CMN Weekly (28 February 2025) - Your Weekly CRISPR Medicine News

Top picks

• Earlier this week, ElevateBio announced new pre-clinical data for LETI-101, a therapeutic candidate for Huntington's disease that is being developed by its subsidiary ElevateBio Life Edit. LETI-101 uses a proprietary CRISPR nuclease with AAV5 delivery to target a specific exonic single nucleotide polymorphism in the huntingtin (HTT) gene. In those studies, LETI-101 demonstrated selective reduction of disease-causing mutant huntingtin (mHTT) protein, supporting its selection as Life Edit’s lead development candidate. The data will be presented at the 20th Annual Huntington's Disease Therapeutics Conference being held February 24-27, 2025, in Palm Springs, CA. See the press release for further details.

Research

• In Science yesterday, scientists at MIT’s McGovern Institute for Brain Research and the Broad Institute of MIT and Harvard publish their efforts to uncover ancient systems with potential to expand the genome-editing toolbox. These systems, which the researchers call TIGR (Tandem Interspaced Guide RNA) systems, use RNA to guide them to specific sites on DNA. TIGR systems can be reprogrammed to target any DNA sequence of interest, with distinct functional modules that can act on the targeted DNA. In addition to its modularity, TIGR is very compact compared to other RNA-guided systems, such as CRISPR, which is a considerable advantage when it comes to delivery.
• Researchers in the United States have developed a digital molecular diagnostic tool called dCRISTOR, by seamlessly integrating deactivated Cas9 (dCas9)-engineered micromotors, extraction-free loop-mediated isothermal amplification (LAMP), low-cost bright field microscopy, and deep learning-enabled image processing. The micromotor incorporates a dCas9 ribonucleoprotein complex, and the presence of human immunodeficiency virus-1 (HIV-1) RNA in a sample results in the formation of large-sized amplicons that can be specifically captured by the micromotors, reducing their velocity induced by an external magnetic field. The assay achieved 100% correlation with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in clinical patient samples (n = 9). Their findings were published today in ACS Nano.
• In an article published yesterday in Analytical Chemistry, scientists in China report a new Cas12a-based assay to detect bacterial biomarkers of colorectal cancer (CRC). Their efforts focused on Porphyromonas gingivalis, which has been identified in the malignant tissues and faeces of CRC patients, establishing it as a significant biomarker for early screening, diagnosis, and prognostic assessment of CRC. To develop the assay, they used a whole-bacterium systematic evolution of ligands by exponential enrichment method to identify highly specific and high-affinity aptamers targeting P. gingivalis through 15 selection cycles. Then, they developed an aptasensor driven by MoS₂ nanoflowers, which integrates strand displacement amplification and CRISPR/Cas12a double amplification for sensitive detection of P. gingivalis, achieving a limit of detection of 10 CFU/mL. When tested on clinical faecal samples from CRC patients compared to healthy individuals, they could corroborate the results obtained from quantitative polymerase chain reaction.
• A team in the United States presents GuideScan2 for memory-efficient, parallelisable construction of high-specificity CRISPR guide RNA (gRNA) databases and user-friendly design and analysis of individual gRNAs and gRNA libraries for targeting coding and non-coding regions in custom genomes. GuideScan2 analysis identifies widespread confounding effects of low-specificity gRNAs in published CRISPR screens and enables construction of a gRNA library that reduces off-target effects in a gene essentiality screen. GuideScan2 also enables the design and experimental validation of allele-specific gRNAs in a hybrid mouse genome. GuideScan2 will facilitate CRISPR experiments across a wide range of applications. The findings were published this week in Genome Biology.
• Researchers in the UK have published the results of a benchmarking study, which involved a comparative analysis of publicly available genome-wide single-targeting sgRNA libraries and evaluated dual targeting as a strategy for pooled CRISPR loss-of-function screens. They then leveraged this data to design two minimal genome-wide human CRISPR-Cas9 libraries that are 50% smaller than other libraries and that preserve specificity and sensitivity, thus enabling broader deployment at scale. Their findings were published this week in BMC Genomics.
• In an article published in EMBO Reports this week, scientists in China report that U1 promoter-driven CRISPR RNAs (crRNAs) increase the efficiency of various applications, including RNA knockdown and editing, without modifying the Cas13 protein effector. They present data to confirm that U1-driven crRNAs are exported into the cytoplasm, while conventional U6 promoter-driven crRNAs are mostly confined to the nucleus. The team also found that the end positions of crRNAs expressed by the U1 promoter are consistent regardless of guide sequences and lengths, and demonstrate that U1-driven crRNAs, but not U6-driven crRNAs, can efficiently repress the translation of target genes in combination with catalytically inactive Cas13 proteins. Finally, the authors show that U1-driven crRNAs can counteract the inhibitory effect of miRNAs.

