gene Therapy and Gene Editing: Beyond the White Paper. This review examines the pace of public health-related gene therapy and gene-editing development since the publication of a key British white paper in 2003. Using a case-based approach across three areas that included rare single-gene disorders, common conditions such as sickle cell disease and genetic engineering of disease-transmitting mosquitoes, the authors found that while most trials have reached Phase 3, cost considerations will limit Medicaid coverage for many therapies. They argue that while select gene therapies could justify public insurance support by meeting effectiveness and equity goals, only limited protocols may advance to public financing, requiring further criteria development to ensure equitable population benefits.
• Research Progress on Signal Conversion Based on Aptamer Combined CRISPR/Cas System in Biosensors. This article provides a brief overview of the mechanisms of action of four Cas proteins, the generation of aptamers, and their combined applications. The authors also focus on the research progress of biosensors based on aptamer-based signal conversion combined with the CRISPR-Cas system.
• Being a better version of yourself: genetically engineered probiotic bacteria as host defense enhancers in the control of intestinal pathogens. This review examines how CRISPR-Cas systems and complementary technologies have enabled precise modification of probiotic strains to enhance their therapeutic potential against intestinal pathogens. The enhanced probiotics demonstrate improved functionality through increased adhesion, targeted antimicrobial activity, and enhanced immunomodulation. The available data shows that genetically-modified probiotics can prevent and treat gastrointestinal infections through competitive exclusion, bacteriocin production, and immune modulation, though challenges remain in ensuring genetic stability and preventing horizontal gene transfer.
• CRISPR for Cystic Fibrosis: advances and insights from a systematic review. This systematic review analysed twenty-seven studies applying CRISPR-based gene editing to correct cystic fibrosis (CF)-causing mutations in the CFTR gene. The F508del and W1282X mutations were most extensively studied, with more than fifteen mutations targeted overall using homology-directed repair, base editing, and increasingly, prime-editing approaches. Some studies addressed multiple mutations or proposed strategies targeting multiple variants with a single approach, while others focused on restoring CFTR function without directly correcting mutations. The review revealed technical difficulties in editing certain CFTR regions and emphasised the need for standardised reporting and further in vivo studies.

Detection

• Researchers in the United States and France report this week in Analytical Chemistry that the background signal and limits of detection of most CRISPR-based detection assays are likely limited by the degradation of reporter molecules, and that this degradation is dynamic and not associated with enzymatic activity. They present theory and experiments to design and calibrate CRISPR assays and introduce a new kinetic framework to account for the degradation of reporter molecules and derive a fundamental limit of detection for CRISPR-based assays. Their data shows that Michaelis-Menten kinetics alone are insufficient to describe reporter cleavage rates, and they argue that their findings should help reduce the frequency and extent of errors currently routinely made in quantifying CRISPR kinetics and interpreting CRISPR diagnostic fluorescence signals.
• A team in China has developed THRUST (translesion synthesis-driven hierarchical regulation using a template-activator construct for Cas12a activity), an economical Cas12a regulation strategy that addresses the complexity and cost limitations of current crRNA-based systems. The strategy leverages a bifunctional template-activator construct that functions as both a transcriptional template for T7 RNA polymerase and an activator for Cas12a, achieving hierarchical regulation through strategic positioning of regulatory units. Through "Dim down" and "Light up" biosensing platforms and lateral flow testing, THRUST enriches the CRISPR/Cas12a regulatory toolbox for molecular diagnostics. The findings were published this week in Chemical Science.

News from CRISPR Medicine News

• On Monday, we highlighted a recent study from China, in which researchers developed a thermosensitive, polyamine-modified hydrogel that significantly improves the co-delivery of CRISPR-Cas9 gene editors and doxorubicin for the treatment of melanoma. This study addresses persistent challenges in CRISPR therapeutics, particularly off-target effects and poor in vivo delivery efficiency, by introducing a sustained-release, intratumoural delivery system tailored to enhance tumour accumulation and cellular uptake. Read our summary here.
• This week's clinical trial update included new long-term durability data from patients with hereditary angioedema (HAE) who received Intellia's experimental CRISPR therapy lonvoguran ziclumeran (lonvo-z) in an ongoing Phase 1/2 trial. The latest data covers three years of follow-up from the Phase 1 portion of the trial in patients who received a single dose of lonvo-z, showing complete freedom from inflammatory attacks after a single dose across all 10 patients in the study. Read our coverage here.