Abstract
Nucleic acid‐based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid‐based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics.
Highlights
Synthetic oligonucleotides (ONs) are small, single- or doublestranded pieces of modified nucleic acids that have been exploited as therapeutic modalities in different ways (Table 1)
This review mainly focuses on the development of single-stranded ONs and covers (i) the numerous methods developed to date to deliver ONs across biological barriers, (ii) the model systems used to test ONs and (iii) the hurdles existing for translating laboratory breakthroughs to the clinic
Patisiran consists of small interfering RNA (siRNA) directed against TTR mRNA formulated as Lipid nanoparticles (LNPs), which are administered systemically by IV infusion
Summary
Synthetic oligonucleotides (ONs) are small, single- or doublestranded pieces of modified nucleic acids that have been exploited as therapeutic modalities in different ways (Table 1). Inhibition of gene expression via target-specific mRNA degradation siRNAs, microRNAs. Therapeutic nucleic acids are chemically modified in several ways to endow them with properties such as increased resistance to nucleases and improved target binding affinity (Jarver et al, 2014) (Fig 1). First-generation chemistries include the widely used phosphate backbone modifications, e.g. phosphorothioate (PS), which imparts resistance to endonucleases and improves bioavailability by reducing renal clearance due to increased affinity for serum proteins (Eckstein, 2014) This modification reduces the affinity for the target RNA. Modifications at the 20-O position of RNA and 20 position of DNA, of which the 2ʹ-O-methyl (2ʹ-OMe), 2ʹ-O-methoxy-ethyl (2ʹ-MOE) and 2ʹ-fluoro (2ʹ-F) modifications are the most commonly used types These modifications increase the binding affinity to RNA and further improve the nuclease resistance. The modified sequences improve target affinity while the central DNA sequence forms the DNA/RNA hybrid
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