Mislocalized #TDP-43 causes neurodegeneration in #ALS, often associating with stress granules containing the protein #ataxin-2 (ATXN2). While antisense oligonucleotides targeting ATXN2 have recently shown promise in mice, clinical trials failed due to poor CNS penetration. A new study showed an AAV-delivered RNAi approach that efficiently reduces Atxn2 expression throughout the CNS at significantly lower doses. In TAR4/4 ALS mice, this therapy increased survival by 50%, improved motor function, and decreased neuroinflammation and phosphorylated TDP-43. Transcriptomic analysis indicated rescue of ALS-related gene signatures, implying molecular reversal of disease processes. Importantly, AAV-RNAi also transduced over 95% of ALS patient-derived motor neurons, supporting its clinical potential. These findings emphasize the importance of effective ATXN2-targeted ALS therapies; however, further human trials are needed to assess long-term safety, efficacy, and optimal dosing. Visit us at https://treventis.com/ #ataxin2 #AAV #genetherapy https://lnkd.in/e6eS6MGZ

📣Call for Reading: #Review Advances and Trends in miRNA Analysis Using DNAzyme-Based Biosensors by Minhyuk Lee, Seungjae Kang, Sungjee Kim, Nokyoung Park https://lnkd.in/g7rfcMdy #miRNA #DNAzyme #biosensors #mdpi #openaccess Abstract: miRNAs are endogenous small, non-coding RNA molecules that function in post-transcriptional regulation of gene expression. Because miRNA plays a pivotal role in maintaining the intracellular environment, and abnormal expression has been found in many cancer diseases, detection of miRNA as a biomarker is important for early diagnosis of disease and study of miRNA function. However, because miRNA is present in extremely low concentrations in cells and many types of miRNAs with similar sequences are mixed, traditional gene detection methods are not suitable for miRNA detection. Therefore, in order to overcome this limitation, a signal amplification process is essential for high sensitivity. In particular, enzyme-free signal amplification systems such as DNAzyme systems have been developed for miRNA analysis with high specificity. DNAzymes have the advantage of being more stable in the physiological environment than enzymes, easy to chemically synthesize, and biocompatible. In this review, we summarize and introduce the methods using DNAzyme-based biosensors, especially with regard to various signal amplification methods for high sensitivity and strategies for improving detection specificity. We also discuss the current challenges and trends of these DNAzyme-based biosensors.

Latest exciting work from me and Mirre Simons (and the first bit of data from my Vivensa Foundation ECR Fellowship) now out as a preprint, looking at effects of knocking down individual spliceosome components on lifespan in vivo: https://lnkd.in/eZ7ceswV We’ve previously shown that spliceosome gene expression is modulated under the pro-longevity treatments mTOR suppression and dietary restriction, which are highly consistent and conserved between species. We knocked down the top-changing spliceosome genes using in vivo conditional RNAi and found that several gene knockdowns induced mortality, whereas the knockdown of the gene encoding an SR protein, Rbp1 (orthologue of human SRSF1), extended lifespan. Considering that pro-longevity treatments which don’t require lifelong application will be easier to translate to the clinic, we also tested Rbp1 knockdown at later timepoints, and excitingly found that this too produced comparable improvements in life expectancy! The spliceosome is made up of many different proteins and RNAs, and our work demonstrates that a deficit of some components is highly detrimental to longevity, whereas the shortage of others (eg. Rbp1) may actually be pro-longevity. We find it fascinating that the components which induce mortality when knocked down are recruited to the spliceosome far later than the point of recruitment of Rbp1, which binds pre-mRNA before even the commitment complex has assembled. Perhaps limiting SR protein (such as Rbp1) abundance improves proteostasis by reducing protein synthesis, whereas limiting later components causes complete translational inhibition through spliceosomal stalling, although this needs far more work to tease apart! As well as revealing Rbp1 knockdown as a pro-longevity treatment, more generally our work has unveiled a tantalising prospect; the fine-tuning of individual spliceosome components could be a pathway to increased health and longevity. We’re excited to pull on this thread and find out where it leads!

