FDA-Approved Oligonucleotide Therapies in 2017

Stein, C. A.; Castanotto, Daniela

doi:10.1016/j.ymthe.2017.03.023

Cited by 558 publications

(447 citation statements)

References 53 publications

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“…To date, a number of approaches for reducing cellular mRNA levels including siRNA and antisense oligonucleotides have reached the clinic [1,2]. However, the ability to upregulate mRNA or increase protein production remains challenging.…”

Section: Introductionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

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ABSTRACTmRNA based therapies hold great promise for the treatment of genetic diseases. However, this therapeutic approach suffers from multiple challenges including the short half-life of exogenously administered mRNA and subsequent protein production. Modulation of untranslated regions (UTR) represents one approach to enhance both mRNA stability and translation efficiency. The current studies describe and validate screening methods using a diverse set of 5′UTR and 3′UTR combinations for improved expression of the Arginase 1 (ARG1) protein, a potential therapeutic mRNA target. Data revealed a number of critical aspects which need to be considered when developing a screening approach for engineering mRNA improvements. First, plasmid-based screening methods do not correlate with protein expression driven by exogenously expressed mRNA. Second, improved ARG1 protein production was driven by increased translation and not improved mRNA stability. Finally, the 5′ UTR appears to be the key driver in protein expression for exogenously delivered mRNA. From the testing of the combinatorial library, the 5′UTR for complement factor 3 (C3) and cytochrome p4502E1 (CYP2E1) showed the largest and most consistent increase in protein expression relative to a reference UTR. Collectively, these data provide important information for the development and optimization of therapeutic mRNAs.

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Section: Introductionmentioning

confidence: 99%

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

et al. 2018

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“…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].…”

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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“…This drug, approved by the USFDA in December 2016, is used in the treatment of spinal muscular atrophy (SMA) [20]. SMA, a leading genetic cause of pediatric mortality, is an autosomal recessive neuromuscular disease caused by progressive loss of α-motor neurons in the anterior horn of the spinal cord [71].…”

Section: Nusinersen (Spinraza)mentioning

confidence: 99%

“…SMA, a leading genetic cause of pediatric mortality, is an autosomal recessive neuromuscular disease caused by progressive loss of α-motor neurons in the anterior horn of the spinal cord [71]. [73] by targeting and blocking an intron 7 internal splice site [20]. These actions increase SMN protein production and thus improve function [74].…”

Section: Nusinersen (Spinraza)mentioning

confidence: 99%

“…The AEs most frequently reported by study participants following treatment with nusinersen were headache (39.3%), post-lumbar puncture headache (21.4%), and back pain (17.9%). While the most common side effects of nusinersen are respiratory infections and constipation, the FDA has also issued warnings with respect to the possibility of thrombocytopenia and renal toxicity [75,76].…”

Section: Nusinersen (Spinraza)mentioning

confidence: 99%

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We Should Continue the Half-Century History of Applications of Antisense Oligonucleotides in Medicine, Agriculture and Forestry: A Mini-Review

Oberemok¹,

Laikova²,

Repetskaya³

et al. 2018

Preprint

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Antisense oligonucleotides (ASO), short single-stranded polymers (based on DNA or RNA chemistries) synthesized in vitro, regulate gene expression by binding in a sequencespecific manner to a RNA target. The functional activity and selectivity in the action of ASOs largely depends on the combination of nitrogenous bases in a target sequence. This simple and natural property of nucleic acids provides an attractive route by which scientists can create different ASO-based techniques. Over the last 50 years, planned and realized applications in the field of antisense technologies have produced astonishing results and posed new challenges for further developments, exemplifying the essence of the post-genomic era. This mini-review critically analyzes some successful cases using the antisense approach in medicine to address severe diseases, such as Duchenne muscular dystrophy and spinal muscular atrophy, and suggests some prospective directions for future research. We also examine in detail the with an efficient signal-to-noise ratio of action, coupled with the affordability of in vitro oligonucleotide synthesis and post-synthesis procedures, we predict that the next half-century will produce a fruitful yield of tools created from effective ASO-based end products.

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FDA-Approved Oligonucleotide Therapies in 2017

Cited by 558 publications

References 53 publications

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

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

We Should Continue the Half-Century History of Applications of Antisense Oligonucleotides in Medicine, Agriculture and Forestry: A Mini-Review

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