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

Top picks

• In an article published yesterday in Nature Biomedical Engineering, researchers in China demonstrate the feasibility of replacing expanded CAG repeats in the mutant HTT allele with a normal CAG repeat in genetically engineered pigs mimicking the selective neurodegeneration seen in patients with Hungtinton's disease. They found that a single intracranial or intravenous injection of adeno-associated virus carrying Cas9, a single-guide RNA targeting the HTT gene, and donor DNA containing the normal CAG repeat led to the depletion of mutant HTT in the animals as well as substantial reductions in the dysregulated expression and neurotoxicity of mutant HTT and in neurological symptoms.
• Disgraced CRISPR-baby scientist’s ‘publicity stunt’ frustrates researchers. Nature writeup about He Jiankui, who refused to answer researchers’ questions about his controversial 2018 experiments at a recent virtual and in-person bioethics event hosted by the University of Kent in Canterbury, UK.

Industry

• Editas Medicine will host a conference call on 22nd February at 8:00 a.m. ET to discuss fourth quarter and full year 2022 results, and to provide a corporate update. See here for access details.
• Aera Therapeutics launches with $193 million in financing to enable and advance the next generation of transformative genetic medicines. The company, which is founded by Feng Zhang, Ph.D., of the Broad Institute of MIT and Harvard, uses a proprietary protein nanoparticle (PNP) genetic medicine delivery platform based on endogenous human proteins that can self-assemble to form capsid-like structures and which can package and transfer nucleic acid cargo. The company plans to develop new genetic medicines across a broad range of modalities and therapeutic areas which have not yet been disclosed.
• Verve Therapeutics announces that its leading base-editing candidate VERVE-101 was awarded an Innovation Passport by the UK MHRA for the treatment of heterozygous familial hypercholesterolemia. Read more in our latest clinical trial update here.

Research

• In an article published yesterday in Nature Medicine, a research team led by Eric Olson at University of Texas Southwestern shows that delivery of an adenine base editor and a single-guide RNA designed to correct a signifiant human pathogenic variant, R403Q, could rescue pathological manifestations of the genetic heart disease hypertrophic cardiomyopathy (HCM) in induced pluripotent stem cell cardiomyocytes derived from patients with HCM and in a humanised mouse model of HCM. The team observed minimal bystander editing and off-target editing at selected sites.
• In the same edition of Nature Medicine, another research group led by Christine Seidman at Harvard Medical School and multiple other affiliations in the U.S. reports that one dose of dual-adeno-associated virus 9 (AAV9) vectors, each carrying one half of an RNA-guided adenine base editor (ABE8e), corrected the same pathogenic variant R403Q in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. The findings of this study can be found here.
• An article published yesterday in Nature Biotechnology describes the use of machine learning to accelerate the development of prime editing. The study, which was carried out by researchers at the Wellcome Sanger Institute (UK) analysed 3,604 DNA sequences of varying lengths that were introduced into the human genome in vitro using prime editors. One week later, the cells were genome-sequenced to assess the outcome of the editing step. The resulting data was then used to train a machine learning algorithm to predict the best editing approach for a given mutation. By using machine learning to streamline the gene correction design process, it may be possible to accelerate the advance of prime editing to the clinic. Read the full study details and findings here.
• A team in China reports the development of a novel, faster (compared to existing methods), lower cost, reliable method for the detection of human bocavirus 1 (HBoV1), a human parvovirus that affects infants aged 6-24 months. The new assay integrates a recombinase polymerase amplification (RPA) step with the CRISPR-Cas12a system, designated the RPA-Cas12a-fluorescence assay. The assay can specifically detect target gene levels as low as 0.5 copies of HBoV1 plasmid DNA per microliter within 40 min at 37°C without the need for sophisticated instruments. The study details and findings were published this week in Animal Models and Experimental Medicine.
• In an article published this week in Molecular Therapy, a team of researchers in the U.S. publish their findings on a comparison of in silico off-target (OT) analysis tools (COSMID, CCTop, and Cas-OFFinder) and empirical methods (CHANGE-Seq, CIRCLE-Seq, DISCOVER-Seq, GUIDE-Seq, and SITE-Seq) following ex vivo haematopoietic stem and progenitor cell (HSPC) editing. In brief, they observed high sensitivity for the majority of OT nomination tools with the the highest positive predictive values for COSMID, DISCOVER-Seq, and GUIDE-Seq. They also found that empirical methods did not identify off-target sites that were not also identified by bioinformatic methods.
• Earlier this week, researchers in Canada reportd the development of LumA (Luminescence ABE), a luciferase reporter mouse model containing the R387X mutation in the luciferase gene located in the Rosa26 locus of the mouse genome. This mutation eliminates luciferase activity but can be restored upon A-to-G correction by SpCas9 adenine base editors (ABEs). The team validated the LumA mouse model through intravenous injection of two FDA-approved lipid nanoparticle (LNP) formulations consisting of either MC3 or ALC-0315 ionizable cationic lipids, encapsulated with ABE mRNA and LucR387X-specific gRNA. Such a reporter system can be useful in evaluating the efficacy and safety of gene-editing enzymes, LNP formulations, and tissue specific delivery systems for optimising genome-editing therapies. The findings were published in Molecular Therapy.
• In an article publishd in Journal of Materials Chemistry B this week, scientists in Taiwan and the U.S. report the synthesis of four guide RNAs (gRNA) for factors that promote specification and maturation of insulin-producing cells. These gRNAs were used to form ribonucleoproteins (RNPs) with tracRNA and dCas9-VPR (a catalytically-dead form of Cas9), and were then immobilised on magnetic peptide-imprinted chitosan nanoparticles, which enhanced transfection. This CRISPR activation approach led to the activation of multiple transcription factors that effectively engineered cells to produce insulin, as determined by a combination of gene expression analyis, and insulin detection and quantifiation via ELISA and immunostaining.

