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  • 1
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    Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-05-02
    Description: Gene silencing by double-stranded RNA, denoted RNA interference, represents a new paradigm for rational drug design. However, the transformative therapeutic potential of short interfering RNA (siRNA) has been stymied by a key obstacle-safe delivery to specified target cells in vivo. Macrophages are particularly attractive targets for RNA interference therapy because they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes. Here we report the engineering of beta1,3-D-glucan-encapsulated siRNA particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo. Oral gavage of mice with GeRPs containing as little as 20 microg kg(-1) siRNA directed against tumour necrosis factor alpha (Tnf-alpha) depleted its messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum Tnf-alpha levels. Screening with GeRPs for inflammation genes revealed that the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) is a previously unknown mediator of cytokine expression. Importantly, silencing Map4k4 in macrophages in vivo protected mice from lipopolysaccharide-induced lethality by inhibiting Tnf-alpha and interleukin-1beta production. This technology defines a new strategy for oral delivery of siRNA to attenuate inflammatory responses in human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879154/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aouadi, Myriam -- Tesz, Gregory J -- Nicoloro, Sarah M -- Wang, Mengxi -- Chouinard, My -- Soto, Ernesto -- Ostroff, Gary R -- Czech, Michael P -- DK 30898/DK/NIDDK NIH HHS/ -- DK 32520/DK/NIDDK NIH HHS/ -- DK 60837/DK/NIDDK NIH HHS/ -- P30 DK032520/DK/NIDDK NIH HHS/ -- P30 DK032520-25/DK/NIDDK NIH HHS/ -- R01 DK030898/DK/NIDDK NIH HHS/ -- R01 DK030898-26/DK/NIDDK NIH HHS/ -- R01 DK060837/DK/NIDDK NIH HHS/ -- R01 DK060837-01A1/DK/NIDDK NIH HHS/ -- R37 DK030898/DK/NIDDK NIH HHS/ -- England -- Nature. 2009 Apr 30;458(7242):1180-4. doi: 10.1038/nature07774.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19407801" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Oral ; Animals ; *Drug Delivery Systems ; Enzyme Activation/drug effects ; *Gene Silencing ; Glucans/metabolism ; Inflammation/genetics/*prevention & control ; Interleukin-1beta/biosynthesis ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lipopolysaccharides/pharmacology ; MAP Kinase Signaling System/drug effects ; Macrophages/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Organ Specificity ; Protein-Serine-Threonine Kinases/*deficiency/*genetics/metabolism ; RNA, Small Interfering/*administration & dosage/genetics/metabolism ; Substrate Specificity ; Tumor Necrosis Factor-alpha/biosynthesis/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
    Electronic Resource
    Electronic Resource
    Molecular cloning with bifunctional plasmid vectors in Bacillus subtilis (1984)
    Springer
    Molecular genetics and genomics 193 (1984), S. 299-305 
    Details
    ISSN: 1617-4623
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Cloning in Escherichia coli and Bacillus subtilis was carried out using the bifunctional plasmid pDH5060. B. subtilis chromosomal DNA and pDH5060 DNA were digested with either BamHI or SalI, then annealed, ligated, and transformed into E. coli SK2267. Transformants containing sequences ligated into the BamHI or SalI sites in the Tcr gene of pDH5060 were selected directly using a modification of the fusaric acid technique. The BamHI and SalI clone banks contain about 250 and 140 B. subtilis fragments, respectively, with an average insert size of 8–9 Kbp in the BamHI and 4–5 Kbp in the SalI bank. The inserts ranged in size from 0.3 Kbp to greater than 20 Kbp. The vector used here therefore accepts inserts which are significantly larger than previously reported for other B. subtilis cloning systems. All individual cloned B. subtilis sequences examined were stably propagated in E. coli SK2267. Eight of eighteen B. subtilis auxotrophic markers tested (aroG, gltA, glyB, ilvA, metC, purA, pyrD, and thrA) were transformed to prototrophy with BamHI or SalI clone bank DNA. All or part of the hybrid plasmid DNA recombined at the sites of homology in the chromosome of these Rec+ recipients. Loss of sequences from hybrid plasmids was not prevented in a r - m - recE4 recipient strain of B. subtilis. Although the recE4 background prevented recombination between homologous chromosomal DNA, a variety of cloned fragments were shown to be unstable and undergo deletions of both insert and plasmid sequences. In addition, B. subtilis sequences propagated in E. coli transformed B. subtilis recE4 recipients with a 500-1,000-fold reduced efficiency.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00330684
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  • 3
    Electronic Resource
    Electronic Resource
    Molecular cloning with bifunctional plasmid vectors in Bacillus subtilis (1984)
    Springer
    Molecular genetics and genomics 193 (1984), S. 306-311 
    Details
    ISSN: 1617-4623
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Recombinant plasmid DNA cloned in E. coli via the bifunctional vector pDH5060 suffered deletions when returned to B. subtilis. However, DNA preparations of identical chimeras containing homologous or heterologous sequences stably transformed B. subtilis at high efficiency when isolated from B. subtilis. The vector pDH5060, however, was not affected and could be stably shuttled between E. coli and B. subtilis at high frequency. These problems affected the transfer of clone pools and individual chimeras, irrespective of the restriction or recombination phenotype of B. subtilis recipients. Deleted chimeras lost at least one end of cloned inserts, and in most cases, flanking plasmid sequences. Single plasmid forms (intact or deleted) were isolated from several hundred individual Cmr-transformants this suggests that events leading to deletion of chimeric plasmid DNA occur during transformation by restriction of unmodified insert sequences propagated in the intermediate host, E. coli. This conclusion is discussed with regard to the mechanism of plasmid transformation in B. subtilis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00330685
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