Delivery of oligonucleotide‐based therapeutics: challenges and opportunities

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.

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

“…Moreover, a high splicing-switching capacity of the 2′- O -MOE-PS chemistry when delivered systemically has also been reported [ 39 ]. Until very recently, this modification was not commercially available, and it has rapidly been extendedly used for many antisense drugs that are now under clinical evaluation [ 40 ]. Therefore, due to recent evidence in antisense drug development, our AON design has been based on the implementation of 2′- O -MOE-PS chemistry for the in vitro screening.…”

An Investigation into the Potential of Targeting Escherichia coli rne mRNA with Locked Nucleic Acid (LNA) Gapmers as an Antibacterial Strategy

“…This pioneering work highlighted the potential of antisense approaches to rationally target essentially any RNA to combat a variety of infections and/or diseases. Although there has been significant progress in the development of therapeutic antisense oligonucleotides to target disease, such as neurodegenerative disorders, cardiovascular disorders and cancer (reviewed in [ 23 , 24 , 25 ]), antisense oligonucleotides for antibacterial applications are yet to make it to the clinic. One of the main reasons why antibacterial antisense oligonucleotide research lags behind other RNA therapeutics is the challenge of cellular uptake [ 17 ].…”

Improving Suppression of Hemipteran Vectors and Bacterial Pathogens of Citrus and Solanaceous Plants: Advances in Antisense Oligonucleotides (FANA)

“…Although FANA's are more stable, there needs to be more research on incorporating them within current agricultural practices such as with slow-release clays, chemical penetrants or surfactants similar to slow release fertilizers and pesticides (Ghosh et al, 2018;Hunter and Sinisterra-Hunter, 2018;Rudmin et al, 2020;Vega-Vásquez et al, 2020). Advances in medical applications includes nanoparticle-assisted delivery is rapidly developing a wide variety of molecules (Hammond et al, 2021;Mendonça et al, 2021). These novel materials may provide greater utility of biopesticide products in agriculture (Vega-Vásquez et al, 2020), aided by bioengineering and novel production methods to reduce costs or to add unique traits (Hochella et al, 2019), providing benefits across the environmental sciences (Lespes et al, 2020;Li et al, 2020;Slaveykova et al, 2020).…”