Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease

Yacyshyn, Bruce; Chey, William Y.; Goff, John S.; Salzberg, Bruce; Baerg, Richard D.; Buchman, Alan L.; Tami, Joseph A.; Yu, Rosie Z.; Gibiansky, Ekaterina; Shanahan, William R.

doi:10.1136/gut.51.1.30

Cited by 215 publications

(109 citation statements)

References 36 publications

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“…However, treatment with ISIS 2302 was judged to be ineffective and enrollment was terminated early [Schreiber et al 2001]. In the second trial, 299 patients in the US and Europe with moderately active steroid-dependent CD received an intensified regimen of ISIS 2302 (2 mg/kg IV three times per week) for up to 4 weeks or placebo [Yacyshyn et al 2002]. After a 1-month interval without treatment, the same treatment schedule was repeated.…”

Section: Vedolizumab/mln0002mentioning

confidence: 99%

Review: Anti-adhesion molecule therapy for inflammatory bowel disease

Ghosh

Panaccione

2010

Therap Adv Gastroenterol

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Although biologic agents directed against tumor necrosis factor alpha (TNFa) continue to be an effective therapeutic strategy for patients with inflammatory bowel disease (IBD), approximately 30% of patients with Crohn's disease (CD) who are refractory to standard treatment do not respond to induction therapy with TNFa inhibitors and, of those who initially respond, 50% or more cease to respond within a year. Moreover, their use can be associated with significant safety issues. Clearly, there is a need to target alternative pathways involved in the inflammatory process. IBD is driven by the trafficking of lymphocytes from the circulation into the gut tissue that is mediated by adhesive interactions between the lymphocytes and endothelial cells. The adhesion molecules involved represent attractive targets for the development of new therapeutics which should aid in the resolution of existing inflammation, prevent recurrence of inflammation, and may potentially lead to long-term control of disease. In this article we review current opportunities and challenges facing anti-adhesion therapy in IBD, and discusses recent clinical development efforts that have focused on having an impact on two particular adhesive interactions: a 4 -integrin/MAdCAM-1 and b 2 -integrin/ICAM-1. Of particular interest is natalizumab, a humanized monoclonal antibody against human a 4 integrin that is approved for the treatment of patients with moderately-to-severely active CD and evidence of active inflammation. This agent represents an efficacious therapeutic option for patients who do not respond to, or have failed, a TNF-a inhibitor.

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Section: Vedolizumab/mln0002mentioning

confidence: 99%

Review: Anti-adhesion molecule therapy for inflammatory bowel disease

Ghosh

Panaccione

2010

Therap Adv Gastroenterol

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“…Oligonucleotides based on the phosphorothioate backbone are highly promising compounds for therapeutic antisense applications. The first of these antisense oligonucleotides was admitted to market in 1998 and further RNase H activating phosphorothioate oligonucleotides are currently in various stages of clinical trial [3,[19][20][21]. Investigation of the dissociation pattern of phosphorothioate, and phosphodiester oligodeoxyribonucleotides in gas-phase revealed that both backbone modifications yield the same types of fragment ions [22,23].…”

mentioning

confidence: 99%

Gas-phase dissociation of oligoribonucleotides and their analogs studied by electrospray ionization tandem mass spectrometry

Tromp

Schürch

2005

J. Am. Soc. Mass Spectrom.

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Oligoribonucleotides (RNA) and modified oligonucleotides were subjected to low-energy collision-induced dissociation in a hybrid quadrupole time-of-flight mass spectrometer to investigate their fragmentation pathways. Only very restricted data are available on gas-phase dissociation of oligoribonucleotides and their analogs and the fundamental mechanistic aspects still need to be defined to develop mass spectrometry-based protocols for sequence identification. Such methods are needed, because chemically modified oligonucleotides can not be submitted to standard sequencing protocols.In contrast to the dissociation of DNA, dissociation of RNA was found to be independent of nucleobase loss and it is characterized by cleavage of the 5=-POO bond, resulting in the formation of c-and their complementary y-type ions. To evaluate the influence of different 2=-substituents, several modified tetraribonucleotides were analyzed. Oligoribonucleotides incorporating a 2=-methoxy-ribose or a 2=-fluoro-ribose show fragmentation that does not exhibit any preferred dissociation pathway because all different types of fragment ions are generated with comparable abundance. To analyze the role of the nucleobases in the fragmentation of the phosphodiester backbone, an oligonucleotide lacking the nucleobase at one position has been studied. Experiments indicated that the dissociation mechanism of RNA is not influenced by the nucleobase, thus, supporting a mechanism where dissociation is initiated by formation of an intramolecular cyclic transition state with the 2=-hydroxyl proton bridged to the 5=-phosphate oxygen. A ntisense oligonucleotides are nucleic acids of about 12 to 20 nucleobases, which are designed to hybridize to a complementary messenger RNA (mRNA) sequence, thus, inhibiting gene expression [1][2][3]. Therefore, they are of great interest in human cancer therapy and for diagnostic applications. Besides the high binding specificity of antisense oligonucleotides to their target mRNA, affinity, bioavailability, and biostability are of foremost importance. However, a major drawback of the application of unmodified phosphodiester DNA or RNA oligonucleotides is that these structures are subjected to rapid nuclease degradation under physiological conditions. To improve these factors, oligonucleotide analogs, exhibiting chemical modifications of the phosphodiester backbone, of the ribose, and, to a limited extent, also of the nucleobases, are evaluated.Mechanisms of inhibition of gene expression by antisense oligonucleotides involve mRNA degrading enzymes such as RNase H, blockade of translation initiation, or modulation of splicing [4][5][6][7]. These mechanisms allow the application of new chemical modifications to increase the binding affinity and the nuclease resistance. Possible positions of the modifications are the phosphodiester backbone, the sugar unit and the nucleobases. Introduction of a phosphorothioate backbone increases nuclease resistance of antisense oligonucleotides and simultaneously serves as a very efficient su...

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“…Only 2 of 60 (3.3%) ISIS-2302-treated and none of placebo treated patients reached the primary endpoint; steroid free remission at week 14. A more recent study by Yasyshyn et al [44] was also negative. A total of 299 patients were enrolled; with a mean baseline CDAI of 276 and steroid dose of 23 mg/day.…”

Section: Integrin Receptor Blockersmentioning

confidence: 79%