CMN Weekly (30 May 2025) - Your Weekly CRISPR Medicine News

Top picks

• Researchers in the US, Canada and Australia have developed a base-editing approach to treat trinucleotide repeat disorders by introducing protective interruptions into disease-causing DNA sequences. The strategy successfully reduced repeat expansions in patient cells and mouse models of Huntington's disease and Friedreich's ataxia. Their findings were published this week in Nature Genetics.
• A team in Australia, US and the Netherlands have developed a lipid nanoparticle (LNP) formulation, referred to as LNP X, with unprecedented potency to deliver mRNA to hard-to transfect resting CD4+ T cells in the absence of cellular toxicity or activation. They report in Nature Communications that, by encapsulating an mRNA encoding the HIV Tat protein, which is an activator of HIV transcription, LNP X enhances HIV transcription in ex vivo CD4+ T cells isolated from HIV+ individuals. They further show that LNP X enables the delivery of CRISPR activation (CRISPRa) machinery to modulate viral and host gene transcription.

Research

• Scientists at Shape Therapeutics report this week that embedding gRNAs into a U7 small nuclear RNA (snRNA) framework greatly enhances RNA editing with endogenous ADAR, and that a 750-plex single-cell mutagenesis screen further improved the framework. They demonstrate that an optimised scaffold with a stronger synthetic U7 promoter enables 76% RNA editing in vitro from a single DNA construct per cell, and 75% editing in a Hurler syndrome mouse brain after one systemic AAV injection, surpassing circular gRNA approaches. The technology also improves published DMD exon-skipping designs 25-fold in differentiated myoblasts. Their findings were published in Nature Communications.
• In article published this week in Genome Biology, scientists at University of California Berkeley present CiBER-seq, a method for optimising CRISPR interference with barcoded expression reporter sequencing, that can dramatically improve the sensitivity and scope of genome-wide screens. The team systematically addressed technical factors that distort phenotypic measurements by normalising expression reporters against closely matched promoters. Using their improved CiBER-seq workflow, the researchers could accurately capture known components of well-studied RNA and protein quality control systems.
• Premature stop codons caused by COL7A1 mutations frequently lead to generalised recessive dystrophic epidermolysis bullosa (RDEB). Earlier research has shown that eliminating mutated COL7A1 exons and subsequently reframing the gene may preserve protein function, suggesting a promising therapeutic approach. However, studies of the long-term in vivo effects of mutant exon removal have mainly focused on a single small exon, exon 80. In a study published this week in Human Gene Therapy, researchers in Spain and Germany investigated whether CRISPR-mediated targeted exon removal through non-homologous end joining could be successfully applied to larger exons, specifically exons 73 and 105 of COL7A1. They found that RNP-mediated delivery of Cas9 and sgRNAs to primary cells from RDEB patients led to deletion of exons 73 and 105 and restored type VII collagen (C7) production. Furthermore, in vivo experiments using regenerated skin grafted onto immunocompromised mice showed that cells edited to remove exon 73 or 105 properly deposited C7 at the basement membrane zone, successfully restoring normal adhesion between the dermis and epidermis.
• In an article published yesterday in Nature Methods, researchers at various institutes in the US present ReLiC, a scalable RNA-linked CRISPR approach that measures how knockout of 2,092 human genes encoding RNA-associated proteins affects diverse RNA metabolic processes. When combined with polysome fractionation, ReLiC identifies key regulators of ribosome occupancy and reveals connections between translation and proteostasis. The method also captures differential regulation by SF3B complex subunits and identifies translational regulators upstream of mRNA decay, including a role for the ribosome collision sensor GCN1 during anti-leukaemic drug treatment.
• A team in China used a genome-wide CRISPR base-editing screen to identify functional lysine residues in host factors required for influenza A virus replication. They identified multiple host genes including GSTM4, FLNC, HMGB1, ZNF236, GRIP1, and PXN, with paxillin (encoded by PXN) emerging as an important host entry factor. Depletion of paxillin significantly reduces IAV infection in both cell cultures and mice. The study reveals that the δ isoform of paxillin, rather than the canonical β isoform, plays the key role, with lysine 68 of paxillin δ undergoing K6-linked ubiquitination to regulate viral replication via endosome-dependent viral entry. Their findings were published this week in Cell Reports.
• In an article published yesterday in Nature Communications, researchers in China report hpCasMINI, an engineered hypercompact CRISPR-Cas12f system with significantly increased gene-editing activity. The team enhanced the compact CasMINI variant by adding an α-helix structure to the N-terminus, resulting in up to 3-fold increased gene activation and 19.5-fold increased DNA cleavage activity while maintaining high specificity. The system successfully activated genes in adult mouse liver and demonstrated superior performance compared to SpCas9 and LbCas12a. Using the same strategy, they also engineered compact versions of hpOsCas12f1 and hpAsCas12f1 with increased activity.
• Researchers at Stanford University and Icahn School of Medicine at Mount Sinai (New York) report a CRISPR interference (CRISPRi) screen that revealed a global portfolio of long non-coding RNAs (lncRNAs) specifically expressed in keratinocyte sub-populations from cutaneous squamous cell carcinoma (cSCC) tissues. By performing pseudobulk analysis of single-cell sequencing data from normal and cSCC human skin tissues, the team determined 294 lncRNAs differentially expressed in tumour cSCC sub-populations. Integration of CRISPRi screens in vitro and in xenograft models identified several lncRNAs impacting cSCC cancer line growth in vitro and in vivo. Among these, they validated LINC00704 and LINC01116 as proliferation-regulating lncRNAs and as potential biomarkers, with LINC00704 showing significantly higher expression in human SCC tissues and reduced patient survival according to The Cancer Genome Atlas. Their findings were published in Journal of Investigative Dermatology.

