Gene therapy death not caused by CRISPR, investigators confirm. STAT News reports findings shared yesterday on the preprint server Medrxiv, revealing that the unexpected death of a duchenne muscular dystrophy patient eight days after receiving a gene-editing treatment in an N-of-1 clinical trial was not caused by gene editing. The patient, Terry Horgan, was treated with a dCas9-VP64 transgene designed to upregulate cortical dystrophin as a custom DMD therapy. The investigators concluded that a fatal innate immune response to the adeno-associated virus used to deliver the treatment was the most likely cause of death.
Resistance to the chemotherapeutic sorafenib poses challenges to the treatment of hepatocellular carcinoma, in which cancer stem cells (CSCs) plays a crucial role. CRISPR-Cas9 may offer a solution to sorafenib resistance in HCC, however, safe and efficient target-specific delivery remains outstanding. Recognising the untapped potential of extracellular vesicles (EVs) in this regard, a team of scientists in China and Korea explored a combination therapeutic approach using engineered EVs derived from normal epithelial cells, to deliver CRISPR-Cas9 reagents targeting the IQGAP1 and FOXM1 genes, both of which are needed for sorafenib resistance. They found that the combination therapy resulted in a synergistic anti-cancer effect both in vitro and invivo, and that that disruption of IQGAP1 and FOXM1 resulted in the reduction of CD133+ population that contributes to the stemness of liver cancer cells. The findings were published yesterday in Journal of Nanobiotechnology.
Scientists in China have undertaken a parallel comparison of four promoters (CAG, ~ 1700 bp; EF1a core, ~ 210 bp; CMV, ~ 500 bp; and PGK, ~ 500 bp) that are commonly used in conjunction with CRISPR-Cas12a editing in mammalian cells, where CRISPR-Cas12a reagents are delivered on plasmid vectors. Based on their findings, they recommend that CAG be used in applications that demand robust editing activity but without size limitation, CMV is a good alternative for CAG when size limitation is an issue, EF1a is comparable to PGK with relatively high specificity, but has a smaller size, and thus is more suitable for in vivo therapeutic applications. The findings were published this week in Cellular & Molecular Biology Letters.
A team of researchers in the United States reported in Discovery Oncology yesterday that virus-like particle (VLP)-based delivery of Cas9-gRNA ribonucleoprotein (RNP) efficiently edits the brachyury gene and inhibits the growth of the rare bone tumour, chordoma, in vivo. Chordoma is driven by the developmental transcription factor brachyury, which is difficult to target given the absence of ligand-accessible small-molecule binding pockets. To investigate the potential of CRISPR-Cas9 in treating chordoma, the team developed a strategy based on Cas9-gRNA RNP delivery through a novel VLP by fusing an aptamer-binding protein to the lentiviral nucleocapsid protein. They found that the "all-in-one" VLP-based Cas9-gRNA RNP system led to transient Cas9 expression in chordoma cells, but maintained efficient editing capacity leading to approximately 85% knockdown of brachyury with subsequent inhibition of chordoma cell proliferation and tumour progression. They also report that the VLP-packaged brachyury-targeting Cas9 RNP avoids systemic toxicities in vivo.
In an article published earlier this week in Nature Communications, scientists from Verve Therapeutics and University of Pennsylvania report the use of structure-guided rational design in murine and non-human primate (NHP) studies to optimise a GalNAc-lipid nanoparticle that permits low-density lipoprotein receptor-independent delivery. In low-density lipoprotein receptor-deficient NHPs that were administered a CRISPR base-editing therapy targeting the ANGPTL3 gene, the introduction of an optimised GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in non-targeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing.
Earlier this week, Verve Therapeutics announced pipeline progress and expansion, and reported first quarter 2023 financial results. The company's most advanced in vivo base-editing therapy VERVE-101, which is designed to permanently switch off the PCSK9 gene, is currently being evaluated in the heart-1 clinical trial for heterozygous familial hypercholesterolemia (FH). The company is also developing a second candidate targeting PCSK9, VERVE-102 for the treatment of FH , as well as VERVE-201 for the treatment of homozygous FH.
German biotech company Vivlion announced recently that it would provide services to clinical-stage precision oncology company Repare Therapeutics on advanced PRCISR™ CRISPR gRNA libraries. Under the agreement, Vivlion will provide its customised PRCISR™ CRISPR libraries for Repare’s synthetic lethality screening applications. Vivlion’s proprietary PRCISR™ CRISPR technology removes the need for PCR amplification, resulting in gRNA libraries with unrivaled uniformity. Read more in the press release here.
