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Cell specific gene silencing by lipid-siRNA conjugates in mouse central nervous system barriers

ABSTRACT: Cell specific gene silencing by lipid-siRNA conjugates in mouse central nervous system barriers

PROVIDER: PRJEB85866 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR14374734_1.fastq.gz	Fastqsanger.gz
	ERR14374734_2.fastq.gz	Fastqsanger.gz
	ERR14374735_1.fastq.gz	Fastqsanger.gz
	ERR14374735_2.fastq.gz	Fastqsanger.gz
	ERR14374736_1.fastq.gz	Fastqsanger.gz

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Cell specific gene silencing of lipid-siRNA conjugates in the mouse central nervous system (CNS)

Project description:Cell specific gene silencing of lipid-siRNA conjugates in the mouse central nervous system (CNS)

| PRJEB74471 | ENA

Cell specific gene silencing of lipid-siRNA conjugates in the mouse central nervous system (CNS)

Project description:We developed a lipid-siRNA conjugate, termed EG18, that potentiates prolonged gene silencing throughout the CNS after injection into CSF. To help inform viable therapeutic targets, we used scRNAseq to determine cell-specific gene silencing. Here, we used an siRNA sequencing targeting Ppib and inject 15 nmol of either Ppib-EG18 or a non-targeting control (NTC)-EG18 into the lateral ventricles of adult mice. After 1 month, brains were dissociated into single cells and bead-sorted into Cd11b+ and Cd11b- populations. The Cd11b+ dataset contains microglia and macrophages, while the Cd11b- sample comprised a sampling of other isolated perivascular and parenchymal populations. scRNAseq revealed gene silencing activity across diverse cell populations in the parenchyma and at brain borders, which may provide new avenues for disease-modifying therapies.

2024-04-30 | E-MTAB-13964 | biostudies-arrayexpress

From Bench to Bedside and Back: Improving the Safety of GalNAc-siRNA Conjugates Using GNA-Destabilized Seed-Pairing

Project description:Preclinical mechanistic studies have pointed towards RNAi-mediated off-target effects as a major driver of hepatotoxicity for GalNAc-siRNA conjugates. Here we demonstrate that a single glycol nucleic acid (GNA) modification can substantially reduce siRNA seed-mediated binding to off-target transcripts while maintaining on-target activity. In siRNAs with established off-target effects leading to hepatotoxicity, these Enhanced Stabilization Chemistry plus (ESC+) designs exhibit a substantially improved therapeutic window in rat. We utilized this strategy to improve the safety of ALN-HBV, which exhibited dose-dependent, transient, and asymptomatic alanine aminotransferase elevations in healthy volunteers.

2022-06-08 | GSE184929 | GEO

Iodine I 131 Monoclonal Antibody 3F8 in Treating Patients With Central Nervous System Cancer or Leptomeningeal Cancer

Project description:RATIONALE: Radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody 3F8, can find tumor cells and carry tumor-killing substances to them without harming normal cells. This may be an effective treatment for central nervous system cancer or leptomeningeal metastases. PURPOSE: This phase II trial is studying the side effects and how well iodine I 131 monoclonal antibody 3F8 works in treating patients with central nervous system cancer or leptomeningeal cancer.

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Efavirenz Central Nervous System Side Effects

Project description:Efavirenz Central Nervous System Side Effects

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Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

Project description:Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

2023-05-17 | PXD041850 | Pride

Transcription profiling by array to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates

Project description:Objectives Pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA. Methods DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix. Results Increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA. Conclusions PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-118]

2012-04-17 | E-BUGS-118 | biostudies-arrayexpress

Deep sequencing of the locust Locusta migratoria manilensis central nervous system transcriptome

Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of nervous system in locust Locusta migratoria manilensis. By obtaining over 57,000,000 bases of sequence from central nervous system, we generated 101836 contigs and 69440 scaffolds. We finally get 41179 unigene with an average length of 570bp. There are 5519 unigenes beyond the length of 1000bp. Using BLAST searches of the NR, NT, Swiss-Prot, KEGG and COG databases we are able to identify 13552 unigene (E<0.0001). Comprehensive assessment of all the unigenes by comparing with the studied genes of other insects nervous system reveals that our unigene are broadly representative of the transcriptome of insect nervous system. Our data provides the most large-scale EST-project for locust nervous system, which greatly benefits the exploring of this insect. In addition, we identify a large number of novel nervous genes which can be used in systematic studies of locust and other insects. Examination of 1 sample

2011-01-04 | E-GEOD-24498 | biostudies-arrayexpress

Genomic aberrations in primary central nervous system lymphoma (PCNSL)

Project description:Genomic aberrations in primary central nervous system lymphoma (PCNSL). Two-condition experiment, PCNSLs vs. healthy men. Biological replicates: 12 tumors replicates, 13 peripheral blood replicates.

2010-11-13 | E-GEOD-25298 | biostudies-arrayexpress

Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo.

Project description:Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clearance tissues, several conjugates achieve significant siRNA accumulation in muscle, lung, heart, adrenal glands and fat. Oligonucleotide distribution to extra-hepatic tissues with some conjugates was significantly higher than with cholesterol, a well studied conjugate, suggesting that altering conjugate structure can enhance extra-hepatic delivery. These conjugated siRNAs enable functional gene silencing in lung, muscle, fat, heart and adrenal gland. Required levels for productive silencing vary (5-200 μg/g) per tissue, suggesting that the chemical nature of conjugates impacts tissue-dependent cellular/intracellular trafficking mechanisms. The collection of conjugated siRNA described here enables functional gene modulation in vivo in several extra-hepatic tissues opening these tissues for gene expression modulation. A systemic evaluation of a panel of conjugated siRNA, as reported here, has not previously been investigated and shows that chemical engineering of lipid siRNAs is essential to advance the RNA therapeutic field.

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