CMN Weekly (29 March 2024) - Your Weekly CRISPR Medicine News

Top picks

• Researchers in the US have demonstrated that a single local injection of lentiviral particles carrying Cas9 and a gRNA targeting the myocilin gene MYOC reverses disease phenotypes in a mouse model of primary open-angle glaucoma (POAG). The team compared a range of GFP-expressing adeno-associated virus and lentiviral (LV) vectors following intravitreal and intracameral injections. They found that a single intravitreal injection of LV particles expressing Cas9 and MYOC-targeting gRNA led to a significant reduction in intraocular pressure and a decrease in myocilin accumulation in the trabecular meshwork in a mouse model of POAG. The study was published in Science Reports.

Research

• In a recent article published in Nature Communications, scientists based at UC San Diego present the Integrated Classifier Pipeline (ICP), a novel genetic tool that can be used to analyse the mechanisms behind CRISPR-based DNA repair outcomes. Developed in flies and mosquitoes, ICP analyses sequences to help track on- and off-target gene edits introduced via CRISPR-Cas9, and the ways in which they are inherited through generations.
• High levels of MerTK (a tyrosine kinase) expression are associated with poor outcomes in patients with gastric adenocarcinoma. While MerTK has shown therapeutic relevance in several other cancer types, until recently it had not been thoroughly explored as a target for gastric adenocarcinoma. Researchers in Germany have now demonstrated that CRISPR-Cas9-mediated knockout of MerTK reduced cell proliferation and migration in vitro and in vivo, and that a small-molecule inhibitor of MerTK (UNC2025) exhibited a significant therapeutic response in vitro and in vivo. In addition, MerTK inhibition sensitised tumour cells to 5-Fluorouracil (5-FU)-based chemotherapy in vitro. Their findings, published in Cancer Medicine, demonstrate the potential of MerTK as a novel therapeutic target and a prognostic biomarker in gastric adenocarcinoma.
• In an article published in Micromachines, a team of researchers in Argentina, Germany and the US present a novel method that seamlessly integrates CRISPR-Cas9 gene-editing with single-cell isolation methods in induced pluripotent stem cell (hiPSC) lines, utilising the combined power of droplets and hydrogels. Their approach was designed to optimise clonal selection and to reduce the cost and time needed to generate stable genetically-modified cell lines.
• Scientists in Japan report the use of CRISPR-Cas13 to suppress the Borna disease virus (BoDV-1) in persistently-infected cells. BoDV-1 is an RNA virus that infects the brain of various animal species, including humans, and causes fatal encephalitis. BoDV-1 also establishes persistent infection in neuronal cells and causes neurobehavioral abnormalities. The team found that the CRISPR-Cas13 system could be used to efficiently decrease the levels of target viral mRNAs and genomic RNA in persistently-infected cells. They also found that their approach also suppressed BoDV-1 infection if the CRISPR-Cas13 reagents were introduced to cells prior to infection. Their findings were published this week in International Journal of Molecular Science.

Industry

• Beam Therapeutics announced that the UK Medicines and Healthcare Products Regulatory Agency has cleared its clinical trial application for BEAM-302 for the treatment of alpha-1 antitrypsin deficiency (AATD). BEAM-302 is an in vivo liver-targeting lipid-nanoparticle-based base-editing formulation designed to precisely correct the PiZ mutation, a single point mutation found in the majority of severe homozygous patients (PiZZ) living with AATD.
• EditCo Bio, Inc. announced yesterday that it has launched its business with the acquisition of Synthego's engineered cell solutions and enhanced guide RNA business. Borne from Synthego's cell engineering expertise, EditCo will deliver edited cells and highly optimised guide RNA designs to the global CRISPR market. EditCo will operate as an independent business with financing and support from life sciences investment firm Telegraph Hill Partners. EditCo will be led by former Synthego President and Chief Operating Officer, John Tan, who has been appointed Chief Executive Officer. See the official press release for more details.
• Precision BioSciences reports fourth quarter and fiscal year 2023 financial results and provides business update. Among the highlights are that the company has initiated the final CTA/IND-enabling studies for its lead in vivo gene-editing programme PBGENE-HBV for the treatment of chronic hepatitis B virus infection. It also reports the completion of licencing agreements with Imugene, TG Therapeutics and Caribou Biosciences including nearly $50 million in upfront and potential near-term payments. See the official company press release for full details.

