CMN Weekly (11 October 2024) - Your Weekly CRISPR Medicine News

Top pick

• Intellia Therapeutics announced earlier this week that it has initiated a global, pivotal Phase 3 trial of NTLA-2002 for the treatment of hereditary angioedema (HAE). The trial, called HAELO, will enrol 60 adult patients who will be randomised 2:1 to receive a single intravenous infusion of NTLA-2002 or a placebo. NTLA-2002 is an in vivo gene-editing candidate designed to knock out the target gene kallikrein B1 (KLKB1) in hepatocytes, to permanently reduce plasma kallikrein activity and halt the production of bradykinin to prevent the inflammatory attacks experienced by HAE patients. NTLA-2002 is administered intravenously as a single dose of Cas9 mRNA and gRNA via lipid nanoparticles. See the official press release for further details.

Research

• In an article published this week in Cell, scientists in the US present the cryo-electron microscopy (cryo-EM) structures of the TnsC-TnsD-att DNA complex and the TnsABCD transpososome from the Tn7-like transposon in Peltigera membranacea cyanobiont 210A, which is a type I-B CRISPR-associated transposon. Their structures reveal a striking bending of the att DNA, featured by the intercalation of an arginine side chain of TnsD into a CC/GG dinucleotide step. The TnsABCD transpososome structure reveals TnsA-TnsB interactions and demonstrates that TnsC not only recruits TnsAB but also directly participates in the transpososome assembly. These findings provide insights into the mechanisms behind targeted DNA insertion by Tn7-like transposons, that may facilitate improvements in their precision and efficiency for genome-editing applications.
• Primary hyperoxaluria type 1 (PH1) is an incurable genetic disorder that causes renal failure due to oxalate accumulation. In an article published this week in Molecular Therapy, scientists at Shanghai Frontiers Science Center of Genome Editing and Cell Therapy and YolTech Therapeutics report pre-clinical data supporting a gene-editing approach to treat PH1. Using lipid nanoparticles (LNPs) to deliver a single dose of CRISPR-Cas9 targeting the Hao1 gene in a PH1 mouse model, the team observed reduced glycolate oxidase expression and urinary oxalate levels, with effects lasting 12 months. No significant side effects were observed. Experiments using a humanised mouse model further validated the efficacy of the therapeutic approach. LNP-CRISPR/Cas9 targeting HAO1 shows promise as a safe, single-dose treatment for PH1, addressing limitations of existing therapies. YolTech Therapeutics is now advancing this approach through the clinic, with an ongoing clinical trial of YOLT-203. You can read more about that in this week's clinical trial update here.
• CRISPR-based correction of pseudogene-associated disorders such as p47^phox-deficient chronic granulomatous disease (p47 CGD) is hampered by chromosomal rearrangements caused by the presence of multiple targets. A team of researchers in Switzerland and Germany reported this week the detection of megabase-scale alterations following editing of the NCF1 gene and its pseudogenes in p47 CGD cell models and patient stem cells. They found that the rearrangements stem from interactions between repetitive sequences, and stress the importance of evaluating genomic context, especially homologous regions, when assessing risks in genome editing of such disorders. Their findings were published in Communications Biology.
• Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure in multiple sclerosis (MS). Researchers in the UK hypothesised that transplantation of oligodendrocyte progenitor cells (OPCs) genetically edited to overcome these obstacles, could improve remyelination. Using CRISPR-Cas9, they edited human embryonic stem cell-derived OPCs (hOPCs) to be unresponsive to a chemorepellent released from chronic MS lesions and transplanted them into rodent models of chronic lesions. They observed that edited hOPCs exhibited enhanced migration and remyelination compared to controls, regardless of host age and length of time post-transplant. They also show that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS. Their findings were published in Nature Communications.
• In an article published this week in Cell Chemical Biology, scientists in China present a strategy to reduce CRISPR-Cas9 off-target effects by optically controlled chemical modifications of guide RNA. By applying this strategy to CRISPR-Cas9 gene editing, they show enhanced gene-editing specificity and reduced off-target effects. Their approach employs a vinyl ether modification in RNA, which is activated under visible light with a phenanthrenequinone derivative, creating a CRISPR-OFF switch that precisely regulates CRISPR system activity. They propose that their approach represents an advance in genomic interventions and also has broad applications in gene regulation, paving the way for safer and more reliable gene editing in therapeutic genomics.
• A team in the US introduce helicase-assisted continuous editing or HACE, a programmable platform for long-range, locus-specific hypermutation. HACE, designed to assist in decoding the context-specific relationship between sequence and function, uses CRISPR-Cas9 to target a processive helicase-deaminase fusion that causes mutations across large (>1000-base pair) genomic intervals. The team applied HACE to identify mutations in mitogen-activated protein kinase 1 (MEK1) that confer kinase inhibitor resistance, to study the impact of mutations on mis-splicing by splicing factor 3B subunit 1 (SF3B1), and to evaluate non-coding variants in a stimulation-dependent immune enhancer of CD69. HACE is presented as a powerful tool for investigating coding and non-coding variants, uncovering combinatorial sequence-to-function relationships, and evolving new biological functions. Their findings were published in Science.

