CMN Weekly (13 September 2024) - Your Weekly CRISPR Medicine News

Top picks

• Researchers in France report the correction of three duplications in the dystrophin gene in cells from Duchenne muscular dystrophy patients, using CRISPR-Cas9 gene editing and a single guide RNA. The findings highlight the potential of using CRISPR-Cas9 to correct DMD duplications in exons that are not addressed by any of the four approved exon-skipping therapies. The findings were published this week in Scientific Reports.
• CMN Live: CRISPR next frontier: in vivo editing of the microbiome. Don't miss our live interview with Xavier Duportet (CEO, Eligo Bioscience) on the 27th of September. We'll be chatting about the human microbiome, its role in health and disease, and how gene editing within the microbiome will open a whole new chapter in medicine. See here for further details.

Research

• In an article published in Molecular Therapy, researchers in Italy report a new nanoplatform for IL-30 knockout as a novel therapeutic strategy for metastatic prostate cancer. Using lipid nanoparticles loaded with CRISPR-Cas9 and gRNA targeting the human IL-30 gene, the team observed efficient gene knockout in vivo and in vitro. Following intravenous injection in mice, the functionalised nanoparticles demonstrated circulation stability and efficient editing of the IL-30 gene and suppressed lung metastasis in mice bearing circulating PC cells and micro-emboli, without serious off-target effects or organ toxicity for the duration of the study.
• A team in the United States has developed an approach to integrate genetic biosensors into endogenous genes without modifying their coding sequence by inserting into their terminator region single-guide RNAs that activate downstream circuits. Using their method, they engineered a cell stress sensor and actuator in CHO-K1 cells that conditionally activates the anti-apoptotic protein BCL-2 through a downstream circuit, leading to increasing cell survival under stress condition. Their findings were published yesterday in Nature Chemical Biology.
• Scientists in China report PerturbDB, a platform to help users unveil gene functions using Perturb-Seq datasets. The PerturbDB platform hosts 66 Perturb-Seq datasets, which encompass 4,518,521 single-cell transcriptomes derived from the knockdown of 10,194 genes across 19 different cell lines. Perturb-Seq can be accessed here. The study findings were published this week in Nucleic Acids Research.
• Despite widespread use of Cas12a in genome editing and molecular diagnostics, the mechanisms that lead to activation of its trans-cleavage activity, particularly in the context of split DNA activators, remain poorly understood. Now, scientists in China report elucidating the synergistic effect of these activators and introduce the concepts of induced targeting effect and exon-unwinding to describe the phenomenon. They demonstrate that upon binding of split DNA activators adjacent to the Protospacer Adjacent Motif (PAM) to the Cas12a ribonucleoprotein (Cas12a-RNP), a ternary complex forms that can capture and interact with distal split DNA activators to achieve synergistic effects. Their findings were published this week in Nucleic Acids Research.

Clinical

• Intellia Therapeutics announced in a press release published yesterday that it will present clinical data from its Phase 2 study of in vivo CRISPR therapy NTLA-2002 at the 2024 American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting, taking place October 24 – 28 in Boston, Massachusetts. The update will be the first presentation of detailed Phase 2 results since the company reported in August 2024 that the study of NTLA-2002 had met primary and all secondary endpoints. Read more about NTLA-2002 in a previous clinical update here.
• Poseida Therapeutics is scheduled to present new clinical data from the ongoing Phase 1 trial of Allogeneic CAR-T P-BCMA-ALLO1 in patients with relapsed or refractory multiple myeloma (MM) at the upcoming 21st International Myeloma Society Annual Meeting later this month in Rio de Janeiro. P-BCMA-ALLO1 is a fully allogeneic, T stem cell memory-rich CAR-T candidate that is engineered to target the B cell maturation antigen. This antigen is primarily expressed by malignant and normal plasma cells and by some mature B cells, and is the most widely studied target in CAR-T-based approaches to MM. Clinical data revealed at the American Society of Hematology Annual Meeting in December 2023 showed early positive signs of safety and efficacy in heavily pre-treated MM patients, following suitable lymphodepletion therapy. Read more in the official press release here.