Industry

• Beam Therapeutics announced yesterday that the US FDA has granted an orphan drug designation to BEAM-302, which is an in vivo liver-targeting LNP formulation of base-editing reagents designed to correct the PiZ mutation found in the majority of severe homozygous alpha-1 antitrypsin deficiency patients. See the official press release for further details. BEAM-302 is being tested in a Phase 1/2 clinical trial and clinical proof-of-concept data released in March 2025 demonstrate the first-ever clinical genetic correction of a disease-causing mutation through base-editing technology. You can read more about that in our recent clinical trial update here.
• According to articles published in BioPharma Dive, Bloomberg, Fierce Biotech and other online sources, Intellia Therapeutics' shares dropped by 25% early yesterday after the gene-editing company disclosed that one patient in the ongoing Phase 3 MAGNITUDE trial of nex-z had shown signs of liver stress. The data was disclosed in a filing with the Securities and Exchange Commission late on Wednesday, in which it states: 'There has been a single, recent, asymptomatic patient with grade 4 liver transaminase elevations based on laboratory tests, which appear to be resolving without hospitalization or medical intervention and have fallen to grade 3 ALT and grade 2 AST elevations. We continue to monitor these events as the MAGNITUDE study progresses.' Nex-z is designed to be a single-dose curative treatment for transthyretin amyloidosis by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-Cas9-based inactivation of the TTR gene in liver cells.
• Fate Therapeutics announced this week that it will present clinical and preclinical data from its off-the-shelf cell therapy product platform at the European Alliance of Associations for Rheumatology European Congress of Rheumatology (EULAR 2025), being held in Barcelona, Spain on June 11-14, 2025. According to the press release, Fate Therapeutics has been selected to provide an oral presentation featuring clinical data from its ongoing Phase 1 clinical trial of FT819, its off-the-shelf, CD19-targeted, 1XX CAR T-cell product candidate, in patients with moderate-to-severe systemic lupus erythematosus.
• CRISPR Therapeutics announced yesterday that it will participate in two upcoming investor conferences: William Blair’s 45th Annual Growth Stock Conference (3rd June, 2025) and Goldman Sachs’ 46th Annual Global Healthcare Conference (9th June, 2025). Live webcasts of both presentations will be available. See the official press release for further details.
• Prime Medicine will participate in two upcoming investor conferences: Fireside chat at Jefferies Global Healthcare Conference (5th June, 2025) and Goldman Sachs’ 46th Annual Global Healthcare Conference (9th June, 2025). Live webcasts of both presentations will be available. See the official press release for further details.
• Caribou Biosciences President and CEO Rachel Haurwitz, PhD, will participate in a fireside chat at the Jefferies Global Healthcare Conference on 4th June. See the press release for further details including instructions on how to access the live webcast.
• Allogene Therapeutics will participate in three upcoming investor conferences in June: Jefferies Global Healthcare Conference (4th June, 2025), Goldman Sachs 46th Annual Global Healthcare Conference (June 10th, 2025) and Oppenheimer Innovators in I&I Summit (25th June, 2025). See the press release for further details and access details for any available webcasts.

