CMN Weekly (3 June 2022) - Your Weekly CRISPR Medicine News
By: Karen O'Hanlon Cohrt - Jun. 3, 2022
- New research findings from University of California, Berkeley, reveal that the native activity of CRISPR-Cas12c protects bacteria from phage infection by binding to DNA targets without cleaving them. The team used a series of biochemical methods to show that Cas12c is a site-specific ribonuclease that is able to generate mature CRISPR RNAs (crRNAs) from precursor transcripts, and that crRNA maturation is essential for Cas12c-mediated DNA targeting. The mature crRNAs then direct double-stranded DNA binding by Cas12c using a mechanism that precludes DNA cutting. The findings, which were published yesterday in Molecular Cell, reveal that anti-viral interference can be accomplished without chemical attack on the invader or general metabolic disruption in the host.
- Better than CRISPR? Another way to fix gene problems may be safer and more versatile. This write-up in Science summarises the major advances and challenges seen throughout the last two decades within therapeutic epigenome editing, including the potential safety advantages compared to gene-editing appraoches that create permanent and sometimes unintended changes.
- Gene therapy’s comeback: how scientists are trying to make it safer. This piece in Nature looks at ongoing research efforts to improve the safety of gene therapies by circumventing undesirable immune responses to viruses such as adeno-associated viruses (AAVs), which are used as delivery vechicles for gene-replacement and well as gene-editing therapies.
- In an article published in Current Biology yesterday, researchers in the U.S. and UK describe new findings that increase our understanding of how CRISPR-harbouring bacteria store information needed to kill foreign invaders (i.e. viruses) without succumbing to auto-immunity. The authors claim that balancing anti-viral defense against auto-immunity predicts a scaling relation between spacer length and CRISPR repertoire size, and they find evidence for this through a comparative analysis of sequenced prokaryotic genomes, which revealed that the association also holds at the level of CRISPR types.
- New findings recently published in Cell reveal that the RNA-editing enzyme, Cas7-11, which was first discovered last year by researchers at MIT's McGovern Institute for Brain Research, can be engineered into a more compact version, making it an even more viable option for RNA editing inside living cells. The findings of this new study, which was undertaken with collaborators from University of Tokyo, include the 2.5-Å resolution cryoelectron microscopy structure of Cas7-11 in complex with a crRNA and its target RNA. The new and compact Cas7-11 variant, known as Cas7-11S, is suitable for for single-vector adeno-associated virus (AAV) packaging for mRNA knockdown in human cells, enabling in vivo Cas7-11 applications.
- In an article published in Gene Therapy this week, scientists in China report the generation of a heart failure (HF) model for the cardiac abnormalities seen in Duchenne muscular dystrophy, which is caused by dystrophin deficiency. The HF mouse model was generated by transverse aortic constriction (TAC), and subsequent in vivo activation of dystrophin transcription was achieved by tail-vein injection of adeno-associated virus 9 (AAV9) carrying a CRISPR-dCas (gene activator) system for dystrophin. Overall, the team found that activation of dystrophin expression in the mice significantly reduced their susceptibility to arrhythmia as well as the mortality rate. The authors argue that their study paves the way for the development of a new therapeutic strategy for HF-related ventricular arrhythmia.
- Researchers at Stanford University have developed a new plug-and-play method for multi-signal parallel recording in human cells using a hyper-efficient dCas12a base editor. By linking signals of interest to expression of guide RNAs to catalyse specific nucleotide conversions as a permanent record, enabled by Cas12’s guide-processing abilities, the team has developed a platform for scalable recording of diverse biologically relevant signals for a variety of biological applications. The findings were published in Nature Chemical Biology earlier this week.
- Scientists in the U.S. and Jordan have applied bioinformatic methods to elucidate the significance of protospacer adjacent motifs (PAMs) and their function, particularly as a part of transcriptional regulatory regions in T4 bacteriophages. The findings were published yesterday in BMC Genomics Data, and the authors suggest that their findings provide novel insights into the location and the subsequent identification of the role of PAMs as transcriptional regulatory elements.
- Scientists in China have developed a CRISPR-Cas9-induced Idol knockout (Idol-/-) hamster model to investigate the effect of Idol depletion on plasma lipid metabolism and atherosclerosis. Idol (inducible degrader of low-density lipoprotein (LDL) receptor) is an E3 ubiquitin ligase coded by Idol, the target gene of liver X receptor (LXR), which primarily mediates the ubiquitination and lysosomal degradation of low-density lipoprotein receptor (LDLR). The findings, which suggest that Idol can regulate plasma lipid metabolism and atherosclerosis independently of LDLR function, were published recently in Oxidative Medicine and Cellular Longevity.
- Scientists in China report the development of a controllable CRISPR-Cas9-based gene-editing tool, whereby in situ-generated boronated gRNA could regulate binding of gRNA molecules with either Cas9 endonuclease or target genes, thus serving as a modulator to control CRISPR-Cas9 gene editing. Subsequent treatment with hydrogen peroxide restores the gene-editing ability of the boronated gRNA to the level of untreated gRNA. The findings were published this week in Cell Biology and Toxicology.
