CMN Weekly (25 March 2022) - Your Weekly CRISPR Medicine News

Top picks

• In an article published in Gene Therapy this week, scientists from ChristianaCare’s Gene Editing Institute report that CRISPR-induced exon skipping can influence the response to conventional chemotherapy in lung cancer cells. The team, which is developing a new combination cancer therapy using CRISPR to knock out the NRF2 gene to render cancer cells more susceptible to chemotherapy, suggests the need for detailed analysis of DNA sequence alterations following CRISPR-Cas gene editing to evaluate how small precise changes created by guide RNA design and execution could have dramatic effects on phenotypic outcomes.
• Don't miss our upcoming webinar about CRISPR-based Control of Insect-borne Diseases. The webinar, hosted by CRISPR Medicine News, will feature a presentation by Professor Omar Abkari from University of California, San Diego, about his team's efforts to develop a precise and scalable CRISPR system for mosquito population control. Sign up to this free webinar here.

Research

• Scientists from AstraZeneca report two strategies to install precise genomic insertions using an SpCas9 nuclease-based prime editor (PEn). The new approach to targeted DNA insertion builds upon prime-editing technology and uses PEn, which combines Cas9 with a reverse transcriptase. They show that this approach can use a range of efficient DNA repair pathways including non-homolgous end joining (NHEJ), which robustly introduces programmed small insertions at DNA double-strand breaks. They also demonstrate that, unlike CRISPR-Cas9, PEn does not induce large unintended deletions at the target site, and this is because PEn efficiently disrupts Cas9 cleavage by destroying its binding site after a successful DNA insertion. The findings were reported in Nature Communications yesterday.
• CRISPR–Cas systems store fragments of foreign DNA, called spacers, as immunological recordings in so-called CRISPR arrays, which are used to combat future infections. Of the many spacers in an array, the most recent ones are prioritised for immune defence, However, the underlying mechanism remains unclear. Researchers in Germany are now closer to solving this mystery, by showing that the leader region upstream of CRISPR-Cas9 arrays enhances CRISPR RNA (crRNA) processing from the newest spacer, thus prioritising defence against the matching invader. The findings were published in Nature Microbiology earlier this week.
• In an article published in Nucleic Acids Research earlier this week, researchers in the U.S. show that fusing Escherichia coli DNA polymerase I to Cas9 greatly increases the frequencies of 1-bp deletions and decreases >1-bp deletions or insertions. The approach also greatly decreased the generation of long deletions, including those >2 kb, and templated insertions were increased relative to other insertions. The authors report that counteracting DNA resection was one of the mechanisms perturbing deletion sizes and suggest that their strategy makes it possible to generate refined DNA mutations for improved safety without compromising genome-editing efficiency.
• Researchers in Greece, Germany and UK report a protocol for the targeted induction of a large chromosomal inversion (>3.7 Mbp) through CRISPR-Cas9-mediated genome editing. As inversions occur at low frequency following Cas9 cleavage, they provide a detailed screening approach of FACS-sorted, single-cell-derived clonal human bronchial epithelial cell (HBEC) cultures. The authors note that although the protocol is tailored to HBECs, it can be readily applied to additional adherent cellular models. The protocol was published recently in STAR protocols.

Industry

• Spotlight Therapeutics has raised $36.5 million in Series B funding to advance its pipeline of cell-targeted in vivo CRISPR-based gene-editing biologics for a range of therapeutic areas including cancer and eye diseases. The company's proprietary technology platform, TAGE (Targeted Active Gene Editors) comprises a new class of biologics that are highly engineered, modular programmable CRISPR effectors designed to target and edit selected cell types in vivo.
• Caribou Biosciences reports fourth quarter and full year 2021 financial results and provides a business update. Among the updates were plans to present initial clinical data at a medical meeting in 2022 from the ongoing ANTLER Phase 1 for CB-010, the company's lead allogeneic cell therapy candidate for B cell non-Hodgkin lymphoma. The company also plans to file an IND application CB-011 this year. CB-011 is an allogeneic cell therapy candidate for multiple myeloma.
• This week, Graphite Bio reported recent business progress as well as fourth quarter and fiscal year 2021 financial results. Patient enrollment is now ongoing at multiple sites for the Phase 1/2 CEDAR clinical trial of GPH101 for sickle cell disease. The company plans to dose the first patient in the second half of 2022, with initial proof-of-concept data anticipated in 2023.
• Allogene Therapeutics announced earlier this week that it had published data from a pre-clinical study highlighting superior tumour killing by healthy donor-derived allogeneic CAR-T cells over patient-derived cells in a BCMA-targeting CAR T therapy for multiple myeloma. The findings were published in Cancer Research Communications.
• CRISP-HR has joined Illumina Accelerator's fourth global funding cycle in the San Francisco Bay area. CRISP-HR Therapeutics is a CRISPR biotech based in California, which aims harness CRISPR-Cas9 technology to transform the treatment landscape for patients with genetic diseases using its next-generation Cas9-HR gene-editing platform.

