Antisense oligonucleotides: absorption, distribution, metabolism, and excretion

ABSTRACT

Introduction

Antisense oligonucleotides (ASOs) have emerged as a promising novel drug modality that aims to address unmet medical needs. A record of six ASO drugs have been approved since 2016, and more candidates are in clinical development. ASOs are the most advanced class within the RNA-based therapeutics field.

Areas covered

This review highlights the two major backbones that are currently used to build the most advanced ASO platforms – the phosphorodiamidate morpholino oligomers (PMOs) and the phosphorothioates (PSs). The absorption, distribution, metabolism, and excretion (ADME) properties of the PMO and PS platforms are discussed in detail.

Expert opinion

Understanding the ADME properties of existing ASOs can foster further improvement of this cutting-edge therapy, thereby enabling researchers to safely develop ASO drugs and enhancing their ability to innovate.

Abbreviations

2′-MOE, 2′-O-methoxyethyl; 2′PS, 2 modified PS; ADME, absorption, distribution, metabolism, and excretion; ASO, antisense oligonucleotide; AUC, area under the curve; BNA, bridged nucleic acid; CPP, cell-penetrating peptide; CMV, cytomegalovirus; CNS, central nervous system; CYP, cytochrome P; DDI, drug–drug interaction; DMD, Duchenne muscular dystrophy; FDA, Food and Drug Administration; GalNAc3, triantennary N-acetyl galactosamine; IT, intrathecal; IV, intravenous; LNA, locked nucleic acid; mRNA, messenger RNA; NA, not applicable; PBPK, physiologically based pharmacokinetics; PD, pharmacodynamic; PK, pharmacokinetic; PMO, phosphorodiamidate morpholino oligomer; PMOplus, PMOs with positionally specific positive molecular charges; PPMO, peptide-conjugated PMO; PS, phosphorothioate; SC, subcutaneous; siRNA, small-interfering RNA; SMA, spinal muscular atrophy.

KEYWORDS:

• Absorption
• distribution
• metabolism
• excretion
• antisense oligonucleotides
• phosphorothioate
• phosphorodiamidate morpholino oligomer
• peptide-conjugated phosphorodiamidate morpholino oligomers

Article highlights

• The two major chemistry backbones that are widely used to build the most advanced ASO drugs are the phosphorodiamidate morpholino oligomers (PMOs) and the phosphorothioates (PSs).

• PMOs and PS oligomers demonstrate superior metabolic stability, sequence specificity, and absence of off-target effects that allow specific RNA targeting in an increasing number of clinical therapeutic areas.

• ASOs can be clinically administered via several routes of administration, such as intravenous, subcutaneous, intravitreal, and intrathecal injections, depending on the target tissues.

• Poor tissue uptake presents one of the biggest challenges in the ASO field; ASO delivery has become an active area of research, focusing on optimizing ASO delivery to target tissues and increasing the cellular uptake.

• ASOs are not CYP substrates and no drug–drug interactions have been reported for any clinical ASO drug.

• PK/PD translation of ASOs from preclinical species into humans is a critical area of research and more data are needed.

This box summarizes key points contained in the article.

Acknowledgments

Django Andrews, Marc Evans, John Haberman, Aaron Novack, and Ihor Sehinovych of Sarepta Therapeutics, Inc. contributed their review, suggestions, and comments.

Declaration of interest

M Shadid is an employee of Sarepta Therapeutics Inc. M Badawi is an employee of AbbVie. Editorial support, provided by Joseph DeSisto Alling of Eloquent Scientific Solutions, was utilized in the production of this manuscript and funded by Sarepta. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This review was funded by Sarepta Therapeutics Inc.