Reality check: lipid-oligonucleotide conjugates for therapeutic applications

ABSTRACT

Introduction

Despite much progress in the field of oligonucleotide therapeutics, delivery in general remains an important aspect for innovation. Various lipids and lipophilic small molecules have long been conjugated to many oligonucleotides in hopes of creating better, drug-like substances. A few conjugates are beginning to enter clinical development as the understanding grows of how such conjugations change the pharmacology of the conjugate relative to the unmodified oligonucleotide. The delivery of different forms of oligonucleotides, such as antisense oligonucleotides and siRNA, is often a challenging, limiting aspect to this form of therapeutics.

Areas Covered

Herein, the origins of covalent attachment of lipophilic moieties to oligonucleotides are described as well as listing a few of those lipids commonly used for lipidation. The author also describes the mechanism by which lipidation may enhance delivery and/or exposure of oligonucleotides in vitro and in vivo.

Expert opinion

The covalent attachment of lipophilic moieties is one means to enhance the delivery and exposure of oligonucleotides. Such methods may also be applicable to other oligonucleotide-based modalities as long as the lipidation does not interfere with some key interaction. Lipidation may also be useful to modulate the cell type-specific delivery within tissues. As the understanding of the effects of such covalent modification grows, more lipidated oligos are soon likely to enter clinical development.

KEYWORDS:

• ASO
• cholesterol
• endocytosis
• lipid conjugation
• lipidic acids
• oligonucleotides
• siRNA

Article highlights

• Despite progress in the field of oligonucleotide therapeutics (oligonucleotides being large, highly hydrophilic molecules), their delivery remains an important avenue for innovation.

• The delivery of different forms of oligonucleotides, such as antisense oligonucleotides and siRNAs, is often challenging, and consequently a limiting factor in their use as therapeutics.

• Covalent attachment of lipophilic molecules can be one means to enhance the delivery and exposure of these molecules, thereby possibly enhancing their therapeutic potential.

• As our understanding of the effects of lipophilic modification grows, more lipidated oligos are likely to enter clinical development.

• These hard-wrought designs have shown advantage and a better understanding of the molecular mechanisms by which such benefit might be brought about will aid in further advance of the field of oligonucleotide therapeutics.

Declaration of interest

RA Goodnow was formally the VP of Medicinal Chemistry at Stoke Therapeutics and is now the Head of Drug Discovery Sciences and Takeda Pharmaceutical Company Limited. He has 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.

Reviewer disclosures

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

Additional information

Funding

This manuscript was funded by Stoke Therapeutics.