Synthego announced yesterday that the U.S. Patent Office has invalidated two Agilent Technologies patents covering CRISPR guide RNAs. The two patents held by Agilent Technologies cover the chemical modification of CRISPR guide RNAs and their use in gene editing. Read more in the press release here. Agilent announced in a press release published today that it would be appealing the decision made by the U.S. Patent Office.
Yesterday, Revvity (U.S.) announced a new license agreement with AstraZeneca for the technology underlying its Pin-point™ base-editing system, a next-generation modular gene-editing platform with a strong safety profile. The non-exclusive agreement will give AstraZeneca access to proprietary gene-editing technology to help advance its work in cell therapy.
Scribe Therapeutics announced earlier this week that it has entered a collaboration with Prevail, a wholly owned subsidiary of Lilly, to accelerate in vivo CRISPR-based therapies for neurological and neuromuscular diseases. The $1.5B partnership will see Preveal gain exclusive rights to Scribe’s CRISPR X-Editing (XE) technologies, and includes an option for Scribe to co-fund and share profits on one programme from the collaboration.
American Society of Gene and Cell Therapy (ASGCT) 26th Annual Meeting
Metagenomi, a genetic medicines company with a portfolio of wholly owned, next-generation gene-editing systems, presented new data for its gene-editing programmes at the ongoing 26th ASGCT annual meeting. The presentations demonstrate enhanced efficiency of Metagenomi’s proprietary type V and type II nucleases, first-in-class CAST systems for large, targeted DNA integration capabilities, and novel base-editing systems. Metagenomi also presented proof of concept data in non-human primates, demonstrating the potential therapeutic translation of the company's lead novel nuclease technologies.
Be Biopharma, a company pioneering the discovery and development of engineered B cell medicines (BeCMs) presented pre-clinical research yesterday at the 26th ASGCT annual meeting, demonstrating the precise genome-engineering of human B cells to express diverse therapeutic proteins using the company’s proprietary platform. Be Bio has designed a versatile CRISPR-Cas9 engineering platform capable of delivering a gene of interest via homology-directed repair to produce stable BeCMs.
ArsenalBio announced oral and poster presentations highlighting pre-clinical data on two of its gene-edited integrated circuit T (ICT) cell therapies AB-1015 and AB-2100 at this year's ASGCT annual meeting. The company is developing gene-edited CAR-T cell therapies for a range of solid tumours, including ovarian and kidney cancer. AB-1015 is currently being evaluated in a Phase 1 trial for the treatment of ovarian cancer. For more details, see the company's press release here.
Prime Medicine also announced that it would present data at the ongoing 26th ASGCT annual meeting. The company is expected to present new pre-clinical data highlighting the broad potential of its PASSIGE™ prime-editing platform to generate multiplex-edited CAR-T cells without using viruses. In addition, the company will also present data demonstrating the potential of prime editing to correct the causative mutation of chronic granulomatous disease.
Poseida Therapeutics presented encouraging pre-clinical data in six presentations encompassing its gene therapy programmes ASGCT 2023 Annual Meeting. The data includes proof-of-concept for site-specific knock-in of a transgene using Cas-CLOVER™, which is Poseida's high-precision gene-editing technology co-formulated with gRNAs as a single lipid nanoparticle. According to the company's press release, the data demonstrated highly efficient editing and favorable tolerability in mice following a single dose of Cas-CLOVER with extremely low off-target editing in the liver. The study establishes proof-of-concept for knock-in of a transgene using Cas-CLOVER and a fully non-viral delivery system in mice and further supports the potential of this technology to develop effective therapies for rare diseases.
CRISPR in Public Health: The Health Equity Implications and Role of Community in Gene-Editing Research and Applications. This article introduces CRISPR and its potential public health benefits, such as improving virus surveillance and curing genetic diseases that pose public health problems, while outlining several major ethical and practical threats to health equity. This includes minorities' grave underrepresentation in genomics research, which may lead to less effective and accepted CRISPR tools and therapies for these groups, and their anticipated unequal access to these tools and therapies in health care.
Deadly mushroom poison might now have an antidote — with help from CRISPR. This news piece by Nature summarises how CRISPR scientists might have finally solved the mystery of how death cap mushrooms (Amanita phalloides) kill hundreds of people each year. When researchers in China and Australia recently identified a potential antidote, they also zoomed in on the biochemical pathway in humans that is necessary for the mushrooms’ toxin — called α-amanitin — to enter cells. The antidote, a chemical named indocyanine green, interrupts that pathway. The scientists reported these findings in Nature Communications earlier this week.
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