CMN Weekly (6 March 2026) - Your Weekly CRISPR Medicine News

Top picks

• Researchers reported interim results from a phase 1 clinical trial of YOLT-101, an investigational in vivo adenine base-editing gene therapy delivered via GalNAc-modified lipid nanoparticles to inactivate PCSK9 in adults with heterozygous familial hypercholesterolaemia. Six participants received a single intravenous dose across three escalating cohorts (0.2, 0.4, or 0.6 mg kg⁻¹), with no grade ≥3 adverse events observed. At 24 weeks, the highest dose cohort achieved sustained reductions of 74.4% in circulating PCSK9 and 52.3% in LDL-C.
• CRISPR-Cas base editing combined with targeted sequencing was used to perform dense mutagenesis of a CD19 enhancer, enabling nucleotide-resolution mapping of regulatory function. The approach identified key MYB, PAX5, and EBF1 transcription factor motifs controlling CD19 expression. Editing MYB and PAX5 sites reduced CD19 levels and conferred resistance to CD19 CAR-T therapy, demonstrating how non-coding variants can drive immunotherapy escape.

Research

• Endogenous RNA/DNA hybrids (R-loops) were found to influence homology-directed repair (HDR) efficiency during CRISPR-Cas9-mediated editing, with R-loop-enriched sites showing reduced HDR in proliferating hepatocyte-derived cells – though not in quiescent hepatocytes in vivo. Reducing R-loop levels via RNaseH1 overexpression or pharmacological G1 arrest increased HDR at these sites, suggesting that endogenous R-loop abundance is a relevant parameter for designing genome-editing strategies.
• Phosphorothioate-modified activators were found to modulate Cas enzyme conformation via hydrophobic anchoring, enabling precise decoupling of Cas activation from trans-cleavage resistance. Exploiting this mechanism, a Scattered PS Nucleic Acid-driven Cas Autocatalytic system (SACA) was engineered to achieve enzyme-free exponential amplification – enhancing CRISPR-Cas12a and Cas13a sensitivity by 50,000-fold and 10,000-fold, respectively – and facilitated precise in situ imaging of HPV16 and HPV18 mRNA in cervical cancer cells.
• A first-in-human, randomised, placebo-controlled dose-escalation trial evaluated SNIPR001 – SNIPR's cocktail of four CRISPR–Cas-armed bacteriophages targeting intestinal E. coli – in 36 healthy participants receiving twice-daily oral doses up to 1012 PFU for seven days. No grade 3-4 or serious adverse events were reported, gut microbiome composition was unaffected, and functional phages were confined to the gastrointestinal tract. At the highest dose, E. coli levels fell by 78% at day 14, though this did not reach statistical significance.
• Despite sequence specificity, guide RNAs in CRISPR-mediated gene activation (CRISPRa) systems were found to compete for dCas9 and activator proteins, breaking modularity and hindering multi-gene control – with increasing gRNA levels capable of switching target gene activation to repression. A chemical reaction-network model capturing these biphasic dynamics was developed and validated as a predictive tool for the systematic design and optimisation of multi-gRNA CRISPRa systems.
• A deep learning model was built to predict the effects of key parameters on Anopheles mosquito suppression and human malaria prevalence, overcoming the computational limitations of individual-based modelling for CRISPR gene drive simulations. Results indicate that reducing embryo and functional resistance whilst increasing drive conversion efficiency promotes suppression, and that the parameter space permitting malaria elimination was substantially broader than that for mosquito elimination – suggesting imperfect drives may still achieve their public health objective.
• The first dual-guide RNA system for CRISPR-Cas13, employing two cooperative RNAs – dcrRNA and dtracrRNA – improves mismatch discrimination and target specificity whilst preserving the effector's sensitive cis- and trans-cleavage activity. The platform accurately detected SARS-CoV-2 RNA, distinguished KRAS G12D and G12C mutations, and differentiated Leishmania sequences, with clinical validation confirming reliable performance across positive and negative samples.
• The conserved crRNA scaffold secondary structure was repurposed as a reversible conformational switch to regulate CRISPR-Cas12a activity, with short complementary DNA blockers of tunable length shifting LbCas12a into an inactive state that could be restored on demand via strand displacement. This programmable framework improved single-nucleotide variant discrimination, enabled compatibility with one-pot isothermal amplification, and was validated in the detection of Klebsiella pneumoniae and Mycobacterium tuberculosis.