Industry

• Allogene Therapeutics announced an expanded strategic collaboration with Foresight Diagnostics, Inc. to include the development of Foresight’s minimal residual disease (MRD) assay as a companion diagnostic to identify patients with large B-cell lymphoma (LBCL) for treatment with cemacabtagene ansegedleucel (cema-cel). Cema-cel is a next-generation anti-CD19 AlloCAR T therapeutic candidate made from healthy donor cells that is being evaluated in the ALPHA3 Phase 2 trial of cema-cel as a first line consolidation treatment for large B-cell lymphoma. You can read more about cema-cel in a previous clinical trial update here.
• Iovance Biotherapeutics reported fourth quarter and full year 2024 financial results and corporate updates yesterday. Among the gene-editing updates, Iovance reported that the ongoing Phase 2 efficacy portion of the IOV-GM1-201 trial in previously treated advanced melanoma and non-small cell lung cancer continues to enrol rapidly. The trial is evaluating the PD-1 inactivated tumour infiltrating lymphocyte (TIL) cell therapeutic candidate IOV-4001. Iovance utilises the TALEN® technology licensed from Cellectis to develop IOV-4001 and other investigational gene-edited TIL cell therapies with multiple knockout targets to potentially improve efficacy. For full details, see the official press release.
• Yesterday, Intellia Therapeutics reported operational highlights and financial results for the fourth quarter and year ended 2024. Intellia Therapeutics now has two gene-editing candidates in Phase 3 clinical trials, having dosed its first patient in the HAELO study for NTLA-2002 (in hereditary angioedema) while enrolment in the MAGNITUDE trial for nexiguran ziclumeran (nex-z, and formerly known as NTLA-2001) in transthyretin amyloidosis (ATTR) cardiomyopathy continues to progress ahead of projections. The company also reported that active screening is underway for participants to join the Phase 3 MAGNITUDE-2 trial for nex-z in hereditary ATTR amyloidosis with polyneuropathy and that it is on track to dose first patient in the first quarter of 2025. See the official press release for full details.
• Danish company SNIPR Biome announced this week that it has been granted patent EP4392563B by the European Patent Office protecting the newly-discovered and characterised CRISPR-CasSTM system. This system and its uses do not rely on Cas9 or Cas3. The patent covers use of the new CasS system in both prokaryotic and eukaryotic cells, as well as when fused to effector domains conferring additional functionality, such as base editors and nuclease domains. Read more in the official press release.
• Today, Prime Medicine reported financial results for the full year ended 2024, and provided a business update. The company reported that it is on track to share initial clinical data from Cohort 1 of the ongoing Phase 1/2 trial of PM359 for prime-editing therapeutic candidate p47^phox for chronic granulomatous disease (CGD) this year. Prime is also advancing a lipid nanoparticle (LNP)-based prime editor for the treatment of Wilson’s Disease and a LNP or adeno-associated virus (AAV)-based prime editor for the treatment of cystic fibrosis (CF), as well as ex vivo T-cell therapies, which are being developed in collaboration with Bristol Myers Squibb. Read the press release here.

Clinical

• YolTech Therapeutics reported first positive clinical data for gene-editing therapy in primary hyperoxaluria type 1. According to the company’s press release, the clinical data from the early Phase 1 trial demonstrates excellent safety and pharmacodynamic profiles and the potential of YOLT-203 to effectively normalise urinary oxalate levels in PH1 patients.
• Precision BioSciences announced positive initial safety and efficacy data from the first cohort of the ELIMINATE-B clinical trial evaluating PBGENE-HBV for chronic Hepatitis B virus (HBV) infection. According to the company's press release, PBGENE-HBV was safe and well tolerated in all three participants after the first administration at the lowest dose level (0.2 mg/kg). Two of the three participants demonstrated substantial reductions in hepatitis B surface antigen (HBsAg) following this initial administration, suggesting anti-viral activity even at the lowest dose tested.
• Children and adults in Denmark living with beta-thalassemia or sickle cell disease can now be treated with CASGEVY, according to the Danish Medicines Council. This makes Denmark the first Nordic country to recommend the only approved CRISPR therapy despite its high price. Read the full article here (article in Danish).

Reviews

• RNA-based therapies in liver metabolic diseases. This new review in Gut explores how advances in RNA-based therapies may impact the treatment of liver metabolic diseases with unprecedented precision and personalisation. Pre-clinical data, clinical successes and remaining challenges are discussed.
• Applications of Gene Editing and Nanotechnology in Stem Cell-Based Therapies for Human Diseases. This review aims to emphasise the significance of gene-editing technologies and nanotechnology in the progress of stem cell treatments, particularly for degenerative pathologies and injuries. It emphasises their capacity to restructure and transform medical treatment paradigms, providing fresh hope and optimism for patients and healthcare practitioners.
• Gene therapy for sickle cell disease and thalassemia. The authors of this review explore the potential to induce foetal haemoglobin production at therapeutic levels or to repair the underlying molecular defect that causes the disease genetically. They review recent gene-editing studies that are opening a new era in curative treatment for haemoglobinopathies.

News from CRISPR Medicine News

• On Monday, we published an interview with AIRNA, a Boston- and Germany-based biotech start-up pioneering a new approach to genetic medicine by harnessing the body's natural RNA-editing machinery. Building on more than a decade of research in ADAR biology, AIRNA aims to develop reversible genetic therapies to treat rare and common diseases. The company is preparing to bring its first candidate, targeting alpha-1 antitrypsin deficiency, a rare lung and liver disorder, into clinical trials in 2025. Read our interview with co-founder Thorsten Stafforst and CEO Kris Elverum here.
• This week's clinical update brought the latest news from YolTech Therapeutics, Precision Biosciences and AccurEdit Therapeutics. YolTech reports positive clinical data for the first in vivo gene-editing therapy in primary hyperoxaluria type 1, Precision demonstrates encouraging initial clinical data for PBGENE-HBV in chronic hepatitis B patients, and AccurEdit shows promising single-dose clinical data for hypercholesterolemia with up to 70% LDL-C reduction. Read our clinical update here.
• On Tuesday, our sister publication CARBON published its monthly newsletter, once again bringing the latest news on how CRISPR can shape agriculture for the future to guarantee food security in times of population growth and climate change. Read that newsletter here.