Clinical Trials of Functional Nucleic Acids: Antisense Oligonucleotides and Aptamers

Clinical Trials of Functional Nucleic Acids: Antisense Oligonucleotides and Aptamers

Martina Traykovska (Sofia University, Sofia, Bulgaria), Sjoerd Miedema (Sofia University, Sofia, Bulgaria) and Robert Penchovsky (Sofia University, Sofia, Bulgaria)
Copyright: © 2018 |Pages: 15
DOI: 10.4018/IJBCE.2018070104

Abstract

This chapter describes how functional nucleic acids, such as aptamers, antisense oligonucleotides (ASOs), small interfering (si) RNAs, and ribozymes are considered by some researchers as valuable tools to develop therapeutic agents. They have not been particularly fast in reaching the market as medicines, due to endogenous barriers to extracellular trafficking and cellular uptake of nucleic acids and their inherent instability when applied in vivo. However, research carried out by the nucleic acid engineering community and pharmaceutical companies to circumvent these obstacles has led to the approval of a few aptamers and ASOs as drugs. Nucleic acid therapeutics are usually administered locally to diseased tissue. The drug candidates currently in clinical trials commonly use the same administration methods as previously licensed nucleic acid therapeutics. These administration techniques carry their own safety risks and advantages. In this article, the present state is discussed and prospective options for the use ASOs and aptamers as drugs are listed.
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Introduction

Functional nucleic acids such as aptamers, antisense oligonucleotides (ASOs) (Penchovsky & Traykovska, 2015), ribozymes (Penchovsky & Breaker, 2005; Penchovsky & Kostova, 2013), and siRNAs have been used in various in vivo stagnates to induce predefined biochemical alterations in many different organisms, including humans (Penchovsky, 2012). Shortly after the discovery of ASOs (Izant & Weintraub, 1984) and aptamers (Griffin, Tidmarsh, Bock, Toole, & Leung, 1993) they are considered to be used as therapeutic agents. In fact, many attempts have been made from the pharmaceutical industry to create various therapeutic agents based on functional nucleic acids since the early nineteen nineties. The first ASO-based drug called Fomivirsen was approved in 1998, while the first aptamer-based medicine named Pegaptanib was approved in 2004. This review will focus on the clinical safety of ASOs and aptamers. ASOs act to suppress gene expression by binding to a complementary sequence within the target mRNA and preventing translation. Antisense strategies have been seen as favorites for therapeutic applications, as the chemistry of nucleic acids is well understood, a wide range of techniques are available for their manipulation, and classical base pairing makes the design of antisense oligonucleotides targeting a given gene relatively straightforward. Furthermore, endogenous and exogenous nucleic acids are at the heart of the majority of infectious diseases, congenital defects, and age-related disorders, making the potential applications of antisense therapy vast and diverse.

Aptamers are oligonucleotides which binding of target moieties is a property of their exact primary, secondary and tertiary structure. Aptamers can be described as a nucleic acid alternative to immunoglobulins. As such, aptamers have potential applications in oncology, inflammation, and autoimmune disease. The fact that aptamers are oligonucleotides makes them advantageous in many respects. Aptamers are cheaper and simpler to produce than antibodies, and they are not a native part of any signaling pathways of the immune system and can be rationally designed and modified. Despite these advantages, aptamers have struggled to find widespread application. In 2004, Pegaptanib received marketing authorization from the United States Food and Drug Administration and the European Medicines Agency. Pegaptanib remains the only aptamer drug on the market to date. In contrast, nine monoclonal antibodies were approved by the FDA in 2015 alone (New Molecular Entity (NME) Drug & Original Biologics License Applications (BLA) Calendar Year Approvals as of December 31, 2015, 2015).

When considering therapeutic agents, safety always remains the primary concern. This review will discuss the clinical safety of aptamers and antisense oligomers. Fomivirsen, Pegaptanib, and Mipomersen will be the primary focus of this review, as the only nucleic acid drugs to have reached the market to date. Clinical trial data will be considered to explore the safety of recently developed drugs.

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