A5050586739- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Animal Virus Infections Studies
- Multiple Sclerosis Research Studies
- Cancer Research and Treatments
- Cellular transport and secretion
- Advanced biosensing and bioanalysis techniques
- Cardiovascular Conditions and Treatments
- interferon and immune responses
- Galectins and Cancer Biology
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- Barrier Structure and Function Studies
- IL-33, ST2, and ILC Pathways
- Optical Imaging and Spectroscopy Techniques
- Immune Cell Function and Interaction
- Neuroendocrine regulation and behavior
- Liver Disease Diagnosis and Treatment
- Virus-based gene therapy research
- Cellular Mechanics and Interactions
- Hippo pathway signaling and YAP/TAZ
- Animal health and immunology
- DNA Repair Mechanisms
Ionis Pharmaceuticals (United States)
2018-2025
University of Veterinary Medicine Hannover, Foundation
2008-2022
AstraZeneca (United Kingdom)
2015-2019
University Hospital of Bern
2017
AstraZeneca (Brazil)
2017
University of Bern
2017
University of Veterinary Medicine
2012
Hebrew University of Jerusalem
2012
Roche (United Kingdom)
2012
Cancer Research UK
2012
BACKGROUNDSpinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein. New SMN-enhancing therapeutics are associated with variable clinical benefits. Limited knowledge baseline and drug-induced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments.METHODSSMN mRNA protein were quantified human isolated during expedited autopsies.RESULTSSMN varied broadly among prenatal control spinal cord samples, but was restricted at...
Activating mutations in KRAS underlie the pathogenesis of up to 20% human tumors, and is one most frequently mutated genes cancer. Developing therapeutics block activity has proven difficult, no direct inhibitor function entered clinical trials. We describe preclinical evaluation AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting mRNA. AZD4785 potently selectively depleted cellular mRNA protein, resulting inhibition downstream effector...
Background The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate activity and augment immunity providing therapeutic benefit...
Measuring the activity and temperature of rats is commonly required in biomedical research. Conventional approaches necessitate single housing, which affects their behavior wellbeing. We have used a subcutaneous radiofrequency identification (RFID) transponder to measure ambulatory individual when group-housed conventional, rack-mounted home cages. The location detected by matrix antennae baseplate under cage. An infrared high-definition camera acquires side-view video cage also enables...
Antisense oligonucleotides (ASOs) are a novel therapeutic approach to target difficult-to-drug protein classes by targeting their corresponding mRNAs. Significantly enhanced ASO activity has been achieved the targeted delivery of ASOs selected tissues. One example is hepatocytes, with N-acetylgalactosamine (GalNAc) conjugation ASO, which results in selective uptake asialoglycoprotein receptor (ASGR). Here we have evaluated potential GalNAc-conjugated as pathways hepatocellular carcinoma...
The small GTP-binding protein ADP-ribosylation factor 6 (Arf6) is involved in plasma membrane/endosomes trafficking. However, precisely how the activation of Arf6 regulates vesicular transport still unclear. Here, we show that, vitro, recombinant Arf6GTP recruits purified clathrin-adaptor complex AP-2 (but not AP-1) onto phospholipid liposomes absence phosphoinositides. We also that phosphoinositides and tightly cooperate to translocate membrane. In vivo, Arf6GDP) was found associated AP-2....
Abstract Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has genetic component but, despite the common variants already identified, there still missing heritability component. Using candidate gene approach, we identify locus (rs71519934) at Pleckstrin and Sec7 domain-containing 3 ( PSD3 ) resulting in leucine to threonine substitution position 186 of protein (L186T) that reduces susceptibility entire spectrum individuals risk. downregulation by...
Abstract Determination of a drug’s biodistribution is critical to ensure it reaches the target tissue interest. This particularly challenging in brain where invasive sampling methods may not be possible. Here, pretargeted imaging methodology disclosed that utilizes bioorthogonal click chemistry determine distribution an antisense oligonucleotide living following intrathecal dosing. A novel PET tracer, [ 18 F]BIO-687, bearing click-reactive trans -cyclooctene (TCO) was discovered and tested...