Detection

• In an article published this week in Biosensors and Bioelectronics, scientists in China show that it is possible to improve the trans-cleavage activity of CRISPR-Cas13a using engineered crRNA with a uridinylate-rich 5′-overhang. In their study, analysis of the top-performing engineered crRNA (24 nt 5′7U LbuCas13a crRNA, where the 5′-end was extended using 7-mer uridinylates) under optimised conditions revealed an increased rate of LbuCas13a-mediated collateral cleavage activity that was up to seven-fold higher than that of the original crRNA. Using isothermal amplification via reverse transcription–recombinase polymerase amplification (RT-RPA), they show that their system could detect SARS-CoV-2 with attomolar sensitivity and accurately identified the SARS-CoV-2 Omicron variant (20/21 agreement) in clinical samples within 40 min.

Reviews

• The dawn of a cure for sickle cell disease through CRISPR-based treatment: A critical test of equity in public health genomics. This timely review summarises the recently approved CRISPR-based therapy for sickle cell disease (CASGEVY), and discusses the challenges that lie ahead and the steps that must be taken to ensure that this and other novel treatments reach people living in areas where sickle cell disease is most prevalent.
• Bacteriophage-Host Interactions and the Therapeutic Potential of Bacteriophages. The authors of this review discuss the attachment of phages to bacterial cells, the penetration of bacterial cells, the use of phages in the treatment of bacterial infections, and the limitations of phage therapy. The therapeutic potential of phage-derived proteins and the impact that genome-edited phages - including those edited with CRISPR-based technologies - may have in the treatment of infections are summarised.
• Challenges and progress related to gene editing in rare skin diseases. This review explores current advances and challenges related to gene editing in rare skin diseases, including different strategies tailored to mutation type and structural organisation of the affected gene, considerations for in vivo and ex vivo applications, delivery into the skin, and immune aspects of therapy.
• Mobile genetic element-based gene editing and genome engineering: Recent advances and applications. This review provides an update on the versatility of mobile genetic elements (MGEs) as genome-engineering tools that offer solutions to challenges associated with other genome engineering approaches. Advantages of MGEs include a broad host range, genome-wide mutagenesis, efficient large-size DNA integration, multiplexing capabilities, and in situ single-stranded DNA generation. The authors highlight the cellular applications of each MGE-based tool, and finish with a discussion on the current challenges of MGE-based genome engineering.
• In vivo LNP-CRISPR Approaches for the Treatment of Hemophilia. The authors of this review summarise the latest advances in treating haemophilia with novel therapeutics that include gene therapy, bispecific antibodies, and rebalancing therapy. While these treatment strategies have shown promising results, they do not offer a permanent therapeutic effect. In this context, the potential of CRISPR-mediated genome-editing therapy using lipid nanoparticles is discussed.
• The sounds of silencing: dynamic epigenetic control of HIV latency. This recent review highlights advances in understanding the epigenetic control mechanisms that regulate HIV-1 latency mechanisms in T cells and microglial cells and describes the potential of current therapeutic strategies that target the epigenetic machinery to eliminate or block the HIV-1 latent reservoir.

News from CRISPR Medicine News

• In this week's clinical trial update, we highlighted recent news on Poseida Therapeutics' fully allogeneic CAR-T candidate for multiple myeloma (P-BCMA-ALLO1), Intellia's and Regeneron's joint Phase 3 candidate for transthyretin amyloidosis with cardiomyopathy (NTLA-2001), and iECURE's recent approval to expand its ongoing clinical trial of ECUR-506 for ornithine transcarbamylase deficiency into the UK. Read the update here.