Effect of TNF-α Antisense Oligomers on Cytokine Production by Primary Murine Alveolar Macrophages

Taylor, Margaret; Weller, Dwight D.; Kobzik, Lester

doi:10.1089/oli.1.1998.8.199

Cited by 15 publications

(8 citation statements)

References 28 publications

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“…25 One such modification in oligomer chemistry has led to the development of the phosphorodiamidate morpholino oligomers (PMO) by AVI BioPharma Inc. (Portland, OR), which are non-ionic antisense agents that inhibit gene expression by binding to RNA and sterically blocking processing or translation in an RNaseH-independent manner. [26][27][28] PMO antisense agents have revealed excellent safety profile and efficacy in multiple disease models [29][30][31][32][33][34][35][36][37] including cancer preclinical studies. [38][39][40][41][42][43][44] Recent studies in our laboratory have characterized in vivo PMO bioavailability in solid tumors and pharmacokinetics of the PMO agents in human clinical trials, revealing the potential of these agents in gene-specific targeting.…”

Section: Genomic-based Strategiesmentioning

confidence: 99%

siRNA-based approaches in cancer therapy

2006

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The availability of the human genome sequence has revolutionized the strategy of employing nucleic acids with sequences complementary to specific target genes to improve drug discovery and target validation. Development of sequence-specific DNA or RNA analogs that can block the activity of selected single-stranded genetic sequences offers the possibility of rational design with high specificity, lacking in many current drug treatments for various diseases including cancer, at relatively inexpensive costs. Antisense technology is one such example that has shown promising results and boasts of yielding the only approved drug to date in the genomics field. However, in vivo delivery issues have yet to be completely overcome for widespread clinical applications. In contrast to antisense oligonucleotides, the mechanism of silencing an endogenous gene by the introduction of a homologous double-stranded RNA (dsRNA), transgene or virus is called post-transcriptional gene silencing (PTGS) or RNA interference. PTGS is a natural mechanism whereby metazoan cells suppress expansion of genes when they come across dsRNA molecules with the same sequence. Short interfering RNA is currently the fastest growing sector of this antigene field for target validation and therapeutic applications. Although, in theory, the development of genomics-based agents to inhibit gene expression is simple and straightforward, the fundamental concern relies upon the capacity of the oligonucleotide to gain access to the target RNA. This paper summarizes the advances in the last decade in the field of PTGS using RNA interference approaches and provides relevant comparisons with other oligonucleotide-based approaches with a specific focus on oncology applications. Cancer Gene Therapy (2006) Genomic-based strategiesThe American Cancer Society estimates that, in 2005, a total of 1 372 910 new cancer cases and 570 280 deaths are expected in the United States. 1 These morbid statistics demonstrate the necessity of newer therapeutic modalities for achieving successful cancer treatment and cure. Downregulation of genes that contribute to cancer progression has been the goal of targeted genomics-based strategies, with the expectation that such an approach may lead to selective and specific inhibition of tumor growth with minimal untoward side effects on normal cells. Identification of target genes involved in neoplastic transformation and tumor progression has triggered the idea that nucleotide sequences of cancer-relevant genes could lead to the development of tailored anticancer agents that lack many of the toxic side effects of traditional cytotoxic drugs. This has led to a recent acceleration in the development and optimization of genomic-based strategies for cancer therapy. This idea dates back to the 1960s when RNA sequences were shown to serve as endogenous inhibitors of gene expression in procaryotes. The antigene approaches include the following:(1) Ribozymes: 2,3 These were discovered in the 1970s, and the elucidation of the transactivating hammerh...