Reviews

• Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy. In this review, authors in China introduce the available CRISPR-based tools for genome editing, focusing on the impact of CRISPR-induced double-strand breaks on cancer immunotherapy. They also discuss CRISPR-Cas9-based genome-wide screening for target identification, emphasising the potential of spatial CRISPR genomics, and present the comprehensive applications and challenges surrounding CRISPR-Cas9 in basic research, translational medicine and the clinic.
• RNA Targeting and Gene Editing Strategies for Transthyretin Amyloidosis. This review discusses emerging and recently approved therapies for transthyretin amyloidosis (ATTR), including small interfering RNA or antisense oligonucleotide drugs, and the ongoing Phase 1 trial for NTLA-2001, a CRISPR-Cas9 candidate therapy for ATTR. The authors highlight the promise of gene-editing approaches to treat ATTR, but also raise important questions about their long-term safety, potential for off-target gene editing, and how best to monitor the cardiac response to treatment.
• CRISPR-Cas9: A Potent Gene-editing Tool for the Treatment of Cancer. This review provides a summary of pre-clinical CRISPR-Cas9-based therapeutic approaches to cancer, along with the challenges involved in translating CRISPR-Cas9 therapeutic strategies into clinical use.

Insight

• Five things you need to know about using CRISPR/Cas9 commercially. This writeup for Labiotech.eu lays out five key facts concerning CRISPR-Cas9 licenses for those interested in commercial applications of the gene-editing technology.
• CRISPR gene-editing therapies for hypertrophic cardiomyopathy. This recent News & Views piece in Nature Medicine discusses two studies published in Nature Medicine this week demonstrating that pre-symptomatic base editing in pre-clinical models of hypertrophic cardiomyopathy shows therapeutic promise, while highlighting the need for clinical studies to assess safety and efficacy of the approach in humans.

Podcasts

• Who Pays for Multimillion-Dollar Miracle Cures? In this Freakonomics podcast episode about rare diseases, Harvard physician and economist Dr. Bapu Jena discusses the finances of chronic treatment vs one-off cures, CRISPR, gene therapy & treatment subscription models.

News from CRISPR Medicine News

• Verve Therapeutics announced earlier this week that its most advanced base-editing candidate VERVE-101 has been awarded the Innovation Passport for the treatment of heterozygous familial hypercholesterolemia by the UK medicines regulator. Read more about this news in our latest clinical trial update here.