Recent preclinical and clinical advances in oligonucleotide conjugates

ABSTRACT

Introduction: Oligonucleotide therapeutics have the potential to change the way disease is treated due to their ability to modulate gene expression of any therapeutic target in a highly specific and potent manner. Unfortunately, this drug class is plagued with inherently poor pharmacological characteristics, which need to be overcome. The development of a chemical modification library for oligonucleotides has addressed many of the initial challenges, but delivery of these payloads across plasma membranes remains difficult. The latest technological advances in oligonucleotide therapeutics utilizes direct conjugation to targeting ligands, which has improved bioavailability and target tissue exposure many-fold. The success of this approach has resulted in numerous clinical programs over the past 5 years.

Areas Covered: We review the literature on oligonucleotide conjugate strategies which have proven effective preclinically and clinically. We summarize the chemical modifications which allow parenteral administration as well as evaluate the efficacy of a multitude of conjugate approaches including lipids, peptides, carbohydrates, and antibodies.

Expert Opinion: The success of future conjugate strategies will likely rely on the effective combination of characteristics from earlier technologies. High-affinity ligand-receptor interactions can be critical to achieving meaningful accumulation in target tissues, but pharmacokinetic modulators which increase the circulating half-life may also be necessary. Synthesis of these approaches has the potential to bring the next breakthrough in oligonucleotide therapeutics.

KEYWORDS:

• Antibody Conjugate
• Antisense
• ASO
• Cholesterol Conjugate
• Drug Delivery System
• DsiRNA
• Exon-Skipping
• GalNAc Conjugate
• Peptide Conjugate
• RNAi
• siRNA
• Splice-Switching
• SSO
• Oligonucleotide Conjugate

Article highlights

• Nucleotide chemical modification development has been critical in the recent clinical successes found across the therapeutic oligonucleotide modalities.

• Lipid-oligonucleotide conjugation has proven to be a highly effective strategy for improving the pharmacokinetics and biodistribution profile of ASOs and siRNAs in vivo.

• Cell-penetrating peptides have been validated as a potential method for improving cytosolic delivery of therapeutic oligonucleotides in the liver, yet safety still remains a concern for this approach.

• N-acetylgalactosamine-mediated oligonucleotide delivery to hepatocytes has been shown to be extraordinarily effective clinically, but newer targeting strategies are needed to expand the therapeutic areas for these technologies.

• Preclinical success of novel oligonucleotide targeting systems, utilizing carbohydrates, peptides, and antibodies, are being investigated to treat diseases outside of the liver.

• The best approach for extrahepatic delivery of therapeutic oligonucleotides may involve the fusion of characteristics from multiple conjugation strategies (e.g. pharmacokinetic modulation with novel targeting ligands).

This box summarizes key points contained in the article.

Declaration of interest

K. Craig and M. Abrams are current employees of Dicerna Pharmaceuticals, Inc.

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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper has been supported by the Department of Biotechnology and Department of Science and Technology, Government of India.