Antisense oligonucleotides (ASOs) locally delivered to the central nervous system (CNS) are being approved as therapies for neurological diseases. After intrathecal injection of some ASOs, transient toxicities have been reported, but considerable inconsistencies remain in classifying them and their underlying mechanisms. Here, we characterize an acute sedation response that can include loss lower spinal reflexes, hypoactivity, paresis, ataxia, peaking ~3 hours post-intrathecal...
We addressed the role of EFA6, exchange factor for ARF6, during development epithelial cell polarity in Madin-Darby canine kidney cells. EFA6 is located primarily at apical pole polarized cells, including plasma membrane. After calcium-triggered E-cadherin-mediated adhesion, recruited to a Triton X-100-insoluble fraction and its protein level increased concomitantly accelerated formation functional tight junction (TJ). The expression results selective retention surface TJ occludin. This...
Sustained therapeutic responses from traditional and next-generation antiandrogen therapies remain elusive in clinical practice due to inherent and/or acquired resistance resulting persistent androgen receptor (AR) activity. Antisense oligonucleotides (ASO) have the ability block target gene expression associated protein products provide an alternate treatment strategy for castration-resistant prostate cancer (CRPC). We demonstrate efficacy potential of this approach with a Generation-2.5...
<b><i>Objectives:</i></b> Theiler’s murine encephalomyelitis virus (TMEV) infection of mice is a widely used animal model for demyelinating disorders, such as multiple sclerosis (MS). The aim the present study was to identify topographical differences TMEV spread and demyelination in brain experimentally infected susceptible SJL/J resistant C57BL/6 mice. <b><i>Methods:</i></b> Demyelination confirmed by Luxol fast blue cresyl violet staining...
Dogs with degenerative mitral valve disease are commonly presented to small animal clinicians. Diagnosis, clinical staging, and therapeutic design based on a combination of examination, radiography, echocardiography. To support diagnosis monitoring, multi-marker-based approach would be conceivable. The aim this study was investigate the suitability Galectin-3 interleukin-1 receptor-like 1 protein (ST2) in dogs accordance N-terminal-prohormone-B-type natriuretic peptide (NT-proBNP) cardiac...
We have previously reported that EFA6, exchange factor for Arf6, is implicated upon E-cadherin engagement in the process of epithelial cell polarization. had found EFA6 acts through stabilization apical actin ring onto which tight junction anchored. Mutagenesis experiments showed both catalytic domain and its C-terminal were required full function. Here we address contribution specific substrate small G protein Arf6. Unexpectedly, depletion Arf6 by RNA interference or expression...
Abstract Regulatory T cells (Treg) critically maintain immuno-suppression in the tumor microenvironment, representing an attractive immuno-oncology target. The Treg lineage is defined by expression of FOXP3 transcription factor, which controls immune-suppressive functions. We have developed clinical candidate AZD8701, a next-generation antisense oligonucleotide inhibitor (utilizing Ionis Gen 2.5 cEt-modified ASO platform). AZD8701 treatment knocked down primary human Tregs via free uptake...
Modulation of the cell cycle may underlie toxicologic or pharmacologic responses a potential therapeutic agent and contributes to decisions on its preclinical clinical safety efficacy. The descriptive quantitative assessment normal, aberrant, degenerate mitotic figures in tissue sections is an important end point characterizing effect xenobiotics cycle. Historically, pathologists used manual counting special staining visualization techniques such as immunohistochemistry for quantification...
Aluminum fluoride (AlFx) is known to activate directly the alpha subunit of G-proteins but not homologous small GTP-binding proteins. However, AlFx can stabilize complexes formed between Ras, RhoA or Cdc42 and their corresponding GTPase-activating proteins (GAPs). Here, we demonstrate that Arf1GDP be converted into an active conformation by form a complex with Arf-GAP ASAP1 in vitro vivo. Within this ASAP1, which GAP activity inoperative, still alter recruitment paxillin focal complexes,...