Reviews

• CRISPR–Cas therapies targeting bacteria. This review by scientists at Institut Pasteur, Sorbonne Université and Eligo Bioscience explores how CRISPR–Cas technology can be engineered to kill or modify specific bacteria. The authors discuss DNA-targeting and RNA-targeting strategies, outlining how these can be applied to disarm bacteria by removing, modifying or silencing specific genes. They also examine the delivery of CRISPR–Cas tools by bacteriophages and through conjugation, as well as intracellular barriers to CRISPR–Cas tool maintenance and expression. Therapeutic opportunities in the treatment of infectious diseases and for the modification of the microbiome are highlighted.
• CRISPR/Cas Multiplexed Biosensing: Advances, Challenges, and Perspectives. Authors at various institutes in China provide a systematic summary of recent advances in CRISPR/Cas multiplexed detection encompassing Cas9, Cas12, and Cas13. Among their key focus areas are multiplex biosensing strategies and their advantages and limitations, sensing mechanisms, and detection performance of novel validated examples. The status and challenges of CRISPR/Cas multiplexed biosensing are critically discussed, and future outlooks are proposed for their potential practical application.
• Therapeutic Application of mRNA for Genetic Diseases. In this review, researchers in the Netherlands explore recent advances in mRNA therapies, building on the success of mRNA COVID-19 vaccines, and extend these insights to the potential treatment of rare genetic diseases. Following an “outside-in” trajectory of mRNA therapies from administration to intracellular function, the authors focus on carrier systems including LNPs and virus-like particles, mRNA modifications, and the potential and challenges for clinical applications. To treat rare diseases, different approaches can be envisioned, including chronic or acute delivery of mRNAs encoding functional enzymes for enzyme deficiencies and delivery of CRISPR/Cas9–based gene-editing tools for gene correction. By exploring genetic, technical, and therapeutic aspects, this review aims to highlight the potential and current challenges of mRNA therapies to address the large unmet needs in rare genetic disorders.
• Role Of Artificial Intelligence In Cancer Drug Discovery And Development. In this review, authors in New York and India examine the role of artificial intelligence (AI) in accelerating cancer drug discovery and development, including its integration with CRISPR-Cas for personalised approaches to cancer therapy. They begin their discussion with a brief overview of AI methodologies before highlighting the application of AI across various stages of drug discovery and development from target identification to clinical trial design and post-market regulatory activities. The authors also discuss current challenges in this field and future perspectives.
• Optimizing homology-directed repair for gene editing: the potential of single-stranded DNA donors. The authors of this review explore the fundamental principles of homology-directed repair (HDR)-dependent gene editing and evaluate current strategies to enhance its efficiency, with particular emphasis on single-stranded DNA (ssDNA) donor-mediated HDR. The authors also discuss the prospects of high-efficiency ssDNA donor-mediated precise gene editing in laboratory research and clinical therapies.
• Lipid Nanoparticles for Delivery of CRISPR Gene Editing Components. This review provides an overview of the widely used CRISPR gene-editing systems followed by a discussion on the impact of LNPs on delivery. Current LNP engineering strategies to achieve non-liver targeting are summarised, while preclinical and clinical applications of LNPs for in vivo genome editing are highlighted. The authors share their perspectives on the future development of LNPs.

Detection

• In an article published in Biosensors and Bioelectronics, researchers in Brazil report a label-free biosensor using CRISPR/Cas12a technology to rapidly detect Staphylococcus aureus DNA. The biosensor achieves ultra-sensitive detection (down to 20 aM limit) without the need for DNA amplification, by exploiting CRISPR/Cas12a's collateral cleavage activity on DNA reporters. They report a critical role for PAM sequences in detection specificity with single mismatches drastically reducing cleavage efficiency. The researchers demonstrated that DNA reporter type affects performance and validated the system using human serum samples, supporting clinical applicability.

News from CRISPR Medicine News

• On Tuesday, our sister publication CARBON published its monthly newsletter, bringing you all the latest advances within gene editing in plants. Check it out here.