Preclinical Profiling of Modified Oligonucleotides: Anticoagulation and Pharmacokinetic Properties

Nicklin, Paul; Ambler, J. E.; Mitchelson, Andrew; Bayley, Deborah; Phillips, J. A.; Craig, S. J.; Mania, Brett P.

doi:10.1080/07328319708006150

Cited by 10 publications

(2 citation statements)

References 8 publications

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“…Acute and transient toxicities from oligonucleotides include cardiovascular collapse and inhibition of clotting has been reported. These toxic responses are believed to be related to both peak plasma concentrations and the sequence lengths of the oligonucleotides (Henry et al ., ; Wallace et al ., ; Griffin et al ., ; Nicklin et al ., ). Subchronic toxicities such as immune stimulation have also been found in rodents, but are far less severe in primates (Crooke, ).…”

Section: Introductionmentioning

confidence: 97%

Determination of therapeutic oligonucleotides using capillary gel electrophoresis

Chen

Bartlett

2011

Biomedical Chromatography

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Oligonucleotides have developed into highly versatile and selective therapeutics over the past 20 years. More than five discrete mechanisms of action have been reported and more than 10 different chemical modifications have been used to extend their in vivo half-life and reduce their toxicity. Capillary gel electrophoresis (CGE) has been used extensively for the quantitative analysis of oligonucleotide therapeutics in both preclinical and clinical studies since the 1990s. The success of CGE is based on its extraordinary resolving power, which allows for the simultaneous determination of the parent drug and its metabolites. More recently, capillary gel electrophoresis has seen renewed interest with the emergence of replaceable gels with single-base resolving power and new capillary electrophoresis-mass spectrometry interfaces. This review discusses the bioanalysis of therapeutic oligonucleotides showing the evolution of the field over the past two decades leading to the current new approaches. Included in this review are topics such as different gel types, sample introduction modes, sample extraction procedures, separation conditions and detection methods used in CGE, along with discussions of the successes and limitations associated with each.

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Section: Introductionmentioning

confidence: 97%

Determination of therapeutic oligonucleotides using capillary gel electrophoresis

Chen

Bartlett

2011

Biomedical Chromatography

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“…29 The improvement in potency and ADME properties for second-generation ASOs in vivo over the firstgeneration chemistry has been shown to be as much as 10-fold, and, fortuitously, MOE Gapmers also benefit from a significantly reduced proinflammatory capacity, resulting in improved safety properties and a significantly increased therapeutic window (see Figure 2). [37][38][39] Although robust clinical efficacy has been achieved for several next-generation ASO and miRNA targeted therapeutics, the ADME properties are still challenges for these agents, and continued efforts to improve on the stability, potency, and cellular delivery have recently led to notable advances. The discovery and development of N-acetyl galactosamine (GalNAc)-conjugated ASOs and RNA, siRNA, have enabled the preferential delivery of these agents to hepatocytes by virtue of the affinity of GalNAc for the hepatocyte-specific asialoglycoprotein receptors.…”

Section: Rna Therapeutics Based On Antisense Principlesmentioning

confidence: 99%

RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

MacLeod

Crooke

2017

The Journal of Clinical Pharma

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RNA-based therapeutic technologies represent a rapidly expanding class of therapeutic opportunities with the power to modulate cellular biology in ways never before possible. With RNA-targeted therapeutics, inhibitors of previously undruggable proteins, gene expression modulators, and even therapeutic proteins can be rationally designed based on sequence information alone, something that is not possible with other therapeutic modalities. The most advanced RNA therapeutic modalities are antisense oligonucleotides (ASOs) and small interfering RNAs. Particularly with ASOs, recent clinical data have demonstrated proof of mechanism and clinical benefit with these approaches across several nononcology disease areas by multiple routes of administration. In cancer, next-generation ASOs have recently demonstrated single-agent activity in patients with highly refractory cancers. Here we discuss advances in RNA therapeutics for the treatment of cancer and the challenges that remain to solidify these as mainstay therapeutic modalities to bridge the pharmacogenomic divide that remains in cancer drug discovery.

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Oligonucleotide Therapeutics

Crooke¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Antisense technology expolits oligonucleotide analogs to bind to cognate RNA sequences through Watson‐Crick hybridization resulting in the destruction or disablement of the target RNA. Durign the past decade, programs on all fronts has continued and there are satisfactory consensus to all the basic questions. In this review, progress in the medicinal chemistry and molecular pharmacology of antisense is reviewed. Further, progress in understanding thepharmacokinetic, pharmacodynamic and toxicologic properties of first and second generations antisense drugs is reviewed. Additionally, a summary of clinical data on a significant number of antisense drugs is provided.

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Preclinical Profiling of Modified Oligonucleotides: Anticoagulation and Pharmacokinetic Properties

Cited by 10 publications

References 8 publications

Determination of therapeutic oligonucleotides using capillary gel electrophoresis

Determination of therapeutic oligonucleotides using capillary gel electrophoresis

RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

Oligonucleotide Therapeutics

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