CMN Weekly (19 November 2021) - Your Weekly CRISPR Medicine News

Top Picks

• The first CRISPR therapy for type 1 diabetes is set to enter a clinical trial in Canada as CRISPR Therapeutics and ViaCyte announce that Canada Health has approved their clinical trial application for the CRISPR-edited stem cell candidate VCTX210. Check out our summary of this news here.
• CRISPR and the Climate: How Gene Editing Can Help Cut Emissions. An opinion piece in Foreign Affairs magazine discusses the ways in which widespread rollout CRISPR-engineered crops could contribute positively to the global climate crisis.
• Our CRISPR and Rare Diseases webinar with speakers Dr. Eric Olson and Dr. Alessia Cavazza is now available to watch on-demand (open access). Watch it here.

Research

• A team of scientists from South Korea and the US describe correction of a double gene mutation and therapeutic effect for the gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC). They developed bio-available nanoliposomes (NL) possessing Cas9-ribonucleoproteins and adenine base editors to conduct KRAS and P53 mutation gene editing directly. The NLs were conjugated with antibodies directed against epidermal growth factor receptor to mediate tumour-specific delivery. The authors report that they could verify an anti-cancer effect in vitro and in an in vivo cancer model. The findings were published in Biomaterials earlier this week.
• In a paper published in Nature Communications earlier this week, a diverse team of researchers from China and US propose several general principles that can guide the design of base editors with a reduced bystander effect. The team applied these principles to design a series of point mutations at T218 position of A3G-BEs to further reduce its bystander editing, and verify experimentally that the new mutations provide different levels of stringency on reducing the bystander editing at different genomic loci, which is consistent with our theoretical model. The authors claim that their study provides a computational-aided platform to assist in the scientifically-based design of base editors with reduced bystander effects.
• Researchers in Russia and US deploy a hybrid of Capsule Networks and Gaussian Processes to develop a new prediction method for the cleavage efficiency of a gRNA with a corresponding confidence interval. The new tool allows the user to incorporate information regarding possible model errors into the experimental design, and marks the first use of uncertainty estimation in computational gRNA design, which the researchers view as a critical step toward accurate decision-making for future CRISPR applications. The findings of the study were published in Nucleic Acids Research yesterday.
• A team in Germany has used CRISPR-Cas9 technology to mutate and effectively remove the major allergen Bra j I - a seed storage protein - from the brown mustard plant, and the CRISPR-Cas9-induced mutations were present in the majority of the next generation of plants. The findings were published in Plant Journal this week.
• Researchers in the US and Canada have chemically modified ribonucleotides of the AsCas12a (from Acidaminococcus sp.) CRISPR RNA 5' handle, a pseudoknot structure that mediates binding to Cas12a. The team shows that the 5' pseudoknot can tolerate near complete modification when design is guided by structural and chemical compatibility, and argue that rules for modification of the 5' pseudoknot should accelerate therapeutic development and be valuable for CRISPR-Cas12a diagnostics. The study details and findings were published in Nature Communications earlier this week.