💡 Some exciting data from Christopher Kirkham's team at Discovery | Charles River. This work demonstrates how NanoString gene expression profiling can reveal molecular signatures in diseases like psoriasis and atopic dermatitis - providing deeper insights that help our clients better understand disease mechanisms and drive smarter drug discovery. 👉 Get in touch if you would like to discuss further! #CharlesRiverLaboratories #CRL #NanoString #Biomarkers #DrugDiscovery #Psoriasis #AtopicDermatitis

🧠The authors present a comprehensive analysis of brain organoids derived from multiple cell lines across four different regional protocols, reaching over 70% of the cell states found in fetal brain. 🗓️Time-course bulk RNA-Seq was used with Lexogen’s #QuantSeq kits and #UMI to infer temporal dynamics of gene programs in four brain organoid differentiation protocols, across seven cell lines. Marker genes that could predict successful organoid differentiation were identified as early at day 40. 💡In parallel, single-cell RNA-Seq was performed at day 120 and data was compared with in vivo fetal brain reference. 🤝The combination of scRNA-Seq and #QuantSeq time-course bulk RNA-Seq data eventually confirmed the assignment of genes to specific cell lines and protocols, or, on the other hand, revealed cell-line and protocol-independent gene sets. Data obtained through this study is shared in an easy-to-visualise, open access online resource: https://lnkd.in/dtbyytm9 👏Congratulations to the authors for this publication, which sets a milestone into a better understanding of gene expression and brain differentiation. Christoph Bock, Christopher Esk, Juergen Knoblich, Thomas Krausgruber, Meritxell Balmaña, Laurenz Holcik, Lina Dobnikar They also call other researchers to validate and expand such a study by adding more protocols and cell lines.   📢RNA-seq addicts, science is waiting for you! ➡️ Read the full publication in Cell Reports here: https://lnkd.in/drVh66vW #organoids #BrainResearch #ExpressionProfiling #NGS #RNAseq #UniqueMolecularIdentifiers #UMI

We’re pleased to expand the STEMCELL Technologies iPSC Platform with the launch of Custom Genome Editing Services for the highly characterized healthy control iPSC lines SCTi003-A and SCTi004-A. This service adds precise CRISPR-Cas9 gene editing capabilities for creating custom iPSC models used in gene function, disease modeling, and target validation. Available edit types include gene knockouts, targeted knock-ins, and large genomic deletions. Learn more or request a custom project below. https://lnkd.in/eVTPe9kE #iPSC #CRISPR #GeneEditing #DiseaseModeling #DrugDiscovery

Noncoding variants that regulate vascular smooth muscle gene expression have been identified as causal factors in coronary artery disease, according to a report in today’s issue of Nature Cardiovascular Research. This finding provides further insight into the critical role of the noncoding genome in disease etiology. https://lnkd.in/e6rE23ee

"BPIFB4 gene: from Supercentenarians to Children's Therapy" A Joint scientific UK and Italian team published their work on the human BPIFB4 gene, a longevity-associated gene, as a major factor for the prevention of diastolic dysfunction in mice. Their data was published in Nature Signal Transduction and Targeted Therapy in late September. Their study is the first to demonstrate that a supercentenarian gene mutation protects the Hutchinson-Gilford Progeria Syndrome (HGPS) heart against fibrosis and promotes cell survival, thereby preserving diastolic function. Data shows that HGPS fibroblasts presents lower endogenous BPIFB4 expression, probably due to progerin-induced transcriptional suppression, and an enhanced aged and fibrotic phenotype, which was rescued by exogenous LAV-BPIFB4. LAV-BPIFB4 transduction may affect nucleolar processes, including ribosome biogenesis and ribonucleoprotein assembly, downstream of the Lamin A/C gene mutation, resulting in therapeutic actions. This major breakthrough research shows how investigations on the biological basis of supercentenarians can provide efficient translational medical tools in order to provide hope for a disease causing rapid aging in children. Other positive targets are expected to be identified from basic research in Aging. Here is the link: https://lnkd.in/eTcSud6F

Inspiring to see this investment in next-gen therapies that hold real promise for people living with cystic fibrosis. Engineered phages (viruses that specifically target and destroy harmful bacteria) highlight what’s possible when science, funding, and mission-driven collaboration align. #ImpactDriven #CFResearch #HealthInnovation

A major milestone in in vivo gene editing was just published in The New England Journal of Medicine. Researchers reported results from a Phase 1 trial of nexiguran ziclumeran (NTLA-2001), a CRISPR-Cas9–based therapy for ATTR. A single infusion reduced serum TTR levels by ~90% within 28 days Reduction was durable through 24–36 months Neuropathy scores, quality of life, and biomarkers largely stabilized or improved Safety profile was manageable, with mainly transient infusion reactions This is the first demonstration of long-term, one-time in vivo gene editing translating into durable clinical benefit in a systemic disease. A Phase 3 trial (MAGNITUDE-2) is now underway. #GeneEditing #CRISPR #Biotech #GenomicMedicine #ATTR