Blocking the Initiation of Coagulation by RNA Aptamers to Factor VIIa

Rusconi, Christopher P.; Yeh, Alice; Lyerly, H. Kim; Lawson, Jeffrey H.; Sullenger, Bruce A.

doi:10.1055/s-0037-1614126

Cited by 73 publications

(4 citation statements)

References 56 publications

(62 reference statements)

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“…An additional benefit imparted by the negative selection step was the maximization of the fraction of the aptamer drug that binds histones in circulation, thereby reducing the therapeutic dose of the aptamer. While binding of oligonucleotide-based drugs to serum proteins is normally viewed as a benefit to improve the pharmacokinetic properties of the drug and prolong circulating times, previous therapeutic aptamers to specific serum proteins (e.g., thrombin and factor IX) which have shown efficacy in humans were developed to minimize off-target interactions with non-target proteins in serum 26,50,51 . In addition, binding of the histone aptamers to multiple histone subtypes could also have a therapeutic advantage by enabling the inactivation of several histone proteins implicated in MODS with one aptamer drug.…”

Section: Discussionmentioning

confidence: 99%

RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome

et al. 2019

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The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality. Extensive cellular injury results in the release of nuclear proteins, of which histones are the most abundant, into the circulation. Circulating histones are implicated as essential mediators of MODS. Available anti-histone therapies have failed in clinical trials due to off-target effects such as bleeding and toxicity. Here, we describe a therapeutic strategy for MODS based on the neutralization of histones by chemically stabilized nucleic acid bio-drugs (aptamers). Systematic evolution of ligands by exponential enrichment technology identified aptamers that selectively bind those histones responsible for MODS and do not bind to serum proteins. We demonstrate the efficacy of histone-specific aptamers in human cells and in a murine model of MODS. These aptamers could have a significant therapeutic benefit in the treatment of multiple diverse clinical conditions associated with MODS.

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Section: Discussionmentioning

confidence: 99%

RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome

et al. 2019

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“…Immunoaffinity chromatography, on the other hand, would normally have required denaturing conditions for the recovery of the target molecule from the affinity column [14,15]. Modified-RNA aptamers to coagulation factor VIIa (FVIIa) exhibit a greater than 500-fold specificity for F VIIa relative to the coagulation factor Xa and greater than 1000-fold relative to coagulation factor IXa, although these proteins share a common set of structural domains [19,40]. Employing subtractive selection strategies can yield aptamers with an even greater ability to discriminate between the target and related nontargeted proteins [41,42].…”

Section: General Properties Of Aptamer Compoundsmentioning

confidence: 99%

“…This aptamer is stable in plasma, with a half-life of approximately 15 hours, and can prolong the clotting time of human plasma. While this aptamer has not been studied in animals, it highlights the potential use of this technology to generate a panel of antagonists to the factors that compose the coagulation pathway[40] (Figure5).…”

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confidence: 99%

Aptamers: Diagnostic and Therapeutic Applications

Fesseha¹

2020

BJSTR

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Nucleic acids that can bind with high affinity and specificity to target molecules are called "aptamers". Aptamers are single-stranded nucleic acids that directly inhibit a protein's function by folding into a specific three-dimensional structure that dictates high-affinity binding to the targeted protein. Aptamers exhibit significant advantages relative to protein therapeutics in terms of size, synthetic accessibility, and modification by medicinal chemistry. Despite these properties, aptamers have been slow to reach the marketplace, with only one aptamer-based drug receiving approval so far. Recently, aptamers constitute a new class of oligonucleotides that have gained therapeutic importance and pegaptanib is the first approved aptamer drug that is class of oligonucleotides and is often referred to as 'chemical antibodies. The development of pegaptanib is looked at for the challenges faced in converting aptamers into therapeutic molecules. Because they inhibit the activity of existing proteins directly, aptamers are more similar to a monoclonal antibody or small molecule drugs than to antisense compounds, and this property greatly increases the number of clinical indications that are potentially treatable by nucleic acid-based compounds.reach specificity and considerable affinity to target molecules,

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“…Aptamers display low to no immunogenicity when administered in preclinical doses 1000fold greater than doses used in animal and human therapeutic applications [22,23]. However, the halt of a phase III clinical trial of REG1 in 2014 due to an excess of severe allergic reactions, suggests that low immunogenicity and toxicity may not be generalizable to all aptamers.…”

Section: Immunogenicitymentioning

confidence: 99%

Aptamers: current challenges and future prospects

Rozenblum

Lopez

Vitullo

et al. 2015

Expert Opinion on Drug Discovery

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Whereas aptamers have shown to bind to targets with similar affinities and specificities to those of antibodies, aptamers have several advantages that could outweigh antibody technology and open new opportunities for better medical and diagnostic solutions. However, the current status of the aptamer technology suffers from several technical limitations that slowdown the progression of novel aptamers into the clinic and makes the business around aptamers challenging.

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Blocking the Initiation of Coagulation by RNA Aptamers to Factor VIIa

Cited by 73 publications

References 56 publications

RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome

RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome

Aptamers: Diagnostic and Therapeutic Applications

Aptamers: current challenges and future prospects

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