Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556


Phosphorothioate Oligonucleotides: Effectiveness and Toxicity

Author(s): Tommaso Iannitti, Julio Cesar Morales-Medina, Beniamino Palmieri.


Background: Many experimental and clinical studies have focused on the antisense strategy. In this context phosphorothioate oligonucleotides are compounds addressed to hybridize to a targeted mRNA inducing a variety of effects including inhibition of the expression of proteins involved in different pathological processes and preventing translation. Methods: In this review, we provide an update on clinical efficacy and toxicological profile of phosphorothioate oligonucleotides used in experimental and clinical studies, also focusing on the use of the antisense strategy in the context of Duchenne muscular dystrophy which is a key pathology to study different aspects of this therapy. Pubmed/Medline was searched using the keyword “Phosphorotioate” combined with “Antisense”, “Oligonucleotide” and “Duchenne muscular dystrophy”. Conclusions: Phosphorothioate oligonucleotide transient activation of the complement cascade represents the most evident toxicological response, as showed by in vivo studies. It is also known that many of these compounds induce a prolongation of activated partial thromboplastin time, a reaction which is often highly transient and proportional to the oligonucleotide plasma concentrations, making that effect clinically insignificant for the current treatment regimens. In summary, current evidence shows limited untoward effects and reversibility of the damage induced, at least for some of those compounds, with promising effectiveness for treatment of various pathologies.

Keywords: Antisense, Duchenne, dystrophy, oligonucleotide, phosphorothioate, toxicology.

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Article Details

Year: 2014
Page: [663 - 673]
Pages: 11
DOI: 10.2174/1389450115666140321100304
Price: $58