CMN Weekly (10 January 2025) - Your Weekly CRISPR Medicine News

Top picks

• A six-month-old infant with ornithine transcarbamylase deficiency has received a first-in-human in vivo gene editing therapy using the Arcus enzyme. The treatment is part of an ongoing phase 1/2 clinical trial by Precision Biosciences and iECURE. The therapeutic ECUR-506 integrates a functional OTC gene into liver cells using two AAVs: one to deliver the Arcus editor and a second to deliver the therapeutic gene. Six months after treatment, the boy's ammonia and glutamine levels are normal, and he hasn't experienced any more metabolic crises, presumably removing the need for a liver transplant. Safety concerns, including transient liver enzyme elevation, persist, and further trials aim to confirm durability and safety. CRISPR Medicine News has a detailed report of the news, that is also covered by Endpoint News.
• A study published in Nature predicts that polygenic genome editing in embryos and germ cells could significantly reduce susceptibility to diseases like coronary artery disease, Alzheimer's, and schizophrenia within decades. However, heritable polygenic editing (HPE) raises ethical concerns, including exacerbating health inequalities, pleiotropy risks, and impacts on genetic diversity. The authors advocate for a collectivist ethical framework to assess HPE's societal consequences.

Research

• Swiss researchers have developed a dual adeno-associated viral vector delivering a split-intein adenine base editor to correct the c.5882G>A ABCA4 mutation in Stargardt disease. In human retinal models and nonhuman primates, the therapy achieved up to 87% gene correction in retinal pigment epithelial cells and 75% in cones, with no detectable off-target effects. No off-target editing was detectable in human retinal explants and RPE/choroid explants.
• Researchers in Germany have developed a CRISPR-based strategy that successfully corrects a common mutation causing LGMD2B muscular dystrophy, achieving more than 60% correction efficiency in patient-derived cells and a new mouse model of the disease. The approach restores the production of functional dysferlin protein by targeting a specific frameshift mutation in the DYSF gene. It represents a potential therapeutic avenue for this rare muscle-wasting disease.
• Researchers in France have developed Nanoscribes, virus-like particles that deliver prime editing ribonucleoprotein complexes into human cells. Optimised pegRNAs, fusogens, and prime editors enable efficient, precise edits, achieving 68% efficiency in HEK293T cells and 25% in myoblasts, hiPSCs, and stem cell derivatives. Supporting pegRNA multiplexing and enhancing fidelity, Nanoscribes advance safe, efficient genome editing for therapeutic applications.
• CRISPR base editing has been used to introduce revertant mutations in cis with the F508del mutation in the CFTR gene, restoring protein folding and ion channel function in cystic fibrosis cellular models. The approach fully recovered ion transport in pseudostratified epithelial cultures from patient-derived cells. When this strategy is combined with small molecule therapies, it might offer a promising step toward definitive CF treatments.
• American researchers used CRISPR-Cas9 saturation genome editing to functionally characterise 6,960 BRCA2 variants in the DNA-binding domain, identifying 91% as pathogenic/likely pathogenic or benign/likely benign. This approach integrated functional data with clinical models to improve variant classification, enabling more precise cancer risk assessments and enhanced management for individuals with BRCA2 variants.
• Researchers in Italy have successfully tested CRISPRi, a non-cleaving version of CRISPR-Cas technology, for its ability to repress antibiotic resistance genes (ARGs) in Escherichia coli. Key findings included a significant reduction in minimum inhibitory concentrations (MICs) of these antibiotics, with susceptibility increases of up to fourfold in some strains. The approach also delayed bacterial regrowth after antibiotic exposure.
• Researchers at Profluent Bio have developed Protein2PAM, a deep-learning model trained on over 45,000 CRISPR-Cas PAMs, to predict PAM specificity from Cas protein sequences across CRISPR-Cas systems. Using in silico mutational scanning, it identifies key residues for PAM recognition. As a proof of concept, Protein2PAM engineered Nme1Cas9 variants with broader PAM compatibility and 50-fold higher cleavage rates, enabling enhanced genome editing precision and expanding targetable genomic sites. Profluent has also covered the news in a press release.
• Scientists in the UK have used CRISPR to integrate an hNIS-mGFP reporter gene into hiPSCs at the AAVS1 safe harbour locus, enabling non-invasive PET imaging of hiPSC-derived liver organoids in vivo. These organoids retained functional differentiation and were successfully tracked post-transplantation in healthy and liver-injured mice. This approach enhances regenerative cell therapy development by enabling real-time monitoring of cell engraftment, survival, and therapeutic efficacy.
• Canadian researchers have demonstrated the use of focused ultrasound (FUS) with microbubbles to deliver CRISPR-Cas9 RNPs into human iPSCs for precise gene editing. Targeting the EGFP gene, the approach achieved effective knockouts, with acoustic cavitation monitoring confirming successful delivery. This non-invasive technique minimises immunogenic risks and holds promise for advancing CRISPR-based therapies, including applications in cardiovascular disease via hiPSC-derived cardiomyocytes.
• CRISPR-Cas nucleases SaCas9 and AsCas12a were redesigned to reduce immunogenicity while maintaining wild-type activity. Using MHC-associated peptide proteomics and computational modelling, the American researchers identified and modified immunogenic epitopes with reduced MHC binding and cytotoxic T-cell activation. In vivo PCSK9 editing with SaCas9.Redi.1 achieved efficient gene editing with fewer immune responses, highlighting the potential for safer therapeutic applications.
• CRISPR-Cas9 has been used to achieve >90% CCR5 gene editing in human haematopoietic stem progenitor cells (HSPCs), enabling transplants that produce CCR5-null T cells resistant to HIV infection. Xenograft models confirmed protection at high editing rates, with reduced efficacy below 54%. This approach highlights the potential of autologous, CRISPR-edited HSCTs as a viable path toward an HIV cure.
• Two independent studies demonstrate the potential of CRISPR-Cas13 for treating C9orf72-linked ALS/FTD by targeting toxic RNA species. A high-fidelity Cas13 variant reduced G4C2 repeat RNA, RNA foci, and dipeptide repeat proteins (DPRs) in rodent models and patient-derived motor neurons, improving transcriptional deficits. Separately, CRISPR-Cas13d (CasRx) targeted both sense and antisense RNA, reduced DPRs and protected neurons from excitotoxicity. These findings highlight RNA-targeting CRISPR systems as promising therapies for ALS/FTD.
• An engineered CRISPR-Cas9 system was developed to protect bacteria from horizontal gene transfer (HGT) of antimicrobial resistance (AMR) genes. Targeting eight AMR genes, the system blocked transformation, transduction, and conjugation in E. coli MG1655, reducing transfer by 2–3 logs. It also protected the probiotic E. coli Nissle 1917, mitigating risks of probiotic conversion into superbugs and advancing safer engineered bacteria for AMR management.