Industry

• ArsenalBio announced in a recent press release that it has received $325 in oversubscribed Series C financing to advance its pipeline of programmable cell therapy programmes through clinical development. The company reported earlier this year that the first patient had been dosed in the Phase 1/2 clinical trial of AB-2100 which is being developed to treat clear-cell renal cell carcinoma. AB-2100 utilises ArsenalBio’s CITE (CRISPR Integration of Transgenes by Electroporation) technology to engineer T cells to selectively target tumour cells and overcome the suppressive tumour microenvironment.
• Excision Biotherapeutics announced this week that it will present data from its programme for Hepatitis B virus, EBT-107, at the 2024 International HBV Meeting, taking place September 11-15, 2024, in Chicago. EBT-107 is a CRISPR-based gene therapy that is being developed as a potential cure for Hepatitis B. EBT-107 uses dual guide RNAs to effectively deactivate the virus and prevent the emergence of escape variants. See the official press release for further details.
• Fate Therapeutics announced in a press release yesterday that it would present data at 2024 Cantor Global Healthcare Conference. Details of the presentation scope have not been released, but if recorded, a live webcast of the presentation will become accessible under “Events & Presentations” in the Investors section of the Company’s website at www.fatetherapeutics.com.

CRISPR screens

• Using a genome-wide CRISPR knockout screen, RNA sequence and ATAC sequencing (to assess chromatin accessibility), researchers at various institutes in the United States report the identification of interleukin-4 (IL-4) as a key factor in CAR-T cell exhaustion, which limits the effectiveness of CAR-T cell therapy. Their findings, published yesterday in Nature Communications​​​​​, shows that blocking IL-4 or its pathway improves CAR-T cell performance and anti-tumour efficacy in mouse models.
• Human astrovirus (HAstV) is a major cause of gastroenteritis globally, however the molecular mechanisms that govern its susceptibility are not fully understood, as the functional receptor used by the virus has yet to be identified. A genome-wide CRISPR-Cas9 screen carried out by researchers in Japan has now identified the neonatal Fc receptor (FcRn) as a functional receptor for classical HAstV. They found that FcRn deletion prevents infection in cells and organoids, while FcRn expression enables viral entry in non-susceptible cells, binding directly to the HAstV spike protein. Their findings, published yesterday in Genes to Cells, could open the door to new, targeted therapies for gastroenteritis.
• CENP-E, a kinesin-7 motor, is crucial for chromosome alignment in mitosis. In an article published yesterday in Cell Proliferation, researchers in China demonstrate using CRISPR-Cas9 knockout studies that CENP-E deletion causes chromosome congression defects, aneuploidy, and spindle disorganisation. CENP-E deletion also affects kinetochore protein localisation, activates spindle assembly checkpoint, and impacts cell division in vivo. The findings provide new insights into the functions and molecular basis of CENP-E in chromosome alignment and cell cycle progression during cell division.

Reviews

• The latest volume of Progress in Molecular Biology and Translational Science contains 11 chapters covering recent advances in gene editing for the treatment of diverse human diseases. Diseases covered include fungal infections, blood cancer, autoimmune diseases, human bacterial disease and others. Access the volume here.
• The transformative potential of AI-driven CRISPR-Cas9 genome editing to enhance CAR T-cell therapy. This narrative review examines the promising potential of integrating artificial intelligence (AI) with CRISPR-Cas9 genome editing to advance CAR T-cell therapy. AI algorithms offer unparalleled precision in identifying genetic targets, essential for enhancing the therapeutic efficacy of CAR T-cell treatments. The author discusses potential benefits of using AI in this regard, including precision in identifying genetic targets, improved manufacturing processes, increased safety and specificity.
• Integrating Prime Editing and Cellular Reprogramming as Novel Strategies for Genetic Cardiac Disease Modeling and Treatment. This review aims to evaluate the potential of CRISPR-based gene-editing tools, particularly prime editors (PE), in treating genetic cardiac diseases. It seeks to answer how these tools can overcome current therapeutic limitations and explore the synergy between PE and induced pluripotent stem cell-derived cardiomyocytes for personalised medicine.
• CRISPR-Cas-based biosensors for the detection of cancer biomarkers. The authors of this review provide a comprehensive overview of the diagnosis strategies for cancer mediated by the CRISPR-Cas system, including four kinds of biochemical-based markers: nucleic acid, enzyme, tumour-specific protein and exosome. The challenges in implementing the CRISPR-Cas system in clinical applications are also discussed.

News from CRISPR Medicine News

• On Wednesday, we published a brief clinical trial update covering new data from Vor Bio's ongoing Phase 1/2 VBP101 trial of trem-cel followed by the anti-CD33 antibody-drug conjugate Mylotarg in patients with relapsed or refractory acute myeloid leukaemia. The data demonstrated early evidence of patient benefit, an increased therapeutic window for Mylotarg, and effective shielding against Mylotarg on-target toxicity. Read the update here.