CRISPR-Cas9 gene editing therapeutic / CRISPR Therap - LARVOL DELTA

Assessment of Efficacy 6 Months After Systemic Injection of an AAV-CRISPR/Cas9 Therapy for Duchenne Muscular Dystrophy (ASGCT 2022) - "We have developed a CRISPR/Cas9 gene editing therapy to delete exons 45-55, thus reframing the DMD gene and generating an in-frame deletion that has been associated with one of the mildest BMD phenotypes, where some Becker patients with a naturally occurring exon 45-55 deletion have been asymptomatic until their 60s...Here we assess efficacy after 6 months to determine the long-term durability of this therapy. This work will advance preclinical development of our AAV-CRISPR therapy for Duchenne muscular dystrophy."

Clinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Caveolin-1 regulates human trabecular meshwork cell adhesion, endocytosis, and autophagy. (PubMed, J Cell Biochem) - "Moreover, the CAV1-KO TM cells had higher expression of extracellular matrix-degrading enzyme genes ( ADMTS13 and MMP14) as well as autophagy-related genes ( ATG7 and BECN1) and protein (LC3B-II) than the wildtype TM cells. In summary, results from this study showed that the CAV1-KO TM cells have reduced adhesion with higher extracellular matrix-degrading enzyme expression, but increased endocytosis and autophagy activities, indicating that CAV1 could be involved in the regulation of adhesion, endocytosis, and autophagy in human TM cells."

Journal • Glaucoma • Ophthalmology

A singular system with precise dosing and spatiotemporal control of CRISPR-Cas9. (PubMed, Angew Chem Int Ed Engl) - "By photocaging this Cas9 activator to render it biologically inert and photoactivatable, and employing next-generation protein engineering approaches, we have built a system with wide-dynamic range, low background, and fast photoactivation using a low-intensity light while rendering the small molecule activator biologically inert. We anticipate these precision controls will propel the development of practical applications of Cas9."

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FoxF1 is Required for Ciliogenesis and Distribution of Sonic Hedgehog Signaling Components in Cilium. (PubMed, Curr Mol Med) - "Together, our data illustrated that FoxF1 is required for ciliogenesis in vitro and in vivo and for the proper localization of Shh signaling components in cilium."

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New Data for Investigational CRISPR/Cas9 Gene-Editing Therapy CTX001™ for Severe Hemoglobinopathies Accepted for Oral Presentation at the 25th European Hematology Association (EHA) Congress (GlobeNewswire, CRISPR Therapeutics AG) - "CRISPR Therapeutics (Nasdaq: CRSP) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that new data from two ongoing Phase 1/2 clinical trials of the CRISPR/Cas9 gene-editing therapy CTX001 in severe hemoglobinopathies have been accepted for an oral presentation at the EHA Congress, which will take place virtually from June 11-14, 2020. An abstract posted online today includes 12 months of follow-up data for the first patient treated in the ongoing Phase 1/2 CLIMB-111 trial in transfusion-dependent beta thalassemia (TDT) and 6 months of follow-up data for the first patient treated in the ongoing Phase 1/2 CLIMB-121 trial in severe sickle cell disease (SCD). Updated data will be presented at EHA, including longer duration follow-up data for the first two patients treated in these trials and initial data for the second patient treated in the CLIMB-111 trial."

Clinical • Clinical data • Enrollment status • Anemia • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

An ATG5 knockout promotes paclitaxel resistance in v-Ha-ras-transformed NIH 3T3 cells. (PubMed, Biochem Biophys Res Commun) - "Interestingly, overexpression of ATG5 N-terminal cleavage product in ATG5 KO cells restored their sensitivity to paclitaxel. Taken together, our results suggest that ATG5 KO cells are resistant to paclitaxel due to the inability to produce tATG5."

Journal • Targeted Protein Degradation

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition. (PubMed, Elife) - "These observations extend across cancers that harbor SMARCB1 loss, which also require expression of the E2 ubiquitin-conjugating enzyme, UBE2C. Our studies identify a synthetic lethal relationship between SMARCB1-deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors."