Reviews

• Auditing the Editor: A Review of Key Translational Issues in Epigenetic Editing. This review highlights recent developments with epigenetic editing technology in comparison with CRISPR-Cas genome editing. The epistemic and ethical considerations with preemptive translation of epigenetic editing into clinical or commercial use in humans are taken int account, as well as key considerations in safety, equity, and access to epigenetic editing in the context of global health equity.
• CRISPR Diagnostics: Advances toward the Point of Care. This review outlines recent developments and advancements in CRISPR diagnostics that have pushed these technologies to the point of care.
• Methods for CRISPR-Cas as Ribonucleoprotein Complex Delivery In Vivo. Poor delivery efficiency and low editing efficacy are known to reduce the overall potency of in vivo genome editing. This review looks at how this obstacle is currently being addressed by the scientific community and what types of in vivo delivery methods based on Cas9/sgRNA ribonucleoproteins (RNPs) have been developed.
• RNA-targeting and gene editing therapies for transthyretin amyloidosis. This review includes a discussion about current RNA silencing approaches explored for the treatment of amyloid TTR (ATTR) amyloidosis as well as the latest genome-editing strategies based on CRISPR-Cas9 to reduce transthyretin (TTR) gene expression.
• Stereotaxic-assisted gene therapy in Alzheimer's and Parkinson's diseases: Therapeutic potentials and clinical frontiers. The authors of this expert review summarise the studies that have explored gene therapy for Alzheimer's disease (AD) and Parkinson's disease (PD) in animal and clinical studies over the past five years, with a special emphasis on the combinatorial potential with stereotaxic delivery, .i.e., local delivery of therapeutic genetic cargos to well-defined brain sites. The advantages, limitations and futuristic challenges of this technique are discussed.
• CRISPR/Cas9 and next generation sequencing in the personalized treatment of cancer. With rapid advances in next-generation sequencing (NGS) and CRISPR-Cas9, the goal within cancer therapy is moving from matching the treatment for the diagnosed tumour towards building a treatment that fits the tumour exactly. In this review, the authors discuss the potential role of CRISPR-Cas9 and NGS in advancing personalised medicine for cancer.
• CRISPR/Cas-Based Gene Editing Strategies for DOCK8 Immunodeficiency Syndrome. The authors of this review discuss the potential application of different CRISPR-Cas-based therapies to correct DIDs, which is a combined immunodeficiency caused by mutations in the DOCK8 gene. The authors suggest that their findings encourage the pursuit of CRISPR-Cas-based gene-editing approaches to develop precise, affordable, and low-risk definitive treatment options for DOCK8 deficiency.

News from CRISPR Medicine News

• Monday's interview reported how researchers in South Korea have turned CRISPR-Cas9 as a cancer killer. In a first proof-of-concept study, they confirm the feasibility of using CRISPR-Cas9 to selectively kill cancer cells in various disease models by targeting cancer-specific InDels. Read the interview here.
• This week's clinical update included news about two gene-editing trials for cancer.Iovance Biotherapeutics' new cancer immunotherapy candidate OV-4001 has been cleared for clinical trial initiation in the U.S. In additional news, the first patient has been dosed in Wugen's WU-CART-007 trial for certain blood cancers. Read the clinical update here.
• Our sister site CARBON - CRISPR AgroBio News - published another newsletter last Tuesday. Check it out to read about how you can soon indulge in healthier peanuts with less saturated fat. Read the CARBON newsletter here.