CMN Weekly (17 March 2023) - Your Weekly CRISPR Medicine News

Top picks

• Gene therapies for inherited skin diseases using CRISPR technology might require special consideration, according to American researchers. They demonstrated that CRISPR transfection in keratinocytes activates antiviral responses that lead to the induction of IFN-κ and decreased plasmid stability. However, JAK inhibition via baricitinib before CRISPR transfection restored regular IFN-κ activity and increased transfection efficiency.
• Science reports from the recent Third International Summit on Human Genome Editing at the Francis Crick Institute in London and concludes that while the gene-editing summit touts sickle cell success, questions on embryo editing linger. The surge in trials that alter nonheritable DNA excites some researchers, but others wonder whether even high-income countries can afford the therapies.
• Chinese scientist Jiankui He, who defied the law and bioethics basics by attempting to create the world's first CRISPR gene-edited babies, is now out of jail. On Twitter, he is recruiting patients and raising funds for more trials, this time in adults, not embryos. In a Science Friction podcast from ABC Radio National, Joy Zhang, founding director of the Centre for Global Science and Epistemic Justice at the University of Kent, and Dr Katie Hasson, Associate Director of the Center for Genetics and Society, discusses if this is an unhelpful distraction or a cautionary lesson for the world's scientists?

Research

• A study from the Wellcome Sanger Institute in Cambridge, UK, has started to map out the rules for using CRISPR activation (CRISPRa) techniques most effectively. The study finds that gene activation by dCas9-VPR is successful in most genomic contexts, whereas dCas9-p300 is ineffective in stem cells. Moreover, certain chromatin states, such as bivalent chromatin, are particularly sensitive to dCas9-VPR, whereas constitutive heterochromatin is less responsive.
• Researchers in China have engineered a photoswitch on G-quadruplex gRNA (GqRNA) for precisely controlled gene editing and expression by embedding dicationic azobenzene derivatives (AZD++). Light-induced isomerisation of AZD⁺⁺ quickly transformed the "on state" of GqRNA, facilitating rapid activation of ribonucleoprotein activity for genome editing of on-target sites in cells with excellent editing efficiency.
• Japanese researchers have found a way to promote the more precise homology-directed repair (HDR) pathway after CRISPR gene editing with Streptococcus pyogenes Cas9 (SpyCas9). The researchers fused the anti-CRISPR protein AcrIIA5 to Chromatin licensing and DNA replication factor 1 (Cdt1) and used it to regulate SpyCas9 fused to human Geminin, thereby significantly increasing HDR efficiency and reducing off-target effects.
• Researchers in China report a dual-activatable binary CRISPR nanomedicine (DBCN) that can efficiently deliver a CRISPR system into tumour tissues and precisely control its activation. The DBCN includes an acid-detachable polymer shell that facilitates the cellular internalisation of the CRISPR system after entering tumour tissues. Subsequently, gene editing is activated by exogenous laser irradiation, thereby maximising the therapeutic benefits and reducing potential safety concerns.
• Chinese researchers have used CRISPR-Cas9 technology to knock out CD43 expression in a murine colorectal cancer (CRC) model. The researchers found that loss of CD43 facilitated the infiltration of immune cells and immunological memory in the tumour immune microenvironment of CRC tumours and synergistically improved PD-L1 blockade immunotherapy for CRC.

Industry

• For those wanting to invest in CRISPR gene editing, The Motley Fool lists the top five exchange-traded funds (ETFs) that track companies in this biotech space.
• ProQR Therapeutics has successfully defended against two oppositions filed against a critical patent for its ADAR-mediated RNA editing platform Axiomer. The European Patent Office (EPO) has ruled in favour of ProQR's position after a minor amendment of the main claim and one dependent claim.
• Artisan Bio and Takeda have announced an extension of their research collaboration which leverages Artisan's genome editing technology to facilitate Takeda's cell therapy research programs. Under the terms of the agreement, Artisan Bio will receive additional funding to provide its genome editing tools for Takeda. At the same time, Takeda will be responsible for developing, manufacturing, and commercialising any potential resulting cell therapy products.

