CMN Weekly (1 March 2024) - Your Weekly CRISPR Medicine News

Top picks

• Epigenome editing provides an opportunity to permanently silence disease-causing genes without changing their DNA sequence, with many therapeutic applications currently being explored. In 2016, a team at San Raffaele Telethon Institute for Gene Therapy reported the development of the first 'hit-and-run' epigenetic silencing platform and demonstrated its efficiency, durablity and specificity in vitro. This week, researchers from the same team report in an article published in Nature that transient delivery of engineered transcriptional repressors to the liver of mice leads to durable epigenetic silencing at therapeutically compatible levels. They demonstrated this by targeting the PCSK9 gene, a gene involved in the control of blood cholesterol levels and which is the target of several ongoing programmes for genetic and acquired hypercholesterolemia.

Research

• To address challenges caused by self-repair during CRISPR-Cas9 gene editing, a team in China devised a strategy based on dual cleavage of the genomic DNA target. Their strategy utilises biologically-produced dual-ribonucleoproteins that are delivered via a metal-organic framework. The team demonstrated the effectiveness of its dual-cut CRISPR-Cas9 system through a therapeutic approach targeting the simultaneous inhibition of lactate and glucose influx in cancer cells. The findings were published this week in Acta Biomaterialia.
• In an article published this week in Acta Biochimica et Biophysica Sinica, a team in China report on the efficiency of CRISPR-Cas9-mediated disruption of the BCR-ABL fusion gene by targeting BCR and c-ABL introns. The BCR-ABL fusion gene, which is formed via the fusion of the breakpoint cluster region protein (BCR) and the Abl Oncogene 1, Receptor Tyrosine Kinase (ABL) genes, encodes the BCR-ABL oncoprotein, which plays a crucial role in leukemogenesis. The team found that BCR-ABL disruption resulted in inhibition of proliferation and induced apoptosis in chronic myeloid leukaemia cells in vitro and in vivo (in mice).
• Scientists in the UK and Belgium demonstrate that baculovirus, alongside its DNA cargo, can be used to package and deliver proteins to human cells. Using protein-loaded baculovirus (pBV), the team demonstrates delivery of Cas9 or base editors, leading to efficient genome and base editing in human cells. By implementing a reversible, chemically inducible heterodimerisation system, they furthermore show that protein cargoes can selectively and more efficiently be loaded into pBVs (spBVs). Using spBVs, the team observed high levels of multiplexed genome editing in a panel of human cell lines in the absence of detectable off-targets events. Finally, by exploiting Cas9 protein and template DNA co-delivery, they demonstrate up to 5% site-specific targeted integration of a 1.8 kb heterologous DNA payload using a single spBV in a panel of human cell lines. Their findings were published this week in Nucleic Acids Research.
• A metabolism-focused CRISPR knockout screen was performed by researchers in the United States and Germany to identify genes that undergo alterations during the treatment of tumour cells with PARP inhibitors (PARPis). Of approx 3,000 genes included in the screen, the team identified mitochondrial pyruvate carrier 1 (MPC1) as an essential factor in desensitising non-small cell lung cancer (NSCLC) lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple-negative breast cancer cells did not exhibit such desensitisation following MPC1 loss; these cells appeared to reprogramme the tricarboxylic acid cycle and oxidative phosphorylation pathways to overcome PARPi treatment. The team concludes that its findings unveil a previously unknown synergistic response between MPC1 loss and PARP inhibition in lung cancer cells. The findings were published this week in Molecular Carcinogenesis.

