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siRNA Therapeutics - Articles and news items

Figure 1 Schematic illustration of arrayed or pooled RNAi screens in cells. Left panel. Pooled-viral vectors encoding libraries of shRNAs targeting multiple genes can be used to transduce a target cell population in a single tissue culture dish. After selection for the desired phenotype, cells are analysed for the identification of genes whose inhibition by RNAi knockdown cause the specific phenotype as described in Table 1. The relative abundance of each shRNA or a random 60-mer barcode expressed from the same vector as the specific shRNA can be identified and quantified by labelling the PCR product with fluorescent dyes (e.g., Cy5 or Cy3). The PCR products are then hybridised to custom designed cDNA microarrays containing barcode or shRNA complementary oligonucleotides. The relative abundance of barcodes obtained from the cells that were exposed to selective pressure are compared to that detected in control cells that have been exposed to the same shRNA library, but not to the selective pressure (for example, drug treatment or genetic mutations). Right panel. Arrayed RNAi screen libraries consist of individual siRNA or shRNA reagents that target different genes and that are placed in each well of a multi-well plate. RNAi reagent libraries can comprise synthetic siRNAs, plasmid-or virally-encoded shRNAs. Various assay readouts are used to determine the effect of RNAi on the phenotype as described in Table 1. Adapted10.

RNAi screens for the identification and validation of novel targets: Current status and challenges

Genomics, Issue 6 2010 / 16 December 2010 / Attila A. Seyhan, Translational Immunology, Inflammation and Immunology, Pfizer Pharmaceuticals

Recent advances in RNA interference (RNAi) technology and availability of RNAi libraries in various formats and genome coverage have impacted the direction and speed of drug target discovery and validation efforts. After the introduction of RNAi inducing reaagent libraries in various formats, systematic functional genome screens have been performed to query the functions of individual genes, pathways or an entire genome in many disease areas, including cancer, viral pathogenesis and others. As a consequence of these screens, novel mediators of cellular response to disease pathogenesis or treatment approaches have been identified leading to the discovery of novel drug targets, development of combinatorial treatment approaches and patient selection biomarkers.

Figure 1 siRNA drug discovery pipeline

The evolution of RNAi technologies in the drug discovery business

Genomics, Issue 5 2010 / 29 October 2010 / Jason Borawski and L. Alex Gaither, Novartis Institutes for Biomedical Research

In the past decade, the pharmaceutical industry has exploited the naturally occurring cellular RNAi pathway to enhance drug discovery research. The RNAi pathway, triggered by dsRNA, selectively, although not always specifically, degrades mRNA leading to substantial decreases in post-transcriptional gene expression1. Researchers have capitalised on this intrinsic pathway by synthesising RNAi reagents to modify the expression of any desired gene. RNAi libraries consisting of synthetic siRNAs or plasmid based shRNAs are amendable to largescale genome-wide screening campaigns to search for new therapeutic targets. Such loss of function screens can reveal novel targets and synthetic lethal interactions for cancer therapy2,3. These screens have also been used to identify novel host factors for diseases such as Hepatitis C4-7 and HIV8-14. Selective gene silencing can deconvolute molecular pathways implicated in disease onset and progression15.

Figure 1 Targeting viral-associated RNAs at different stages of infection. Step 1, targeting of incoming RNA; step 2, targeting of viral mRNAs following provial integration; and step 3, targeting viral outgoing pregenomic template DNA.

RNAi-based therapies for the treatment of HIV

Genomics, Issue 3 2010 / 24 June 2010 / Marc S. Weinberg and Fiona van den Berg, Antiviral Gene Therapy Research Unit, Department of Molecular Medicine and Haematology, University of Witwatersrand

Since the discovery of RNA interference (RNAi) in 1998 and the demonstration of RNAi in mammalian cells in 2001, research into the mechanisms and applications of this pathway has moved swiftly. RNAi is capable of mediating potent and specific silencing of genes and has therefore shown promise in the development of alternative anti-viral therapies with the potential to avoid disadvantages associated with conventional drug regimens. A number of synthetic and expressed constructs have been investigated against HIV with varying success. Despite rapid progress, important hurdles need to be surmounted before a safe, effective and widely applicable therapy can be implemented clinically. Here, we review different RNAi-based strategies against HIV and highlight future developments necessary for the realisation of an effective anti-HIV therapy…

MicroRNAs and their relatives – new avenues in biomedical research

Issue 6 2007, Past issues / 23 November 2007 /

Non-coding RNAs (ncRNAs) consist of a growing heterogeneous class of transcripts defined as RNA molecules that lack any extensive “Open Reading Frame” (ORF) and function as structural, catalytic or regulatory entities rather than serving as templates for protein synthesis. While non-coding sequences make up only a small fraction of the DNA of prokaryotes, among eukaryotes, […]

RNAi: an attractive choice for future therapeutics

Issue 3 2007 / 23 May 2007 / John J. Rossi, Division of Molecular Biology, Beckman Research Institute of the City of Hope, Graduate School of Biological Sciences, Duarte, United States

RNA interference (RNAi) is a regulatory mechanism of most eukaryotic cells that uses small double stranded RNA (dsRNA) molecules as triggers to direct homology-dependent control of gene activity (Almeida and Allshire 2005).

Forging therapeutics from small interfering RNAs

Issue 1 2005, Past issues / 7 March 2005 / Olaf Heidenreich, Department of Molecular Biology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tübingen

Small interfering RNAs are irreplaceable tools for the functional analysis of pathological gene products. Therapeutic siRNA development leads to new treatment strategies for gene products, where conventional small molecule approaches have failed.


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