New research on protein degradation with CRISPR and PROTACs

I am thrilled to share my recent lead-authored publication in #NatureChemicalBiology! Our proximity-triggered protein trans-splicing technology allows precise, time-resolved activation of diverse proteins by manipulating control elements, revealing the molecular connections of oncofusion kinases like DNAJ-PKAc. Inspired by how chromosomal translocations redirect protein behaviors to cause cancer, we developed the CAGE system to achieve this at a post-translational level. This method matches protein activation kinetics to the timescale of cellular processes, including oncogenic signaling. Combining quantitative phosphoproteomics, we uncovered distinct phases in cell signaling initiated by DNAJ-PKAc, a hallmark of pediatric liver cancer FL-HCC. From time-resolved phosphoproteomics datasets, we discovered that a protein kinase SGK1 links DNAJ-PKAc activity to the MAPK pathway in liver tissues, suggesting a potential drug target for FL-HCC. The CAGE system can reveal molecular disease mechanisms linked to aberrant protein behaviors with time-resolved omics, providing time-dimension data for bioinformatic analysis and identifying novel therapeutic biomarkers for cancer treatments. We are also excited about its applications in synthetic biology. Many thanks to my boss, Tom, and all Muir lab members for their invaluable support of this work! #ChemicalBiology #ProteinEngineering #Proteomics #Signaling #Oncofusion Check out the publication here: https://lnkd.in/eFrF6geZ

🌟 I am excited to share some great news! 🌟 At the beginning of this month our research, co-authored with Amir Regev, has been published in Polysaccharides MDPI Journal. We extend our gratitude to Prof. Joseph Kost and Prof. Moshe Elkabets for their invaluable guidance 🤗 Our research investigates the enhancement of RNA interference (RNAi) using starch-based carriers, specifically quaternized starch (Q-Starch). We discovered that while reducing the degree of substitution lessens electrostatic interactions, it doesn't improve cancer cell transfection efficiency; however, decreasing the molecular weight of our starch based drug delivery system significantly boosts transfection capabilities by 25% https://lnkd.in/dXAwqV4V

Just published today, scientists at Genentech’s Analytical Development Group showcased the successful utilization of the single-cell Tapestri Genome Editing Solution to enhance the characterization of gene-edited CD8+ T-cell therapies! Detailed in the journal Frontiers of Bioengineering and Biotechnology, researchers utilized the DNA + protein multiomic assay for characterizing their triple gene-edited cell therapy, revealing heterogeneity in the combinations of on-target and off-target edits made in each cell as well as the correlation to cell immunophenotype. Congrats to Maryam Moshref, Ph.D., Ho-Young (Grace) Lee, PhD, MBA, CQA, Nori U., Saurabh Gulati, Shu Wang and the rest of the authors on this exciting accomplishment! Check out the paper here ➡ https://lnkd.in/gv-ZqcY5 Learn more about our Genome Editing Solution here ➡ https://lnkd.in/gKg3DdKD

Cancer cells often have elevated levels of symmetric dimethylarginine (SDMA), but the PTM is difficult to distinguish from its asymmetric isomer, asymmetric dimethylarginine (ADMA), using traditional mass spectrometry techniques. Read the blog to learn how PTMScan Methylation Proteomics antibodies can be used to distinguish between the two. https://hubs.ly/Q02yRzZs0

*Preprint news* We've posted a substantial update to our study of an important aspect of Alzheimer's disease biology thought to contribute to disease spreading through the brain: how neurons take up extracellular tau. Using whole genome CRISPR screens in human neurons, we identified genes required for uptake of tau by neurons, including the known tau receptor, LRP1. Surprising result: LRRK2, an important gene for Parkinson's disease, is required for neuronal uptake of both tau and synuclein, and LRRK2 mutations that increase risk of Parkinson's increase neuronal uptake of both proteins. Could LRRK2 therapeutics in development for PD be useful in Alzheimer's and other tauopathies? https://lnkd.in/eYecGXZ6

