Antisense oligonucleotides against TNFR1 prevent toxicity of TNF/IFNγ treatment in mouse tumor models

Hauwermeiren, Filip Van; Vandenbroucke, Roosmarijn E.; Grine, Lynda; Puimège, Leen; Wonterghem, Elien Van; Zhang, Hong; Libert, Claude

doi:10.1002/ijc.28704

Cited by 14 publications

(12 citation statements)

References 37 publications

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“…That TNF-R1 receptor is mainly responsible for the toxicity is demonstrated by its reduction by treating with antisense TNF-R1 [41]. Tumor resistance to the cytotoxic effects of TNF-alpha is mediated by TNF-R2.…”

Section: Tnf-alpha Receptors 1 Andmentioning

confidence: 99%

Unleashing endogenous TNF-alpha as a cancer immunotherapeutic

Josephs¹,

Ichim

Prince³

et al. 2018

J Transl Med

194

151

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Tumor necrosis factor (TNF)-alpha was originally identified in the 1970s as the serum mediator of innate immunity capable of inducing hemorrhagic necrosis in tumors. Today, a wide spectrum of biological activities have been attributed to this molecule, and clinical translation has mainly occurred not in using it to treat cancer, but rather to inhibit its effects to treat autoimmunity. Clinical trials utilizing systemic TNF-alpha administration have resulted in an unacceptable level of toxicities, which blocked its development. In contrast, localized administration of TNF-alpha in the form of isolated limb perfusion have yielded excellent results in soft tissue sarcomas. Here we describe a novel approach to leveraging the potent antineoplastic activities of TNF-alpha by enhancing activity of locally produced TNF-alpha through extracorporeal removal of soluble TNF-alpha receptors. Specifically, it is known that cancerous tissues are infiltrated with monocytes, T cells, and other cells capable of producing TNF-alpha. It is also known that tumors, as well as cells in the tumor microenvironment produce soluble TNF-alpha receptors. The authors believe that by selectively removing soluble TNF-alpha receptors local enhancement of endogenous TNF-alpha activity may provide for enhanced tumor cell death without associated systemic toxicities.

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Section: Tnf-alpha Receptors 1 Andmentioning

confidence: 99%

Unleashing endogenous TNF-alpha as a cancer immunotherapeutic

Josephs¹,

Ichim

Prince³

et al. 2018

J Transl Med

194

151

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“…As a consequence of the rising levels of C. albicans multi-resistance to the traditional antifungal treatments, new alternative therapies, with novel mechanisms of action, enhanced therapeutic potential, improved pharmacokinetics, and less toxicity, are urgently needed 16, 17. Antisense therapy (AST) holds great promise for the treatment of many human chronic non-infectious diseases;18, 19, 20, 21, 22, 23, 24 however, for controlling Candida species growth, the knowledge is scarce 23, 25. Moreover, the control of yeast virulence determinants has never been exploited before with AST.…”

Section: Introductionmentioning

confidence: 99%

Application of 2′-OMethylRNA′ Antisense Oligomer to Control Candida albicans EFG1 Virulence Determinant

Araújo

Azevedo

Barbosa

et al. 2019

Molecular Therapy - Nucleic Acids

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Antisense oligomers and their analogs have been successfully utilized to silence gene expression for the treatment of many human diseases; however, the control of yeast's virulence determinants has never been exploited before. In this sense, this work is based on the key hypothesis that if a pathogen's genetic sequence is a determinant of virulence, it will be possible to synthesize a nucleic acid mimic based on antisense therapy (AST) that will bind to the mRNA produced, blocking its translation into protein and, consequently, reducing the pathogen virulence phenotype. EFG1 is an important determinant of virulence that is involved in the regulation of the Candida albicans switch from yeast to filamentous form. Thus, our main goal was to design and synthesize an antisense oligonucleotide (ASO) targeting the EFG1 mRNA and to validate its in vitro applicability. The results show that the anti-EFG1 2 0-OMethylRNA (2 0 OMe) oligomer was able to significantly reduce the levels of EFG1 gene expression and of Efg1p protein translation (both approximately 60%), as well as effectively prevent filamentation of C. albicans cells (by 80%). Moreover, it was verified that anti-EFG1 2 0 OMe keeps the efficacy in different simulated human body fluids. Undeniably, this work provides potentially valuable information for future research into the management of Candida infections, regarding the development of a credible and alternative method to control C. albicans infections, based on AST methodology.

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“…Antisense oligonucleotides are short, synthetic, nucleic acid fragments that specifically bind to the target RNA sequences to form a DNA:RNA hybrid (for antisense DNA) or RNA:RNA duplex (for antisense RNA). This may block reverse transcription or translation by ribosomal blockage or induce RNase H-mediated RNA cleavage of RNA:DNA hybrids ( Figure 2 ) [ 19 , 30 ]. Since the first application of ASOs against HBV in 1990 [ 31 ], several studies have further demonstrated the potential of ASOs in gene therapy.…”

Section: Antisense Oligonucleotidesmentioning

confidence: 99%

Progress and Prospects of Anti-HBV Gene Therapy Development

Maepa

Roelofse

Ely

et al. 2015

IJMS

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Despite the availability of an effective vaccine against hepatitis B virus (HBV), chronic infection with the virus remains a major global health concern. Current drugs against HBV infection are limited by emergence of resistance and rarely achieve complete viral clearance. This has prompted vigorous research on developing better drugs against chronic HBV infection. Advances in understanding the life cycle of HBV and improvements in gene-disabling technologies have been impressive. This has led to development of better HBV infection models and discovery of new drug candidates. Ideally, a regimen against chronic HBV infection should completely eliminate all viral replicative intermediates, especially covalently closed circular DNA (cccDNA). For the past few decades, nucleic acid-based therapy has emerged as an attractive alternative that may result in complete clearance of HBV in infected patients. Several genetic anti-HBV strategies have been developed. The most studied approaches include the use of antisense oligonucleotides, ribozymes, RNA interference effectors and gene editing tools. This review will summarize recent developments and progress made in the use of gene therapy against HBV.

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Antisense oligonucleotides against TNFR1 prevent toxicity of TNF/IFNγ treatment in mouse tumor models

Cited by 14 publications

References 37 publications

Unleashing endogenous TNF-alpha as a cancer immunotherapeutic

Unleashing endogenous TNF-alpha as a cancer immunotherapeutic

Application of 2′-OMethylRNA′ Antisense Oligomer to Control Candida albicans EFG1 Virulence Determinant

Progress and Prospects of Anti-HBV Gene Therapy Development

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