Antisense oligonucleotides (ASOs) are often utilized to interfere with gene expression at mRNA level for cancer treatment. Here, we synthesized fluorescein doped silica nanoparticles (FSNPs) and coated them by polyethyleneimine (PEI) for carrying ASOs. Agarose gel electrophoresis proved that PEI/FSNPs could load ASOs by a weight ratio as high as 30:1. We tracked the delivery process of ASOs from the ASOs/PEI/FSNPs composites to HeLa cells in situ by the confocal laser scanning microscopy (CLSM) techniques, including nuclear staining and Z-axis scanning. We found the ASOs/PEI/FSNPs composites exhibited their biological effects at specific intracellular localization, and the fluorescence of the FSNPs showed the dynamic delivery process in the cells.
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http://dx.doi.org/10.1016/j.talanta.2014.03.045 | DOI Listing |
PLoS One
January 2025
Ionis Pharmaceuticals, Inc., Carlsbad, CA, United States of America.
Lateral Meningocele Syndrome (LMS), a disorder associated with NOTCH3 pathogenic variants, presents with neurological, craniofacial and skeletal abnormalities. Mouse models of the disease exhibit osteopenia that is ameliorated by the administration of Notch3 antisense oligonucleotides (ASO) targeting either Notch3 or the Notch3 mutation. To determine the consequences of LMS pathogenic variants in human cells and whether they can be targeted by ASOs, induced pluripotent NCRM1 and NCRM5 stem (iPS) cells harboring a NOTCH36692-93insC insertion were created.
View Article and Find Full Text PDFBackground: Progressive supranuclear palsy (PSP) is a devastating primary tauopathy with rapid progression to death. Although several therapies currently in the development pipeline show promising safety profiles and robust target engagement, few demonstrated significant efficacy in patients, underscoring the need to interrogate additional targets with novel therapeutic modalities to expand the potential therapeutic arsenal. To diversify the therapeutic avenues for PSP and related tauopathies (e.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Background: Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α-synuclein (α-syn) and amyloid beta (Aβ). Misfolded and aggregated α-syn has been implicated in neurological disorders such as Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB), but less so in Alzheimer's Disease (AD) despite the fact that synuclein pathology is present in over 50% of postmortem brains of AD patients. We are now expanding on our previous studies which showed positive therapeutic effects of downregulating α-syn in AD mice to understand the overall brain transcriptomic and mechanistic changes induced by treatment.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Drexel University college of medicine, Philadelphia, PA, USA.
Background: In tauopathies, such as Frontotemporal Dementia (FTD), tau loses association with microtubules (MTs) and forms neurofibrillary tangles. Tau is an abundant MT-associated protein in neurons, which essentially regulate MT properties. Because pathological tau binds less avidly to MTs, which was thought to reduce the levels and stability of axonal MTs.
View Article and Find Full Text PDFSci Rep
January 2025
Osaka Medical and Pharmaceutical University, 4-20-1, Nasahara, Takatsuki, 569-1094, Osaka, Japan.
Recent advances in the clinical development of oligonucleotide therapeutics, such as antisense oligonucleotides (ASOs) and small interfering RNAs, have attracted attention as promising therapeutic modalities for genetic and intractable diseases. These oligonucleotide therapeutics exert their efficacy by binding to target RNAs present within cells; however, the mechanisms underlying their cellular uptake, especially their passage through membranes, remain largely unclear. In the nematode, Caenorhabditis elegans, the multi-pass transmembrane protein, SID-1, is involved in the cellular uptake of double-stranded RNAs.
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