Great paper underscoring the importance of single-cell multi-omics analysis in ex vivo-engineered T-cell therapies. They were able to quantity on-target and off-target edits as well as chromosomal translocations- all critical for both development and quality control in cell & gene therapy. #celltherapy #genetherapy #geneediting #singlecell

Human peripheral blood mononuclear cells (PBMCs) consisting of lymphocytes, dendritic cells and monocytes play an important role in both innate and adaptive immune systems. As such, #PBMCs are increasingly being used in the drug development of biological therapeutics. Should you be concerned how #cryopreservation will affect the various sub-populations of immune cells contained in your PBMC sample or performance parameters of those cells? Are you looking for more convenience in your immunology research workflows? Lonza scientists investigated what possible effects cryopreservation could have on the functionality of PBMC samples. https://lnkd.in/dNGFQiRY #Cryopreservation #Freezing #Phenotype #DrugDevelopment #Webinar #Biosamples #Research #Biobank #Biobanking #CellFreezing Aurita Antao Menezes | Katherine Dunnick, PhD | Sarah Thacker | InsideScientific | A Scientist.com Company

Vivet Therapeutics is thrilled to announce the publication of our latest paper in the peer reviewed scientific journal, International Journal of Molecular Sciences MDPI, titled “In Vivo Selection of S/MAR Sequences to Favour AAV Episomal Maintenance in Dividing Cells.” Recombinant adeno-associated viruses (#rAAVs) have emerged as one of the most promising tools for #genetherapy, and in our paper we describe some of the results obtained by the inclusion of S/MAR sequences inside rAAV vectors to overcome the loss of the therapeutic vector during cell division. One of #Vivet’s key goals is to overcome the so called “dilution effect” to treat young patients suffering from rare inherited liver metabolic disorders and to obtain long lasting therapeutic benefit after only one dose. Read the full publication here👉https://lnkd.in/eAJUXfPs. Follow #VivetTherapeutics on LinkedIn to stay up to date with the latest developments on S/MAR sequences from Andrea Llanos Ardaiz, PhD student and the #Vivet team! #Innovation #AAVGeneTherapy #GenomicMedicines #CGT #CellandGeneTherapy #GenomeEditing 

Very interesting idea. Quick fellowup questions: will the D-domain has better penetration to solid tumor and make ARC-T more efficiently in infiltrating tumor? Meanwhile, could we dose the D-domain inside the tumor trying to physically increase the penetration capacity? If we consider this as a logic loadabke system, will we design two D-domain to load/activate same ARC-T at primary/metastatic tumor or primary /resistant tumor considering the heterogeneity nature of cancer?(read the paper and found the answer ) Congratulations for the achievement 👍👍👍

Very cool article from David Baker and colleagues in which they used de novo protein design to create "EndoTags" to enhance targeted degradation of cell surface receptors. Key highlights from the study: 🔹 Versatile Targeting: EndoTags can be engineered for various receptors, including IGF2R, ASGPR, sortilin, and transferrin receptors, allowing for targeted degradation across different tissues 🔹 Enhanced Efficacy: Fusing EndoTags to a PD-L1 antibody significantly boosts its effectiveness in mouse tumor models, highlighting potential in cancer therapeutics 🔹 Increased Signaling: This system can amplify signaling through engineered ligand-receptor interactions nearly 100-fold 🔹 Therapeutic Potential: EndoTags not only enable targeted degradation but also enhance cellular uptake for antibody-drug and antibody-RNA conjugates I envision that future studies like this one could utilize #Platinum Next-Generation Protein Sequencing™️ in multiple ways: 1) To better understand native protein sequence and function, leading to more informed design choices and optimizations, and 2) To ensure that de novo designed proteins meet the expected specifications, enhancing their reliability for research and therapeutic applications. #Platinum Quantum-Si #Biotechnology #TargetedTherapeutics #Endocytosis #CancerResearch #InnovationsInMedicine #Biopharma