Industry

• Editas Medicine recently announced the sale of certain future license fees and other payments owed to Editas Medicine under its Cas9 license agreement with Vertex Pharmaceuticals to a wholly-owned subsidiary of DRI Healthcare Trust (DRI) for an upfront cash payment of $57 million. According to a press release published by Editas Medicine, the upfront cash payment brings non-dilutive capital to Editas Medicine, helping enable further pipeline development and related strategic priorities.
• ProQR Therapeutics announced earlier this week that it will present pre-clinical data for its proprietary Axiomer™ RNA-editing technology platform and its AX-0810 pipeline programme for cholestatic diseases targeting sodium taurocholate co-transporting polypeptide (NTCP) at the 20th Annual Meeting of the Oligonucleotide Therapeutics Society, held this week in Montreal, QC, Canada. A copy of the oral presentation can be found here.
• HuidaGene Therapeutics announced this week that it will make 11 presentations at the upcoming European Society of Gene and Cell Therapy (ESGCT) 2024 Annual Congress which will be held later this month in Rome. The 10 poster and one oral presentation will include updates from the company's broad pipeline of gene-editing therapeutics to age-related macular degeneration, MECP2 duplication syndrome, Alzheimer’s disease, and ALS, Huntington’s disease, Angelman syndrome, and Duchenne muscular dystrophy. See the official press release for a full overview of the presentations.
• Vertex Pharmaceuticals announced today that it will share third quarter 2024 financial results on November 4th. See the official press release for further details.

Clinical

• Today, Intellia Therapeutics announced that its upcoming investor webcast to review the data from the Phase 2 study of NTLA-2002 will take place on Thursday, October 24 at 8:30 a.m. ET. See the press release for further details.
• Intellia Therapeutics will present new clinical data from the ongoing Phase 1 trial of nexiguran ziclumeran (nex-z) for the treatment of transthyretin (ATTR) amyloidosis at the this year's American Heart Association's (AHA) scientific sessions. Nex-z, also known as NTLA-2001, is jointly developed by Intellia Therapeutics and Regeneron and was the first in vivo CRISPR therapy to be administered to humans via the bloodstream. It is designed to be a single-dose curative treatment for transthyretin amyloidosis by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-Cas9-based inactivation of the TTR gene in liver cells. The presentation at AHA will include safety, reduction in serum TTR and biomarkers of disease progression, and functional capacity data in patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM). For more details, see the official press release here.

Detection and CRISPR screens

• Researchers in China introduced CrisprAIE, a new CRISPR-based nucleic acid detection method combining CRISPR-Cas with aggregation-induced emission luminogens (AIEgens). This method aims to overcome limitations of existing CRISPR diagnostics, including low signal transduction efficiency, poor sensitivity and poor stability. In comparison to conventional methods, CrisprAIE showed improved performance in detecting norovirus and SARS-CoV-2, with 80- to 270-fold higher sensitivity depending on the quencher group used. The technique can be integrated with a portable cellphone-based device and may be adaptable to enhance various CRISPR-based diagnostics. The findings were published in Nature Communications.
• Researchers in Switzerland, China and US report the outcomes of genome-wide CRISPR knockout screens in pleural mesothelioma (PM) cells untaken to systematically unravel genetic vulnerabilities and druggable targets in this type of cancer. The screen identified known as well as new gene factors involved in PM cell proliferation and survival, with an enrichment in stress-responsive pathways including DNA repair, cell cycle, and transcriptional regulation. The findings, published in Lung Cancer, provide an initial landscape of genetic vulnerabilities and provide new opportunities for cancer drug discovery in PM.

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News from CRISPR Medicine News

• In a move to potentially treat blindness, researchers in the US used CRISPR-Cas9 technology to permanently disrupt VEGFA expression in the eyes of rhesus macaques. The treatment reduced choroidal neovascularisation - a major cause of vision loss in conditions like age-related macular degeneration - but also led to retinal damage, probably due to the viral vector used for delivery. Read more in this week's CMN Highlight here.
• In this week's clinical trial update, we brought the latest news from four gene-editing trials sponsored by RenJi Hospital (Shanghai, in collaboration with YolTech Therapeutics), The University of Texas MD Anderson Cancer Center, Poseida Therapeutics, and Intellia Therapeutics. Read the update here.