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The desirable donor pig to eliminate all xenoreactive antigens. (PubMed, Xenotransplantation) - "Recent studies have also considered the aetiology and existence of antibodies directed at the swine leucocyte antigen (SLA) complex, and potential genetic engineering strategies to avoid these antibodies. Evaluation of xenoreactive antibody binding is very important for the advancement of xenotransplantation, because if patients do not have any detectable xenoreactive antibody, then it is reasonable to expect that cellular rejection and not antibody-mediated rejection (AMR) will be the next hurdle to clinical application."

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Axin-1 binds to Caveolin-1 to regulate the LPS-induced inflammatory response in AT-I cells. (PubMed, Biochem Biophys Res Commun) - "Disrupting the interaction between Caveolin-1 and Axin-1 using CRISPR/Cas9 technology led to a significant increase in TNF-α and IL-6 from AT-I cells, along with a significant reduction in β-catenin expression. In conclusion, Axin-1 functions as an adaptor of Caveolin-1 and affects the production of inflammatory cytokines in AT-I cells challenged with LPS via β-catenin-mediated negative regulation."

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CRISPR/Cas9 engineering of ERK5 identifies its FAK/PYK2 dependent role in adhesion-mediated cell survival. (PubMed, Biochem Biophys Res Commun) - "This was evident from the detection of cleaved PARP and caspase 9 in these cells. Thus, our data suggests a FAK/PYK2 regulated pro-survival role of ERK5 in response to cell adhesion."

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RNA-guided endonuclease - in situ labelling (RGEN-ISL): a fast CRISPR/Cas9-based method to label genomic sequences in various species. (PubMed, New Phytol) - "Real-time visualisation of the CRISPR/Cas9-mediated DNA labelling process revealed the kinetics of the reaction. The broad range of adaptability of RGEN-ISL to different temperatures and combinations of methods has the potential to advance the field of chromosome biology."

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XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in IPF Airway Epithelia. (PubMed, Am J Respir Crit Care Med) - "A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing a UPR-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF."

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CRISPR Therapeutics and Vertex Announce Positive Safety and Efficacy Data From First Two Patients Treated With Investigational CRISPR/Cas9 Gene-Editing Therapy CTX001® for Severe Hemoglobinopathies (GlobeNewswire, CRISPR Therapeutics AG) - "CRISPR Therapeutics (NASDAQ: CRSP) and Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) today announced positive, interim data from the first two patients with severe hemoglobinopathies treated with the investigational CRISPR/Cas9 gene-editing therapy CTX001 in ongoing Phase 1/2 clinical trials."

Clinical • P1/2 data

Neuron-Specific Genome Modification in the Adult Rat Brain Using CRISPR-Cas9 Transgenic Rats. (PubMed, Neuron) - "One rat represents the first knockin rat model made by germline gene targeting in spermatogonial stem cells. The rats described herein serve as a versatile platform for making cell-specific and sequence-specific genome modifications in the adult brain and potentially other Cre-expressing tissues of the rat."

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The BOLF1 gene is necessary for effective Epstein-Barr viral infectivity. (PubMed, Virology) - "Our results indicate that BOLF1enhances the infectious potential of progeny virions, at least partly by increasing nuclear transportation of incoming nucleocapsids. We also found that BOLF1 interacted with BKRF4, and the BOLF1 and BKRF4 proteins were localized in the nucleus and perinuclear area, during the viral lytic cycle."

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Modification of T2 phage infectivity toward Escherichia coli O157:H7 via using CRISPR/Cas9. (PubMed, FEMS Microbiol Lett) - "The resultant recombinant showed the adsorption rate comparable to PP01. Thus we provided the evidence that the short tail fiber of PP01 plays an important role in adsorption to E. coli O157:H7."