Clinical

• Tune Therapeutics has announced regulatory approval to begin a Phase 1b trial of its chronic hepatitis B therapy in Hong Kong, marking a strategic expansion of the TUNE-401 clinical programme. The company's novel epigenetic silencing approach, designed as a potential 'one-and-done' treatment, targets viral DNA to achieve what could be a functional cure for chronic hepatitis B infection. Also, read CRISPR Medicine News' take on the news.
• HuidaGene Therapeutics' HG004 gene therapy has received orphan designation from the EMA for inherited retinal dystrophy caused by RPE65 gene mutations, complementing prior FDA designations. HG004, using an optimised viral vector, demonstrated superior efficacy and safety over Luxturna, addressing limitations like progressive retinal atrophy. Early trials show improved visual outcomes with a lower vector dose, offering a promising advancement in treating inherited retinal diseases.

Industry

• Inverna Therapeutics has launched with a focus on sequence-based RNA splice modulation, targeting Huntington's disease. Its proprietary technology enables precise, allele-specific RNA editing with reduced off-target effects. Backed by Argobio and the University of Southern Denmark, Inverna aims to develop safer, more effective treatments for neurodegenerative and chronic diseases, leveraging insights from RNA splicing expert Professor Brage Storstein Andersen.
• Intellia Therapeutics has announced 2025 milestones, prioritising pivotal Phase 3 trials for its CRISPR-based therapeutics NTLA-2002 (hereditary angioedema) and nex-z (ATTR amyloidosis). NTLA-2002 aims to eliminate chronic treatments, while nex-z showed the potential to halt or reverse ATTR disease progression. Development of NTLA-3001 for the treatment of alpha-1 antitrypsin deficiency-associated lung disease has been discontinued. The strategic reorganisation, including 27% workforce reductions, will focus resources on these high-value programmes.
• RheumaGen has secured $15M in Series A funding to advance its HLA-targeting gene therapy, RG0401, for refractory rheumatoid arthritis (RA). Using precision gene editing, RG0401 modifies harmful HLA alleles to halt autoimmune responses, aiming for a one-time curative treatment. Phase I trials are slated for 2026. RheumaGen is also developing therapies for other HLA-driven autoimmune diseases, including multiple sclerosis and type 1 diabetes.

Detection

• The PathCrisp assay combines loop-mediated isothermal amplification with CRISPR-based detection to rapidly identify antibiotic resistance genes directly from culture samples. It detected as few as 700 copies of the NDM gene with 100% concordance to PCR-Sanger sequencing. The assay, requiring no DNA purification and yielding results in ~2 hours, offers a precise, accessible tool for guiding antibiotic therapy.

Reviews

• Recent developments and future directions in point-of-care next-generation CRISPR-based rapid diagnosis. This review discusses the development, applications, and future potential of CRISPR-based diagnostic tools, highlighting their advantages, integration with AI/ML, and challenges in revolutionising accessible disease detection and personalised medicine.
• Delivery of genetic medicines for muscular dystrophies. This review summarises the key features of major muscular dystrophies and explores emerging muscle-targeted delivery methods for genetic therapies.