- Vertex and CRISPR Therapeutics announced yesterday that they had received acceptance of a late-breaking abstract for CTX001™ at the 2022 Annual European Hematology Association Congress. The companies are expected to present clinical data on CTX001 (now known as exagamglogene autotemcel) in an oral presentation on 12th June, which will include patients treated in the ongoing CLIMB‑111 and CLIMB‑121 clinical trials for beta thalassemia and sickle cell disease and followed in CLIMB‑131. Read more about CTX001 in a previous article here.
- Caribou Biosciences announces webcast conference call to highlight initial CB-010 ANTLER Phase 1 data presentation at the European Hematology Association Congress on June 10th, 2022. The presentation is expected to include longer duration data on the six patients already treated at dose level 1 based on a new data cutoff date. Read about the recently released clinical data for CB-010 in our previous clinical trial update here.
- In an article published in The Lancet Microbe earlier this week, researchers at Tulane University School of Medicine, New Orleans, along with collaborators in the U.S. and Africa, describe a new and highly sensitive CRISPR-based blood test for tuberculosis (TB). The test, which relies on the collatoral cleavage activity of Cas12a, screens for cell-free DNA fragments of the Mycobacterium tuberculosis bacteria, delivering results within two hours, with 96.4% sensitivity and 94.1% specificity in adults and 83.3% sensitivity and 95.5% specificity in a paediatric population. CRISPR-Cas12a has been used previously to detect pathogen-derived material in other assays, but the current study is the first to apply the approach to detect circulating M tuberculosis genomic DNA for TB diagnosis with good diagnostic performance.
- Scientists in China describe a new programmable DNA-fuelled electrochemical analysis strategy to detect PD-L1-expressing exosomes, which represent an emerging biomarker in lung cancer. Specifically, PD-L1-expressing exosomes are enriched onto magnetic beads functionalised with a PD-L1 antibody and are able to interact with cholesterol-modified hairpin templates. Programmable DNA synthesis then begins, starting from the hairpin template-triggered primer exchange reaction, which generates a large number of extension products that can activate the trans-cleavage activity of CRISPR-Cas12a. CRISPR-Cas12a-catalysed random cleavage of these products boosts the degradation of methylene blue-labelled signalling strands, which is quantified on a cucurbituril-modified electrode. The authors report high sensitivity and specificity, and that the method revealed elevated levels of circulating PD-L1-expressing exosomes in lung cancer patients. The findings were published earlier this week in Analytical Chemistry.
- Modifying mosquitoes to suppress disease transmission: Is the long wait over? In this review, Jeffrey Powell, Professor of Ecology and Evolutionary Biology at Yale University, presents a synopsis of the mostly fruitless strategies explored in the last 50 years to control insect-borne diseases such as malaria and dengue fever by modifying the insect vectors that transmit them to humans. He then discusses three recently-developed or emerging novel approaches, including CRISPR-Cas9 driven genetic modification, shifting naturally occurring allele frequencies, and microbe-based modifications.
- Genetic therapeutic advancements for Dravet Syndrome. This review by scientists at UCL Institute for Women's Health, UK, summarises the state-of-play for novel genetic therapies under development for Dravet syndrome, a genetic epileptic syndrome that is characterised by severe and intractable seizures associated with cognitive, motor, and behavioral impairments. Because the syndrome usually does not respond to antiepileptic drugs, which only have a modest reducing effect on seizures, a range of alternative treatment strategies are currently being investgated, including new medications, gene therapy, antisense oligonucleotides, and gene editing, e.g., CRISPR-mediated transcriptional activation.
- Materiomically Designed Polymeric Vehicles for Nucleic Acids: Quo Vadis? This review summarises recent developments in combinatorial polymer synthesis, high-throughput screening of polymeric vectors, omics-based approaches to polymer design, barcoding schemes for pooled in vitro and in vivo screening, and identifies materiomics-inspired research directions that will help to realise the long-unfulfilled clinical potential of polymeric carriers in gene therapy.
News from CRISPR Medicine News
- On Monday, we published an interview with researchers from Denmark who have used an energy-based model to identify mechanisms regulating CRISPR-Cas9 activity and specificity. They found that local gRNA-DNA interactions due to Cas9 ‘sliding’ on overlapping PAMs influences cleavage activity. This energy-based model can help researchers to design highly specific gRNAs to increase CRISPR-Cas9 efficiency and minimise off-target effects. Read the interview here.
- Last week, we hosted a successful webinar on the topic: 'Deliver CRISPR to the Brain - A New Treatment Strategy for Mucopolysaccharidoses'. Our invited speaker, Guilherme Baldo, Associate Professor, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, presented his team's work on a new CRISPR-based method to treat the inherited brain disorder mucopolysaccharidoses. The method involves nasal delivery of CRISPR gene-editing reagents to the brain, and so far the team has demonstrated that this approach can improve cognitive symptoms in a mouse model of MPS. Watch the webinar on-demand right here.
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Beta-Thalassemia, BT, (NCT05442346)
Sickle Cell Disease, SCD, and Transfusion Dependent Beta-Thalassaemia, TDT, (NCT04208529)
Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
View all clinical trials
T-cell Acute Lymphoid Leukaemia, ALL, (NCT05397184)
Great Ormond Street Hospital for Children NHS Foundation Trust
Great Ormond Street Hospital for Children NHS Foundation Trust