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Long noncoding RNA MALAT1 releases epigenetic silencing of HIV-1 replication by displacing the polycomb repressive complex 2 from binding to the LTR promoter. (PubMed, Nucleic Acids Res) - "Successful combination antiretroviral therapy (cART) was accompanied by significantly diminished MALAT1 expression in patients, suggesting a positive correlation of MALAT1 expression with HIV-1 replication. Our data have identified MALAT1 as a promoter of HIV-1 transcription, and suggested that MALAT1 may be targeted for the development of new therapeutics."

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The dynamin-like protein Fzl promotes thylakoid fusion and resistance to light stress in Chlamydomonas reinhardtii. (PubMed, PLoS Genet) - "Most importantly, we show that CrFzl is required for the fusion of thylakoids during mating. Together, our results suggest that thylakoids fusion may be necessary for resistance to light stress."

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Comparative study of commercially available and homemade anti-VAMP7 antibodies using CRISPR/Cas9-depleted HeLa cells and VAMP7 knockout mice. (PubMed, F1000Res) - "We propose a simple profiling method to analyze western blotting and immunocytochemistry staining profiles and determine the extent of the antibodies' specificity. Using this method, we were able to rank the performance of a set of available antibodies and further showed an optimized procedure for VAMP7 immunoprecipitation, which we validated using wild-type and KO mouse brain extracts."

Journal • Preclinical

Targeted Gene Disruption in Pacific Oyster Based on CRISPR/Cas9 Ribonucleoprotein Complexes. (PubMed, Mar Biotechnol (NY)) - "These results demonstrate that CRISPR/Cas9 can be successfully used as an effective targeted gene editing system in C. gigas. The method reported here provides a powerful tool for gene functional studies in oysters and other marine bivalves, and potentially as a new technology for genetic engineering to improve oyster traits for aquaculture."

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Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. (PubMed, Nat Biomed Eng) - "The effect can also rescue mice from the exaggerated repetitive behaviours caused by fragile X syndrome, a common single-gene form of autism spectrum disorders. CRISPR-Gold may significantly accelerate the development of brain-targeted therapeutics and enable the rapid development of focal brain-knockout animal models."

Journal • Preclinical

Integrating balanced mevalonate pathway into chromosome for improving lycopene production in Escherichia coli (PubMed, Sheng Wu Gong Cheng Xue Bao) - "In this study, a plasmid-free, genetically stable, high-yielding lycopene strain was constructed, which could be used for industrialization. Also, the platform strain can be used for the synthesis of other terpenoids."

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Application and optimization of CRISPR/Cas system in bacteria (PubMed, Sheng Wu Gong Cheng Xue Bao) - "At present, CRISPR/Cas9 technology has been successfully applied to the genome editing of eukaryotes such as zebrafish, mice and human cells, whereas limited progress has been made in the genome editing of bacteria. In our review, we describe CRISPR/Cas system, its mechanism and summarize the optimization and progress of genome editing in bacteria."

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Development of drug-inducible CRISPR-Cas9 systems for large-scale functional screening. (PubMed, BMC Genomics) - "In this study, we have developed a drug-inducible CRISPR-Cas9 system that shows high cleavage efficiency upon induction but low background activity. Using this system, we have achieved inducible gene disruption in a wide range of cell types both in vitro and in vivo. For the first time, we present a systematic side-by-side comparison of constitutive and drug-inducible CRISPR-Cas9 platforms in large-scale functional screens. We demonstrate the tightness and efficiency of our drug-inducible CRISPR-Cas9 system in genome-wide pooled screening. Our design increases the versatility of CRISPR-based genetic screening and represents a significant upgrade on existing functional genomics toolbox."

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Characterization of Two Polyketide Synthases Involved in Sorbicillinoid Biosynthesis by Acremonium chrysogenum Using the CRISPR/Cas9 System. (PubMed, Appl Biochem Biotechnol) - "We further confirmed that the sorbicillinoid biosynthetic gene cluster is regulated by an autoinduction mechanism. This work will lay a solid foundation for gene function research and regulation in the sorbicillinoid biosynthetic pathway."

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