<i>In Vivo</i>Evaluation of a Morpholino Antisense Oligomer Directed Against Tumor Necrosis Factor-α

Qin, Guozhong; Taylor, Margaret; Ning, Yao; Iversen, Patrick L.; Kobzik, Lester

doi:10.1089/oli.1.2000.10.11

Cited by 34 publications

(16 citation statements)

References 11 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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“…MOs also display little toxicity and have no known cellular binding proteins or nucleases (reviewed in Summerton, 1999). MOs were developed as potential therapeutics (Arora et al, 2000;Qin et al, 2000) and are now being used for functional genomics applications (see Ekker, 2000 for review).…”

Section: Morpholino Phosphorodiamidate Gene Targeting Strategiesmentioning

confidence: 99%

Morphant technology in model developmental systems

Ekker

Larson

2001

Genesis

224

175

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“…PMOs have been previously shown to have high efficacy in vivo (Qin et al, 2000), particularly for targets in the liver following intraperitoneal (Arora and Iversen, 2000a,b) and oral administration (Arora et al, 2002). This approach to CYP3A4 inhibition by antisense PMO represents a potential strategy (reviewed by Arora and Iversen, 2001) for altering pharmacokinetics and pharmacodynamics of multiple, clinically relevant drugs metabolized by this enzyme.…”

Section: Cytochromes P450 (P450mentioning

confidence: 99%

Phosphorodiamidate Morpholino Antisense Oligomers Inhibit Expression of Human Cytochrome P450 3A4 and Alter Selected Drug Metabolism

Arora¹,

Cate²,

Ghosh³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Antisense phosphorodiamidate morpholino oligomers (PMO) inhibit targeted gene expression by preventing ribosomal assembly, thus preventing translation. Inhibition of cytochrome P450 (P450) 3A4 expression was examined in primary human hepatocytes from 11 donors and in Caco-2 cells (stably transfected with CYP3A4 cDNA on an extrachromosomal vector) by evaluating the metabolism of substrate 7-benzyloxy-4-[trifluoromethyl]-coumarin and Western immunoblot analysis. Cellular uptake of PMO was confirmed in both cell systems using fluorescein-labeled PMOs. Three antisense PMO sequences and two control PMO sequences were tested. AVI-4557, a 20-mer PMO with the sequence 5-CTGGGAT-GAGAGCCATCACT-3 was selected as the optimal agent. AVI-4557 inhibited expression of CYP3A4 in Caco-2/h3A4 cells by 64% at 24 h following administration of 2.8 M by an assisted delivery protocol. Inhibition of CYP3A activity was observed in primary human hepatocytes after 24 h exposure to AVI-4557 by an average of 32 ؎ 11%. Furthermore, AVI-4557 exposure resulted in a sequence-dependent inhibition of cyclophosphamide-related cytocidal activity and a sequence-dependent induction of paclitaxelrelated cytocidal activity in both cell types. Finally, the cytocidal activity of cisplatin was not affected with AVI-4557 treatment in either cell type. These studies indicate AVI-4557 is an effective and specific inhibitor of CYP3A4 expression.

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In VivoEvaluation of a Morpholino Antisense Oligomer Directed Against Tumor Necrosis Factor-α

Cited by 34 publications

References 11 publications

siRNA-based approaches in cancer therapy

siRNA-based approaches in cancer therapy

Morphant technology in model developmental systems

Phosphorodiamidate Morpholino Antisense Oligomers Inhibit Expression of Human Cytochrome P450 3A4 and Alter Selected Drug Metabolism

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