Clinical and preclinical

• SNIPR reports positive phase 1 data for its experimental CRISPR-Cas-armed phage cocktail, SNIPR001. In healthy volunteers, seven days of dosing showed good tolerability, limited gastrointestinal tract confinement, and preservation of overall microbiome composition. A non-significant pharmacodynamic signal indicated up to 78% reduction of E. coli. A Phase 1b trial in stem-cell transplant patients is ongoing. not simply as a novel anti-infective, but as the clinical proof point for an entirely new category of precision antimicrobials. The original phase 1 data were published in The Lancet Microbe.
• YolTech Therapeutics announced phase 1 clinical data for YOLT-101, an in vivo base editing medicine that disrupts PCSK9 in adults with heterozygous familial hypercholesterolaemia. A single infusion produced dose-dependent and durable lipid-lowering effects, lowering PCSK9 by up to 74% and LDL-C by 52.3% at 24 weeks. Treatment was generally well-tolerated with no serious adverse events. The original phase 1 data were published in Nature Medicine.
• Intellia Therapeutics reported long-term data on CRISPR-Cas9 therapy lonvoguran ziclumeran (NTLA-2002), which inactivates the KLKB1 gene to treat hereditary angioedema. In pooled Phase 1/2 results (n=32), a single 50 mg dose produced durable plasma kallikrein suppression and a 96% reduction in attack rates, with most patients remaining attack-free for up to three years, supporting ongoing Phase 3 evaluation.
• The US FDA has lifted a clinical hold on Phase 3 trials of Intellia Therapeutics' CRISPR-Cas9 therapy nexiguran ziclumeran (nex-z), which inactivates the TTR gene in transthyretin amyloidosis. The hold followed a case of severe liver enzyme elevation meeting protocol pausing criteria. Updated monitoring and eligibility measures have been implemented, allowing enrolment to resume in ongoing trials evaluating single-dose in vivo gene editing.

Industry

• Precision BioSciences announced a milestone in the development of azercabtagene zapreleucel (azer-cel), an ARCUS gene-edited cell therapy advancing in a Phase 1 trial for progressive multiple sclerosis. Trial progress triggered a $7.5 million payment from TG Therapeutics under their licensing agreement. Azer-cel is being developed for autoimmune indications, with Precision eligible for further development, regulatory, and commercial milestone payments.

Q4 and full-year 2025 financial results

• Prime Medicine reports full-year net loss of $201 million and a cash deposit of $191 million. Q4 net results were not reported.
• Fate Therapeutics reports full-year net loss of $136 million and a cash deposit of $205 million. Q4 net loss was $32 million.
• Caribou Biosciences reports full-year net loss of $148 million and a cash deposit of $143 million. Q4 net loss was $27 million.

Screening

• Base editing was applied to mutate 7,293 SLiM-containing regions across 80,473 variants in HAP1 cells, generating a proteome-wide SLiM dependency map that identified 450 reported and 264 predicted short linear motifs required for normal cell proliferation. Beyond cataloguing known classes, the screen uncovered numerous uncharacterised essential SLiMs – including binding partners providing mechanistic insight into a disease-associated ANKRD17 mutation – establishing a substantial resource for understanding SLiM function in cellular homeostasis.
• A genome-wide CRISPR-Cas9 knockout screen in Ishikawa endometrial carcinoma cells exposed to medroxyprogesterone identified 5 genes promoting progestin resistance and 20 genes inhibiting it, with enrichment analysis implicating DNA and RNA synthesis and metabolic pathways. Functional validation confirmed key candidates, including resistance-promoting NNMT and sensitivity-associated SOX17, the latter two further validated in xenograft models – establishing a reliable gene network underlying progestin resistance in endometrial carcinoma.

Detection

• A customisable one-pot CRISPR diagnostic system was developed by decoupling the dual functions of crRNA design, allowing target programming and cis-cleavage activity to be controlled independently. Introducing a crRNA-complementary RNA oligonucleotide selectively modulates the reaction energy barrier, enabling cis-cleavage activity to match isothermal amplification conditions regardless of the programmed target sequence. Validation across 120 patient-derived samples demonstrated sensitivity and specificity comparable to quantitative PCR.
• Researchers in Peru have developed C12a, a CRISPR-Cas12a-based detection toolbox capable of identifying key antibiotic resistance genes with attomolar sensitivity in settings from fully equipped laboratories to portable field units. The system showed full concordance with conventional antimicrobial susceptibility testing and whole-genome sequencing when applied to clinical E. coli isolates.
• Four CRISPR-Cas13d crRNAs were adapted into a SHERLOCK diagnostic assay capable of detecting single copies of SARS-CoV-2 RNA without cross-reactivity to other respiratory viruses. The crRNAs targeted a conserved 26-nucleotide sequence in coronavirus nsp12 and were selected for their potent antiviral activity across all seven human coronaviruses in vitro. Bioinformatic analysis further revealed high conservation of the target sequence across animal coronaviruses, suggesting that this dual-function platform could accelerate the development of therapeutics and diagnostics in future coronavirus pandemics.

News from CRISPR Medicine News

• In a Clinical Trial Update on Tuesday, we reported on new phase 1 data for SNIPR's CRISPR-Cas-armed phage cocktail, SNIPR001. We interviewed Eric van der Helm, VP Business Development at the Copenhagen-based biotech, to learn what the first-in-human means – not only for infection prevention in high-risk cancer patients, but for the broader emergence of precision antibiotics as a platform category. The original phase 1 data were published on the same day in The Lancet Microbe.
• On Tuesday, we also published an article by the pan-European, non-profit initiative European Genomic Medicine Consortium (EGMEDC). The article describes the case of a young boy, August, and his parents’ attempts to access experimental genomic medicine for a progressively debilitating condition, which illustrates how fragmented regulation, funding barriers, and slow clinical translation continue to delay care, often with irreversible consequences.