Industry

• Celularity presents positive pre-clinical data on CYNK-101 at the Society for Immunotherapy of Cancer 36^th Annual Meeting. CYNK-101 is a placental-derived allogeneic genetically-modified natural killer cell therapy candidate that is being developed as a combination treatment for certain types of non-small cell lung cancer and head and neck squamous cell carcinomas.
• Graphite Bio enrols first patient in Phase 1/2 CEDAR clinical trial of GPH101 for sickle cell disease. The first patient expected to be treated in the first half of 2022, with initial proof-of-concept data anticipated by the end of 2022. GPH101 is engineered using patient-derived CRISPR-edited blood stem cells using a strategy that essentially cuts the disease mutation out of the genome and replaces it with the correct sequence. GPH101 is anticipated to provide a permanent cure by targeting the root cause of disease and restoring completely normally-functioning red blood cells.
• Chroma Medicine launches with $125M in financing to deliver new therapies based on epigenetic editing. Chroma builds upon key epigenetic-editing technologies developed by its scientific founders which include some of the most esteemed researchers in the field. The company’s modular epigenetic editors can be precisely programmed to durably turn genes on or off or alter the expression of several genes at once, enabling the company to seamlessly silence, activate, and multiplex genes in a single platform.
• Cellectis presents the first pre-clinical data on UCARTMESO, a TALEN-edited allogeneic CAR-T cell therapy candidate designed to target mesothelin, which is expressed by certain solid tumours. The data demonstrated potent activity of UCARTMESO in vitro and in vivo against mesothelin-expressing cell lines, and in vivo activity in mouse models of pancreatic and pleural mesothelioma.
• Editas Medicine presents pre-clinical data on its novel engineered IPSC-derived natural killer (iNK) cells for the treatment of cancer at the Society For Immunotherapy of Cancer 36^th Annual Meeting. The company is deploying its proprietary CRISPR/Cas12a-mediated SLEEK (SeLection by Essential-gene Exon Knock-in) technology to achieve high levels of expression of CD16 and Interleukin-15 (IL-15) in iNK cells, modifications that resulted in improved serial tumour killing and dramatically increased NK cell persistence.
• Metagenomi presents in vivo pre-clinical gene-editing data using a small, hypoimmune CRISPR-associated Type V gene-editing system at The Liver Meeting of American Association for the Study of Liver Diseases held virtually this week. The presentation revealed that the company’s novel Type V CRISPR-associated nuclease was highly active in mice livers when systemically administered via lipid nanoparticles (LNP), and that no antibodies to this nuclease were detected in serum from 50 healthy human donors.
• Metagenomi is to present at CRISPR 2.0 Conference late this week, with three highlighting the company’s novel compact adenine base editor, novel CRISPR systems optimised for cell therapy development, and Metagenomics Discovery Engine.
• ElevateBio announces issuance of U.S. patent providing protection for RNA-guided nucleases identified through its Life Edit Gene-Editing Platform. According to a company press release, this patent is the first to provide composition and methods of use protection for various RNA-guided nucleases (RGNs) in Life Edit’s gene-editing platform. Life Edit is an ElevateBio company and holds an array of novel RGNs and base editors.

Reviews

• CRISPR and KRAS: a match yet to be made. In this review, cancer researchers from Germany and the Netherlands highlight the work published on CRISPR applications targeting KRAS mutations and KRAS-related molecules, focusing on lung, colorectal and pancreatic cancers. Following an overview on what has been done in this area so far, the authors conclude that, for now, despite its potential, CRISPR remains to be underutilised for targeting KRAS mutations in cancer.

COVID-19

• CEO of Mammoth Biosciences, Trevor Martin, discusses the role of CRISPR technology in COVID-19 testing, in an interview with Shery Ahn from Bloomberg on the sidelines of Bloomberg's New Economy Forum in Singapore. Watch and listen to their chat here.
• Scientists in China have designed and analytically validated a CRISPR-Cas12a system for direct detection of SARS-CoV-2 variants of concern. Their approach combines ordinary reverse transcription-PCR (RT-PCR) and CRISPR-Cas12a to improve the detection sensitivity, and they demonstrated that the multiplex allele-specific assay could rapidly detect a range of signature spike protein mutations (including K417N/T, L452R/Q, T478K, E484K/Q, N501Y, and D614G) to distinguish alpha, beta, gamma, delta, kappa, lambda, and epsilon variants of SARS-CoV-2. The findings were published in Microbiology Spectrum yesterday.
• Researchers in Spain describe application of the CRISPR-Cas12a system to detect SARS-CoV-2 genomes harboring the E484K escape mutation, independantly of sequencing. They then analysed a series of foecal samples from hospitalised patients in Spain, and detected one infection with SARS-CoV-2 harbouring E484K. The authors argue that CRISPR diagnostics can be a useful tool in epidemiology to monitor the spread of such escape mutations, and their results were published in ACS Synthetic Biology yesterday.

3rd Quarter company financial reports

• Gamida Cell: Third Quarter 2021 Financial Results and Company Update. Gamida provides brief updates covering the recent expansion of its NAM-enabled natural killer (NK) cell pipeline targeting solid tumours and blood cancers, including genetically-modified variants of proprietary NK therapies using both CRISPR-Cas9 and CAR methodologies.