Oligonucleotide Therapies: The Past and the Present

Lundin, Karin E.; Gissberg, Olof; Smith, C. I. Edvard

doi:10.1089/hum.2015.070

Cited by 230 publications

(201 citation statements)

References 138 publications

(147 reference statements)

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“…In this context, especially addition of stearic acid or stearylation has been used with great success. Futaki et al was to our knowledge the first to introduce this modification in CPPs [6]. In their early report, they showed the benefit of the modification on Arg8 peptide and demonstrated its applicability for plasmid transfections in cell culture models.…”

Section: Non-covalent Nanoparticle-based Approach For the Delivery Numentioning

confidence: 99%

“…These mostly antisense-based methods are unique, as they are highly specific and can be used to target virtually any single or group of genes. Antisense methodologies include classical antisense ONs (ASOs), splice-switching ONs (SSOs), antigene ONs, small interfering RNAs (siRNAs), microRNAs (miRNAs), anti-miRNAs (antimiRs) (as further described in many excellent reviews [1][2][3][4][5][6]). Typically, effects of such compounds lead to enhanced target gene expression, modulation/conversion between the different gene products, or silencing of specific genes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peptides for nucleic acid delivery

Lehto

Ezzat

Wood

et al. 2016

Advanced Drug Delivery Reviews

191

132

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Nucleic acids and their synthetic oligonucleotide (ON) analogs are a group of gene therapeutic compounds which hold enormous clinical potential. Despite their undoubted potential, clinical translation of these molecules, however, has been largely held back by their limited bioavailability in the target tissues/cells. To overcome this, many different drug delivery systems have been devised. Among others, short delivery peptides, called cell-penetrating peptides (CPPs), have been demonstrated to allow for efficient delivery of nucleic acids and their ON analogs, in both cell culture and animal models. In this review, we provide brief overview of the latest advances in nucleic acid delivery with CPPs, covering the two main vectorization strategies, covalent conjugation and nanoparticle formation-based approach. In conclusion, CPP-based drug delivery systems have the capacity to overcome the hurdle of delivery and thus have the potential to facilitate the clinical translation of nucleic acid-based therapeutics.

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Section: Non-covalent Nanoparticle-based Approach For the Delivery Numentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peptides for nucleic acid delivery

Lehto

Ezzat

Wood

et al. 2016

Advanced Drug Delivery Reviews

191

132

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“…ODNs comprise an oligonucleotide sequence, containing 10-50 nucleotides [1,2]. Numerous ODNs have been investigated so far [1][2][3][4]. But only six ODNs (fomivirsen, pegaptanib, mipomersen, eteplirsen, nusinersen and defibrotide sodium) have been approved by the US FDA since 1998 [5].…”

mentioning

confidence: 99%

Quantitative Analysis of Imetelstat in Plasma with LC–MS/MS Using Solid-Phase or Hybridization Extraction