Industry

• AvenCell recently announced dosing of the first patient in a Phase 1A trial of its lead product candidate AVC-201, a novel allogeneic CD123-directed switchable CAR-T candidate for the treatment of relapsed or refractory acute myeloid leukaemia and other CD123 blood cancers. Read more about AVC-201 in our previous clinical trial update here.
• Precision BioSciences has announced the commencement of a proposed underwritten public offering of its common stock and accompanying warrants to purchase shares of common stock, including pre-funded warrants to purchase common stock in lieu of common stock for certain purchasers. All shares of common stock, pre-funded warrants and accompanying warrants to be sold in the proposed offering will be sold by Precision. The pre-funded warrants will be issued to certain purchasers who have elected to purchase them in lieu of shares of common stock in this offering. See press releaase for full details.

2023 financial updates from the industry

• Iovance Biotherapeutics reports fourth quarter and full year 2023 financial results and corporate updates. Iovance is currently sponsoring a Phase 1/2 clinical trial of IOV-4001, a PD-1 inactivated autologous tumour-infiltrating lymphocyte therapeutic candidate for solid tumours.
• Repare Therapeutics provides business update and reports fourth quarter and full year 2023 financial results. The company has several small molecular inhibitors in the clinic for oncology indications, and is leveraging its proprietary CRISPR-enabled SNIPRx platform to discover and develop novel targeted cancer therapies focused on genomic instability, including DNA damage repair.
• Editas Medicine announces fourth quarter and full year 2023 results and business updates. The company's lead programme, reni-cel (formerly known as EDIT-301) is in late- (RUBY) and early-stage (EDITHAL) trials for sickle cell disease and beta thalassemia, respectively. Among the updates were that Editas is aligned with the FDA that RUBY is a single Phase 1/2/3 trial and that it is on track to present additional clinical data from those trials in mid-2024 with additional updates by year-end 2024. The company reports a strong financial position with operational runway expected into 2026.
• Verve Therapeutics provides pipeline progress and reports fourth quarter and full year 2023 financial results. The company expects to have three clinical-stage programmes targeting PCSK9 and ANGPTL3 in 2024, and it also reported cash, cash equivalents and marketable securities of $624 million with cash runway into late 2026.
• Fate Therapeutics reports fourth quarter and full year 2023 financial results and business updates. Among the updates were that the California Institute of Regenerative Medicine has awarded a grant to support a Phase 1 autoimmunity study of Fate's FT819 CD19-targeted CAR T-cell programme for systemic lupus erythematosus, with study start-up now ongoing at multiple clinical sites. The company reported $316 million in cash, cash equivalents, and investments.

Detection

• Exosomal miRNAs are considered to have great potential as non-invasive biomarkers for cancer. Realising this potential, a team in China have developed an exponential amplification reaction (EXPAR) that induces activation of the Cas9/sgRNA complex to allow sensitive fluorescent detection of exosomal miRNAs-21 (miR-21) via cleavage of a fluorescently-labelled reporter DNA. In an article published yesterday in Analytical Chemistry, the team report using its novel assay to distinguish healthy people and cancer patients by naked-eye observation of the fluorescence, thus demonstrating its great potential for accurate and point-of-care cancer diagnosis.

Reviews

• GMP-manufactured CRISPR/Cas9 technology as an advantageous tool to support cancer immunotherapy. The authors of this review aim to provide a comprehensive overview of the available GMP-grade CRISPR-Cas9-mediated approaches used to support cancer therapy, highlighting how this technology is opening new opportunities for treating tumours.
• Programmable RNA base editing via targeted modifications. This review provides a summary of emerging RNA editors based on A-to-inosine, C-to-U and U-to-pseudouridine changes. The authors review the programmable RNA-targeting systems as well as modification enzyme-based effector proteins and highlight recent technological breakthroughs. Editing tools are compared, and limitations and opportunities are discussed, before the authors finish with insights for the future directions of RNA base editing.

News from CRISPR Medicine News

• On Monday, we published an interview with Countagen. Located in the Karolinska Institute in Sweden, Countagen is on a mission to simplify, accelerate and improve quality control within gene editing. Its unique GeneAbacus technology provides an accurate and reliable method to count the number of intended edits following a gene-editing experiment. Read our interview with the team here.