CMN Weekly (2 February 2024) - Your Weekly CRISPR Medicine News

Top picks

• This week, the US FDA released its final guidance for industry on "Human Gene Therapy Products Incorporating Humane Genome Editing". In that document, which can be found here, the FDA provides recommendations to sponsors developing human gene therapy products incorporating genome editing (GE) of human somatic cells. The FDA Center for Biologics Evaluation and Research Office of Therapeutic Products is hosting a free, virtual public webinar on Thursday, February 29 at 1:00 p.m. to highlight key considerations in the final guidance. Register for the webinar here.

Research

• In an article published this week in Nature Biotechnology, a team from the Buchholz lab at the TU Dresden in Germany reports the development of a zinc-finger conditioned recombinase which combines the targeting ease of programmable nucleases and the precise DNA editing capabilities of recombinases. The technology is considered to overcome existing limitations in genome editing and will be advanced towards therapeutic use by the biotechnology company Seamless Therapeutics to develop a pipeline of disease-modifying product candidates across a broad spectrum of indications.
• Scientists at the clinical stage mRNA-immunotherapy company Myeloid Therapeutics (US) have introduced CREATE, the 'CRISPR-Enabled Autonomous Transposable Element'. CREATE is an RNA-based genome-editing system that merges CRISPR-Cas9 with the human L1 retrotransposon to insert gene-sized payloads without DNA donors or double-strand breaks. In a manuscript shared on the pre-print server bioRxiv, the team demonstrates that CREATE allows L1-mediated reverse transcription and integration of an RNA-encoded payload gene specifically at two Cas9-induced nick sites. CREATE is delivered using mRNA components and achieves integration of >1 kb payload in mammalian cells, which could pave the way for in vivo mRNA-mediated therapeutic genome editing.
• Researchers at Arc Institute (US) and the University of California, Berkeley report the development of RESPLICE - RNA-guided trans-splicing with Cas editor - which is inspired by the rare, natural process of trans-splicing that joins exons from two distinct primary transcripts. According to a manuscript shared on bioXriv, RESPLICE uses two orthogonal RNA-targeting CRISPR effectors to co-localise a trans-splicing pre-mRNA and to inhibit the cis-splicing reaction, respectively. The team reports efficient, specific, and programmable trans-splicing of multi-kilobase RNA cargo into nine endogenous transcripts across two human cell types, with up to 45% trans-splicing efficiency in bulk, or 90% when sorting for high effector expression.
• In a recent article in Nature Biotechnology, a team of researchers led by Jennifer Doudna demonstrates that cell surface marker recognition by antibody fragments displayed on membrane-derived particles encapsulating CRISPR–Cas9 protein and guide RNA can deliver genome-editing tools to specific cells. They show that antibody-targeted Cas9-enveloped delivery vehicles preferentially confer genome editing in cognate target cells over bystander cells in mixed populations, both ex vivo and in vivo.
• Scientists in China present CRISPR-TE, a web-based application to design single guide RNAs (sgRNAs) targeting transposable elements (TEs). CRISPR-TE features an accessible graphical user interface, which is currently tailored to the human and mouse genomes. According to an article published yesterday in Mobile DNA, CRISPR-TE identifies all potential sgRNAs for TEs and provides a comprehensive solution for efficient TE targeting at both the single copy and subfamily levels.
• To circumvent one of the current bottlenecks of prime editing, namely the competition of the reverse-transcribed 3' flap with the original 5' flap DNA, a team in Germany generated an enhanced fluorescence-activated cell sorting reporter cell line to develop an exonuclease-enhanced PE strategy ('Exo-PE'). Exo-PE is composed of an improved PE complex and an aptamer-recruited DNA-exonuclease to remove the 5' original DNA flap. The team demonstrates that Exo-PE achieves better overall editing efficacy than the reference PE2 strategy for insertions ≥30 base pairs in several endogenous loci and cell lines, while maintaining the high editing precision of PE2. By enabling the precise incorporation of larger insertions, Exo-PE complements the growing palette of different PE tools and spurs additional refinements of the PE machinery. Their findings were published yesterday in Nature Methods.

