Oligonucleotide-based pharmaceuticals: Non-clinical and clinical safety signals and non-clinical testing strategies

Mustonen, Enni-Kaisa; Palomäki, Tiina; Pasanen, Markku

doi:10.1016/j.yrtph.2017.09.028

Cited by 22 publications

(29 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oligonucleotide therapeutics are metabolized by ubiquitous nucleases; parent compound and metabolites are then primarily excreted in urine . Antisense oligonucleotides that contain a PS backbone are extensively bound to plasma proteins (≥ 85%) and mainly to albumin across all species including man .…”

Section: Translational Strategies Encompassing Preclinical Evaluationmentioning

confidence: 99%

“…A significant advantage of oligonucleotide therapy is low risk of drug interactions. Oligonucleotide therapeutics are not substrates, inhibitors, or inducers of common transporters and cytochrome P450 enzymes . Clinical drug interaction studies that are often conducted for small molecules are not typically necessary for this class of drugs.…”

Section: Translational Strategies Encompassing Preclinical Evaluationmentioning

confidence: 99%

“…Although oligonucleotide therapeutics are becoming a promising drug platform, several safety concerns have been raised in nonclinical and clinical studies . For example, severe thrombocytopenia has been reported for inotersen and volanesorsen; both are antisense oligonucleotides with 2ʹ‐MOE PS modifications.…”

Section: Translational Strategies Encompassing Preclinical Evaluationmentioning

confidence: 99%

“…The mechanism of action, chemical evolution, and intracellular delivery of oligonucleotide therapies are only briefly reviewed to provide a background for this class of therapies. Reviews specific in these areas have been published elsewhere and the readers are encouraged to review them …”

mentioning

confidence: 99%

See 3 more Smart Citations

Targeting RNA: A Transformative Therapeutic Strategy

Yin

Rogge

2019

Clinical Translational Sci

114

103

View full text Add to dashboard Cite

The therapeutic pathways that modulate transcription mechanisms currently include gene knockdown and splicing modulation. However, additional mechanisms may come into play as more understanding of molecular biology and disease etiology emerge. Building on advances in chemistry and delivery technology, oligonucleotide therapeutics is emerging as an established, validated class of drugs that can modulate a multitude of genetic targets. These targets include over 10,000 proteins in the human genome that have hitherto been considered undruggable by small molecules and protein therapeutics. The approval of five oligonucleotides within the last 2 years elicited unprecedented excitement in the field. However, there are remaining challenges to overcome and significant room for future innovation to fully realize the potential of oligonucleotide therapeutics. In this review, we focus on the translational strategies encompassing preclinical evaluation and clinical development in the context of approved oligonucleotide therapeutics. Translational approaches with respect to pharmacology, pharmacokinetics, cardiac safety evaluation, and dose selection that are specific to this class of drugs are reviewed with examples. The mechanism of action, chemical evolution, and intracellular delivery of oligonucleotide therapies are only briefly reviewed to provide a general background for this class of drugs.

show abstract

Section: Translational Strategies Encompassing Preclinical Evaluationmentioning

confidence: 99%

Section: Translational Strategies Encompassing Preclinical Evaluationmentioning

confidence: 99%

Section: Translational Strategies Encompassing Preclinical Evaluationmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Targeting RNA: A Transformative Therapeutic Strategy

Yin

Rogge

2019

Clinical Translational Sci

114

103

View full text Add to dashboard Cite

show abstract

“…RNA interference (RNAi) as well as antisense oligonucleotides and aptamers have been postulated to exert immune stimulatory effects in mammals (Agrawal and Kandimalla, 2004;Cullen, 2006;Mustonen et al, 2017). However, at present, there is still an important open debate about agents exerting physiologically relevant functions at systems level biology (Cullen, 2006;Kleinman et al, 2008).…”

Section: Lessons From Rna-based Therapeuticsmentioning

confidence: 99%

Literature review of baseline information on non‐coding RNA (ncRNA) to support the risk assessment of ncRNA‐based genetically modified plants for food and feed

Dávalos

Henriques

Latasa

et al. 2019

EFS3

View full text Add to dashboard Cite

This report is the outcome of an EFSA procurement (NP/EFSA/GMO/2016/01) reviewing relevant scientific information on ncRNA and on RNA interference (RNAi) that could support the food and feed risk assessment of ncRNA-based genetically modified (GM) plants. Information was retrieved through key words and key questions covering the stability and degradation of ncRNAs after oral ingestion, the passage of ncRNAs from food and feed to human and animal organs and tissues via the gastrointestinal tract and other barriers, as well as the potential effects on the gastrointestinal tract, the immune system or the entire organism. Full description of the strategy used for the literature search and for studies selection is provided and the number of retrieved publications is reported. This report is divided into four parts discussing the kinetics of exogenous ncRNAs in humans and animals, with focus on ingested ncRNAs (Part 1); the possible effects of ncRNAs on the gastrointestinal tract (Part 2), systemically (Part 3) and on the immune system (Part 4). This report suggests that some plant ncRNAs (e.g miRNAs and siRNAs) show higher stability as compared to other ncRNAs due to peculiar chemical characteristics (2'-O-methylation at 3' end). However, ingested or administered ncRNA must overcome many extracellular and cellular barriers to reach the intended target tissue or functional location in sufficient amount to exert any biological effect. Literature data indicate that chemically unmodified and unformulated ncRNAs exhibit very low stability in the gastrointestinal tract and in biological fluids and, in general, do not elicit major biological effects. This report also provides an overview of the RNA content in plant-derived foods and diets and discusses the controversies on the presence of dietary exogenous RNAs in the biological fluids of humans and animals and their effects. Finally, gaps in the scientific literature are highlighted and recommendations provided.

show abstract

Class‐Related Proinflammatory Effects

Séguin

2018

Oligonucleotide‐Based Drugs and Therapeutics

View full text Add to dashboard Cite

Oligonucleotide-based pharmaceuticals: Non-clinical and clinical safety signals and non-clinical testing strategies

Cited by 22 publications

References 107 publications

Targeting RNA: A Transformative Therapeutic Strategy

Targeting RNA: A Transformative Therapeutic Strategy

Literature review of baseline information on non‐coding RNA (ncRNA) to support the risk assessment of ncRNA‐based genetically modified plants for food and feed

Class‐Related Proinflammatory Effects

Contact Info

Product

Resources

About