<i>In vivo</i>and<i>in vitro</i>studies of antisense oligonucleotides – a review

Kilanowska, Anna; Studzińska, Sylwia

doi:10.1039/d0ra04978f

Cited by 52 publications

(39 citation statements)

References 121 publications

(265 reference statements)

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“…Hence, the differential abundance and activity of endo- and exonucleases in different organs and species can affect the metabolic pathway of LNA gapmers. Moreover, as a disparity between in vitro incubation and animal models can be observed [ 69 , 118 ], careful interpretation of these data, together with metabolite profiling, is warranted.…”

Section: Discussionmentioning

confidence: 99%

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

Valenzuela

Tardiveau²,

Ayuso

et al. 2021

Pharmaceutics

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The adult Göttingen Minipig is an acknowledged model for safety assessment of antisense oligonucleotide (ASO) drugs developed for adult indications. To assess whether the juvenile Göttingen Minipig is also a suitable nonclinical model for pediatric safety assessment of ASOs, we performed an 8-week repeat-dose toxicity study in different age groups of minipigs ranging from 1 to 50 days of age. The animals received a weekly dose of a phosphorothioated locked-nucleic-acid-based ASO that was assessed previously for toxicity in adult minipigs. The endpoints included toxicokinetic parameters, in-life monitoring, clinical pathology, and histopathology. Additionally, the ontogeny of key nucleases involved in ASO metabolism and pharmacologic activity was investigated using quantitative polymerase chain reaction and nuclease activity assays. Similar clinical chemistry and toxicity findings were observed; however, differences in plasma and tissue exposures as well as pharmacologic activity were seen in the juvenile minipigs when compared with the adult data. The ontogeny study revealed a differential nuclease expression and activity, which could affect the metabolic pathway and pharmacologic effect of ASOs in different tissues and age groups. These data indicate that the juvenile Göttingen Minipig is a promising nonclinical model for safety assessment of ASOs intended to treat disease in the human pediatric population.

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Section: Discussionmentioning

confidence: 99%

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

Valenzuela

Tardiveau²,

Ayuso

et al. 2021

Pharmaceutics

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“…Thus, this salient benefit of Gal-NAc conjugation on tiny LNAs could be ascribed to the poorer tissue uptake of parent tinyLNA (8-mer) compared to that of gapmer ASOs (generally 15-20-mer phosphorothioate ASO) [29]. The latter are larger and more hydrophobic, and are thought to accumulate more naturally in the liver without ligand conjugation, while shorter phosphorothioate oligonucleotides are generally less likely to bind to plasma proteins, which are supposed to accelerate their elimination from the circulation [29][30][31]. Further experimental support is required to uncover the underlying mechanisms that provide this important benefit.…”

Section: Evaluation Of Dose Responsiveness Of In Vivo Activity Of Galmentioning

confidence: 99%

Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides

et al. 2021

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The development of clinically relevant anti-microRNA antisense oligonucleotides (anti-miRNA ASOs) remains a major challenge. One promising configuration of anti-miRNA ASOs called “tiny LNA (tiny Locked Nucleic Acid)” is an unusually small (~8-mer), highly chemically modified anti-miRNA ASO with high activity and specificity. Within this platform, we achieved a great enhancement of the in vivo activity of miRNA-122-targeting tiny LNA by developing a series of N-acetylgalactosamine (GalNAc)-conjugated tiny LNAs. Specifically, the median effective dose (ED50) of the most potent construct, tL-5G3, was estimated to be ~12 nmol/kg, which is ~300–500 times more potent than the original unconjugated tiny LNA. Through in vivo/ex vivo imaging studies, we have confirmed that the major advantage of GalNAc over tiny LNAs can be ascribed to the improvement of their originally poor pharmacokinetics. We also showed that the GalNAc ligand should be introduced into its 5′ terminus rather than its 3′ end via a biolabile phosphodiester bond. This result suggests that tiny LNA can unexpectedly be recognized by endogenous nucleases and is required to be digested to liberate the parent tiny LNA at an appropriate time in the body. We believe that our strategy will pave the way for the clinical application of miRNA-targeting small ASO therapy.

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“…ASOs are usually modified to increase their half-life and affinity to plasma proteins and nearly all blood circulating PS ASO bind to plasma proteins [ 177 ]. In contrast, PNAs and PMOs exhibit lower plasma protein affinity (less than 25%) [ 178 ]. Other oligonucleotides such as siRNAs also require albumin transportation [ 176 ].…”

Section: Overcoming Challenges Of Oligonucleotide Therapeuticsmentioning

confidence: 99%

Recent Advances in Oligonucleotide Therapeutics in Oncology

Xiong

Veedu

Diermeier

2021

IJMS

129

103

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Cancer is one of the leading causes of death worldwide. Conventional therapies, including surgery, radiation, and chemotherapy have achieved increased survival rates for many types of cancer over the past decades. However, cancer recurrence and/or metastasis to distant organs remain major challenges, resulting in a large, unmet clinical need. Oligonucleotide therapeutics, which include antisense oligonucleotides, small interfering RNAs, and aptamers, show promising clinical outcomes for disease indications such as Duchenne muscular dystrophy, familial amyloid neuropathies, and macular degeneration. While no approved oligonucleotide drug currently exists for any type of cancer, results obtained in preclinical studies and clinical trials are encouraging. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in oncology, review current clinical trials, and discuss associated challenges.

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In vivoandin vitrostudies of antisense oligonucleotides – a review

Abstract: Metabolism of ASOs is based on exonucleases degradation of subsequent nucleotides, with the activity of endonucleases in the case of some modifications.

Cited by 52 publications

References 121 publications

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides

Recent Advances in Oligonucleotide Therapeutics in Oncology

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