et al. 2017

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Aim: Imetelstat, a 13-mer oligonucleotide with a lipid tail is being evaluated for treating hematologic myeloid malignancies. This report describes the development of extraction and quantification methods for imetelstat. Methodology & results: Imetelstat was extracted using SPE (rat plasma) or by hybridization using a biotinylated capture probe (human plasma) and was quantified by LC-MS/MS. Calibration curves were established (0.1-50 μg/ml). Stability of imetelstat in plasma was demonstrated. Concentrations of imetelstat extracted using either of the methods and quantified with LC-MS/MS were comparable with a validated ELISA. Conclusion: Two extraction methods (solid phase and hybridization) were developed for quantifying imetelstat in plasma using LC-MS/MS. The hybridization extraction in combination with LC-MS/MS is a novel extraction approach. In recent years, oligonucleotide drugs (ODNs) have gained popularity owing to their ability to target specific genes and provide specificity. ODNs comprise an oligonucleotide sequence, containing 10-50 nucleotides [1,2]. Numerous ODNs have been investigated so far [1][2][3][4]. But only six ODNs (fomivirsen, pegaptanib, mipomersen, eteplirsen, nusinersen and defibrotide sodium) have been approved by the US FDA since 1998 [5].Pharmaceutical development of ODNs has several technical challenges such as maintaining in vivo stability, ensuring delivery and bioavailability, and minimizing off-target effects. These challenges can be minimized by chemical modifications of ODNs to enhance their pharmacokinetic and pharmacodynamic properties [4,6]. These chemical modifications include: sulfurization of the phosphodiester bond to avert degradation by enlindogenous exonucleases, addition of methoxy or methoxyethyl groups to sugar moieties [7,8], locked and unlocked nucleic acids, and alterations in the internucleotide linkage (e.g., amide linkage) resulting in peptide nucleic acids [1]. Sulfurization results in phosphorothioate analogs that are more hydrophobic, exhibit more complex secondary structures with higher protein binding and greater accumulation in organs than phosphodiester analogs [9][10][11].Imetelstat is a novel, first-in-class telomerase inhibitor ODN [12], being investigated for the treatment of hematologic myeloid malignancies [13,14] and certain solid tumors [12,15,16]. Imetelstat is a 13-mer oligonucleotide N3 -P5 thio-phosphoramidate (NPS) with a covalently linked C16 (palmitoyl) lipid moiety at the 5 -end (Figure 1; Supplementary Table 1). Addition of a lipid chain and the modified oligonucleotide backbone enables imetelstat to penetrate cells and tissues, with high biodistribution into normal and malignant cells [12].Imetelstat differs from antisense oligonucleotides in its mechanism of action. Imetelstat is complementary to the template region of the RNA component of telomerase, to which it binds with high affinity and specificity, and directly competes with telomere binding, thereby inhibiting telomerase activity [17]. Thus, imetelstat acts as a classical ac...

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“…Consequently, since its discovery in the late 1990s, RNAi-based therapeutics have been used in more than 50 clinical trials involving 26 different siRNAs (Ling et al 2013;Lundin et al 2015;Wittrup et al 2015). Two phase III clinical trials are in progress to treat familial neurodegenerative and cardiac syndromes caused by transthyretin mutations (Singh and Peer 2016) while studies on the potential of miRNA replacements or miRNA inhibitions to reduce hypertrophic dermal scarring by targeting connective tissue growth factor or to treat pancreatic cancer have also started (Singh and Peer 2016).…”

Section: Substance-induced Alterations In Ncrna Expression Profilesmentioning

confidence: 99%

Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

Aigner¹,

Buesen²,

Gant³

et al. 2016

Regulatory Toxicology and Pharmacology

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The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that the abundance of data obtained from ncRNA expression profiling requires careful evaluation to determine the utility of specific ncRNAs for regulatory toxicology. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify candidate ncRNAs for further assessment as potential biomarkers of toxicity and areas of toxicology where ncRNA expression profiling can address prevailing scientific deficiencies.(2) Develop consensus on how to conduct and report ncRNA expression profiling in a toxicological context to support applicability for regulatory decision-making. (3) Conduct experimental projects to evaluate the toxicological relevance of the expression profiles of selected ncRNAs. As necessary, retrospective analyses (e.g. from surplus samples from control groups from regulatory studies) can be supplemented with new (90-day) rat oral toxicity studies. These projects should aim at establishing physiological ncRNA expression profiles including the biological variability of healthy individuals. To substantiate the relevance of key ncRNAs for cell homeostasis or pathogenesis, molecular events should be linked with substance-induced apical effects in a dose-dependent manner. Applying a holistic approach, knowledge on ncRNAs, and relevant information from 'omics and epigenetics technologies, should be integrated into adverse outcome pathways to improve the understanding of the functional roles of ncRNAs within a regulatory context.

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Oligonucleotide Therapies: The Past and the Present

Cited by 230 publications

References 138 publications

Peptides for nucleic acid delivery

Peptides for nucleic acid delivery

Quantitative Analysis of Imetelstat in Plasma with LC–MS/MS Using Solid-Phase or Hybridization Extraction

Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

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