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Section: Genomic-based Strategiesmentioning

confidence: 99%

siRNA-based approaches in cancer therapy

2006

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“…When duplexed to RNA, they do not form a substrate for RNase H (72). Regions of eukaryotic mRNA sequence that are likely to be effective targets for PMO antisense agents can be predicted with relative ease and usually involve either pre-mRNA splice sites or the region comprising the 5Ј-untranslated region, the AUG translational start codon, and the first 20 or so bases of protein coding sequence (24,74,77). PMO treatment has resulted in efficacious and specific reduction of target protein levels in a number of tissue culture (40,43,45) and in vivo systems (6,31,58).…”

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confidence: 99%

Antisense Morpholino-Oligomers Directed against the 5′ End of the Genome Inhibit Coronavirus Proliferation and Growth†

Neuman

Stein

Kroeker

et al. 2004

J Virol

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Conjugation of a peptide related to the human immunodeficiency virus type 1 Tat represents a novel method for delivery of antisense morpholino-oligomers. Conjugated and unconjugated oligomers were tested to determine sequence-specific antiviral efficacy against a member of the Coronaviridae, Mouse hepatitis virus (MHV). Specific antisense activity designed to block translation of the viral replicase polyprotein was first confirmed by reduction of luciferase expression from a target sequence-containing reporter construct in both cell-free and transfected cell culture assays. Peptide-conjugated morpholino-oligomers exhibited low toxicity in DBT astrocytoma cells used for culturing MHV. Oligomer administered at micromolar concentrations was delivered to >80% of cells and inhibited virus titers 10-to 100-fold in a sequence-specific and dose-responsive manner. In addition, targeted viral protein synthesis, plaque diameter, and cytopathic effect were significantly reduced. Inhibition of virus infectivity by peptide-conjugated morpholino was comparable to the antiviral activity of the aminoglycoside hygromycin B used at a concentration fivefold higher than the oligomer. These results suggest that this composition of antisense compound has therapeutic potential for control of coronavirus infection.Coronaviruses are medically and economically important pathogens of humans, livestock, and birds. Coronavirus infections cause a wide range of symptoms, including upper respiratory illness, gastroenteritis, myocarditis, nephritis, central nervous system demyelination, encephalitis, hepatitis, and peritonitis, and can have a debilitating effect on the host immune system, leading to secondary microbial infection. In humans a coronavirus infection marked by aerosol transmissibility and a high degree of immunopathology-related mortality has been linked with the outbreak of severe acute respiratory syndrome (52, 64). Other human coronaviruses cause approximately one-third of all cases of common colds (20,29,56

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“…This approach allowed the antisense molecules to be delivered as a renewable source under the control of the CMV promoter or the Visna LTR, rather than a single bolus, as employed in previous studies. [6][7][8][9][10] This study demonstrated by transient transfection that the 216 bp TNF␣ antisense was more effective than shorter (70 bp) or longer (750 bp) versions. Each of the antisense fragments constructed included the AUG transcription start site.…”

Section: Discussionmentioning

confidence: 83%

“…Although, many studies suggest that TNF␣ antisense molecules may be effective at inhibiting TNF␣ secretion, [6][7][8][9][10] controversy exists concerning the most effective TNF␣ antisense sequence. The 5Ј AUG transcription start site and sequences of the first exon flanking donor splice sites have recently been CMV promoter or the Visna LTR.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of adenoviral TNFα antisense is enhanced by a macrophage specific promoter

et al. 2001

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Macrophage-derived TNF␣ is a critical mediator of inflammation and destruction in diseases such as rheumatoid arthritis and Crohn's disease. These studies were undertaken to develop an effective adenovirus-based strategy to specifically suppress TNF␣ in primary human macrophages. A variety of promoters and LTRs were evaluated for effective expression in the macrophage cell line RAW 264.7. The CMV promoter and the Visna LTR were the most strongly expressed and were therefore used to drive the expression of TNF␣ antisense fragments. In transient transfection assays, the antisense fragment terminating at the 3Ј end of the first exon (216 bp) was superior to the others (70 and 750 bp), when expressed under the control of either the

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Effect of TNF-α Antisense Oligomers on Cytokine Production by Primary Murine Alveolar Macrophages

Cited by 15 publications

References 28 publications

siRNA-based approaches in cancer therapy

siRNA-based approaches in cancer therapy

Antisense Morpholino-Oligomers Directed against the 5′ End of the Genome Inhibit Coronavirus Proliferation and Growth†

Efficacy of adenoviral TNFα antisense is enhanced by a macrophage specific promoter

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