Structure Activity Study of Clinically Observed Adverse Events and Oligomer Chemistry

Special Article - Antisense Drug Research and Development

J Drug Discov Develop and Deliv. 2016; 3(2): 1022.

Structure Activity Study of Clinically Observed Adverse Events and Oligomer Chemistry

Iversen PL*

Department of Environmental & Molecular Toxicology, Oregon State University, USA

*Corresponding author: Iversen PL, Department of Environmental & Molecular Toxicology, Oregon State University, Agricultural Life Sciences Bldg, Corvallis, Oregon 97331, USA

Received: January 28, 2016; Accepted: April 29, 2016; Published: May 03, 2016


The number and diversity of new nucleic acid based therapeutics in clinical trial illustrates the remarkable flexibility of this approach to therapy. The use of synthetic oligomers has the advantage of control of dose and duration of action over gene therapy and Cas9/CRISPR approaches that are developed in parallel. Further, synthetic compounds may contain a variety of modifications to fine tune their therapeutic purpose and define their mechanism of action. The expansion in diversity of nucleic acid therapeutics may also reflect the approaches to barriers observed in previous clinical trials. The objective of this review is to provide new insight into the clinical adverse event data reported for nucleic acid based therapeutics in advanced development, with the goal of establishing a comprehensive framework for evaluating the current implications, and future direction, of therapeutic antisense technologies. A pattern of adverse events, some sufficiently severe to require discontinuation of treatment, include Flu-Like Symptoms (FLS), Injection Site Reactions (ISR), kidney abnormalities, elevated liver enzymes, and thrombocytopenia are frequently observed with oligomer chemistries that have negatively charged phosphate linkages and naturally occurring sugars. Anti-Drug Antibodies (ADA) have been reported in high percentages following chronic treatment with oligomer chemistries designed to enhance duration of tissue residence time. However, these common adverse events are not observed with Phosphorodiamidate Morpholino Oliogmers (PMO) containing morpholino sugars and no negative charge in the phosphate linkage.

Keywords: Antisense therapy; Maximum tolerated dose; Clinical trials; Oligonucleotide toxicity


ADA: Anti-Drug Antibodies; PTT: Partial Thromboplastin Times; BCL2: B-Cell Leukemia-Lymphoma Gene 2; DAMPS: DNA Damage-Associated Molecular Patterns; DNA: Deoxyribonucleic Acid; FDA: Food and Drug Agency of the United States; FLS: Flu- Like Symptoms; G4: highly structured guanosine quartets; GRO: Guanosine Rich Oligomer; hsCRP: high sensitivity C-Reactive Protein; ISR: Injection Site Reactions; MTD: Maximum Tolerated Dose; NDA: New Drug Application; PMO: Phosphorodiamidate Morpholino Oliogmers; Poly I:C: Polyriboinosinic- Polyribocytidylic Acids; PSO: Phosphorothioate Oligonucleotides; PSO-2-OMe: Phosphorothioate 2’O-methyl RNA; PSO-2-MOE: Phosphorothioate 2’O-methoxyethyl RNA; RNA: Ribonucleic Acid; ROS: Reactive Oxygen Species; TLR: Toll-Like Receptor; TNFα: Tumor Necrosis Factor Alpha; ULN: Upper Limit of Normal


Oligonucleotide drug development must be viewed through a lens, which recognizes that humans are well equipped to recognize both foreign and endogenous DNA/RNA in the circulation. This protective recognition arises either as part of an innate, microbial DNA immune response or in response to cellular danger signaled by DNA Damage-Associated Molecular Patterns (DAMPs) [1,2]. Now that synthetic analogues of DNA and RNA are being developed as therapeutics for both acute and chronic treatment regimens, it is critical that we clarify the extent to which these emerging therapeutics result in chronic or inappropriate activation of these nucleic-acid sensors.

Information available to guide optimal therapeutic oligomer chemistry has transitioned from what chemical structures can be made to properties in biological systems and then on to efficacy in animal models. Recently, advanced therapeutic development of oligonucleotides has provided a wealth of information from well controlled clinical trials. Human data are the most pertinent information as, in some cases, the preclinical efficacy reports are discordant with human efficacy observations such as the case with TKM-100802 which was highly effective in nonhuman primates [3] but its use in patients from the recent Ebola outbreak were not effective [4] and off-target effects including activation of inflammatory cytokines were notable outcomes [5]. In addition, detailed summaries are only recently publicly available for Ampligen, mipomersen, drisapersen, and eteplirsen which provide comprehensive evaluation of efficacy and safety from multiple human studies (Figure 1).