Financial results and updates

• Century Therapeutics provides business updates and reports full-year 2022 financial results. The year ended with a cash position of $367 million, revenue of $5 million and a net loss of $131 million. In February, the company dosed the first-in-human phase 1 ELiPSE-1 trial evaluating CNTY-101 in relapsed or refractory CD19-positive B-cell lymphomas.

American Association of Cancer Research (AACR) Annual Meeting, April 14-19

• Cellectis will present preclinical data exploring the purposeful armouring of CAR T-cells to enhance the efficacy of MUC1 CAR T-cells in targeting triple-negative breast cancer.
• CRISPR Therapeutics will present an oral presentation entitled "CTX112 and CTX131: Next-generation CRISPR/Cas9-engineered allogeneic (allo) CAR T cells incorporating novel edits that increase potency and efficacy in the treatment of lymphoid and solid tumors".
• Allogene Therapeutics will present an oral presentation of interim data from its Phase 1 TRAVERSE trial of ALLO-316, the company's first AlloCAR T candidate for solid tumours.

Detection

• Researchers in South Korea have developed a dCas9-mediated, PCR-free assay for detecting oncogenic mutations in EGFR DNA, a carcinogenesis indicator. In one minute, the assay can detect single base substitutions in EGFR, and the presence/absence of mutations is identified at a glance, like a commercial pregnancy test kit.

Reviews

• Recent advances in CRISPR-based genome editing technology and its applications in cardiovascular research. This review summarises the advances involving newly identified Cas orthologs, engineered variants and novel genome editing systems. Then it discusses the applications of the CRISPR-Cas systems in precise genome editing, such as base editing and prime editing.
• Shaping the future from the small scale: dry powder inhalation of CRISPR-Cas9 lipid nanoparticles for the treatment of lung diseases. This review is focused on the delivery of CRISPR-Cas9 to the lungs, taking advantage of lipid nanoparticles (LNPs), the most clinically advanced nucleic acid carriers.
• New advancements in CRISPR based gene therapy of Duchenne Muscular dystrophy. The review provides an overview of recent progresses in dystrophin gene editing using updated versions of CRISPR to introduce novel opportunities in DMD gene therapy.
• Genome-engineering technologies for modelling and treatment of cystic fibrosis. The review outlines the potential and possibilities of using the CRISPR-Cas9-based gene-editing technology in cystic fibrosis modelling.
• Mechanisms regulating the CRISPR-Cas systems. This review from researchers in Poland summarises current knowledge of the various molecular mechanisms that affect the activity of CRISPR-Cas systems.
• The potential of gene editing for Huntington’s disease. This review presents recent preclinical findings demonstrating the efficacy of such gene-editing approaches in animal models. In addition, it describes potential CRISPR-Cas designs and cellular delivery methods that might be used to correct mutant genes.

Opinions and perspectives

• An article in Nature discusses why CRISPR babies are still too risky and points to recent embryo studies highlighting challenges. It is argued that while society grapples with the social and ethical implications of heritable genome editing, technical obstacles still abound.
• A plastic surgeon suggests that CRISPR could be the future of pediatric craniofacial surgery. He argues that many of the most morbid conditions treated by craniofacial surgeons are syndromic craniosynostoses caused by mutations in fibroblast growth factor receptor (FGFR) genes. The plastic surgeon believes CRISPR could be used to develop "off-the-shelf" gene editing therapies to correct these mutations in affected children.

News from CRISPR Medicine News

• On Wednesday, we broke the news that the FDA has cleared an Investigational New Drug application for NTLA-2002, a single-dose in vivo CRISPR therapeutic candidate designed to cure hereditary angioedema. This allows the company to include the United States in the global Phase 2 portion of Intellia's ongoing Phase 1/2 trial of NTLA-2002.