Industry

• Intellia Therapeutics shared positive interim clinical results from the Phase 1 portion of the ongoing Phase 1/2 trial of NTLA-2002 in hereditary angioedema (HAE) this week. NTLA-2002 is an investigational in vivo CRISPR-based gene editing therapy in development as a single-dose treatment for HAE, and the results were published online in the New England Journal of Medicine.
• 2seventy bio announced a new strategic path forward this week, which includes the sale of its R&D pipeline to Regeneron to launch Regeneron Cell Medicines business, which will be led by 2seventy bio’s Chief Scientific Officer, Philip Gregory. According to a press release, Regeneron will fully acquire 2seventy’s dual-targeting CAR-T cell therapy bbT369 in B-cell non-Hodgkin lymphoma, SC-DARIC33 in acute myeloid leukaemia, MUC16 for ovarian cancer, and several other targets, some of which are developed using 2seventy bio's megaTAL gene-editing technology.
• Tome Biosciences announced this week that it has appointed industry veteran Daniel Curran, MD, to its board of directors. Dr. Curran was most recently Head of Rare Genetics and Hematology at Takeda Pharmaceuticals. Read the full announcement here.
• Prime Medicine announced that its President and CEO Keith Gottesdiener, M.D. will participate in a fireside chat at the Guggenheim Healthcare Talks 6^th Annual Biotechnology Conference on Thursday, February 8, 2024, at 2:00 p.m. ET in New York, NY. A live audio webcast of the fireside chat will be available under “Events & Presentations” in the News & Events section of the Company’s website at www.primemedicine.com.
• Verve Therapeutics announced that Sekar Kathiresan, M.D., co-founder and chief executive officer, will participate in a fireside chat at the Guggenheim Healthcare Talks 6^th Annual Biotechnology Conference on Thursday, February 8, 2024 at 11:30 a.m. ET in New York. A live webcast will be available in the investor section of the company's website at www.vervetx.com.
• Editas Medicine has announced that its management will participate in two upcoming investor conferences to discuss the company and its programmes, including its lead asset reni-cel (EDIT-301, which is being developed as a one-time treatment severe sickle cell disease and transfusion-dependent beta thalassemia. This includes a fireside chat at the Guggenheim Healthcare Talks 6^th Annual Biotechnology Conference (Wednesday, February 7, at 9.30 a.m. ET in New York), and a virtual firechat chat at the Oppenheimer 34th Annual Healthcare Life Sciences Conference (Tuesday, February 13, at 8.40 a.m. ET)

CRISPR screens

• In a manuscript entitled 'A benchmark of computational methods for correcting biases of established and unknown origin in CRISPR-Cas9 screening data', scientists at Human Technopole in Milan share the results of their efforts to benchmark seven of the latest methods to emerge within CRISPR screening analysis. The team rigorously evaluated the effectiveness of these seven appraoches for the first time in reducing both copy number amplification bias and proximity bias in the two largest publicly available cell-line-based CRISPR-Cas9 screens to date. In addition, the team evaluated the ability of each method to preserve data quality and heterogeneity by assessing the extent to which the processed data allows accurate detection of true positive essential genes, established oncogenetic addictions, and known/novel biomarkers of cancer dependency. Their findings can be read on bioXriv here.
• Alternative polyadenylation (APA) is strikingly dysregulated in many cancers and associated with poor prognosis, yet the importance of most individual APA events remains elusive. To address the gaps in our understanding of APA, a team of researchers at multiple institutions in the US performed a CRISPR-Cas9-based screen to manipulate endogenous polyadenylation and systematically quantify how APA events contribute to tumour growth in vivo. Among their findings, published in Nature Communications, was the identification of individual APA events that control mouse melanoma growth in an immunocompetent host, with concordant associations in clinical human cancer.

Reviews and commentary

• Revolutionizing in vivo therapy with CRISPR/Cas genome editing: breakthroughs, opportunities and challenges. This review examines emerging studies, focusing on CRISPR-Cas-based pre-clinical and clinical trials for new therapeutic approaches for a wide range of diseases. The authors emphasise approaches that involve targeting of cancer-specific sequences in tumour-associated genes, shedding light on the diverse strategies employed in cancer treatment. They furthermore highlight the challenges associated with in vivo CRISPR-Cas-based cancer therapy and explore their prospective clinical translatability as well as the strategies employed to overcome these obstacles.
• Sharper scissors: How TREX2 fine-tunes CRISPR-Cas9 nickases for precise editing. This commentary published in Molecular Therapy Nucleic Acids examines the methodology, results, and implications of a recent study that presented a novel approach involving TREX2 and paired CRISPR-Cas9 nickases to enhance genome-editing efficiency and safety.

News from CRISPR Medicine News

• This week's clinical trial update focused on news from Ascidian Therapeutics, which announced this week that the FDA has cleared its investigational new drug (IND) application and granted fast track designation to ACDN-01. ACDN-01 is an RNA-editing candidate designed to treat Stargardt disease. Read the news here.
• Last Friday, we launched CMN Live. For the inaugural session, we spoke with Dr. Eric Kmiec, who is the Scientific Director at the ChristianaCare Gene Editing Institute in Delaware and Chief Scientific Officer at CorriXR Therapeutics. We discussed the successes of therapeutic gene editing to date and the challenges that lie ahead. Watch the recording of that live discussion here.