A perspective on oligonucleotide therapy: Approaches to patient customization

Abstract

It is estimated that the human genome encodes 15% of proteins that are considered to be disease-modifying. Only 2% of these proteins possess a druggable site that the approved clinical candidates target. Due to this disparity, there is an immense need to develop therapeutics that may better mitigate the disease or disorders aroused by non-druggable and druggable proteins or enzymes. The recent surge in approved oligonucleotide therapeutics (OT) indicates the imminent potential of these therapies. Oligonucleotide-based therapeutics are of intermediate size with much-improved selectivity towards the target and fewer off-target effects than small molecules. The OTs include Antisense RNAs, MicroRNA (MIR), small interfering RNA (siRNA), and aptamers, which are currently being explored for their use in neurodegenerative disorders, cancer, and even orphan diseases. The present review is a congregated effort to present the past and present of OTs and the current efforts to make OTs for plausible future therapeutics. The review provides updated literature on the challenges and bottlenecks of OT and recent advancements in OT drug delivery. Further, this review deliberates on a newly emerging approach to personalized treatment for patients with rare and fatal diseases with OT.

Keywords: antisense RNA; antisense oligonucleotide; bioconjugation; microRNA; oligonucleotide therapeutics.

FIGURE 1

(A) The number of publications on oligonucleotides till 2022; (B) Publication date from major countries. The data was obtained from the Scopus database on 23 September 2022.

FIGURE 2

Documents published on “oligonucleotides” in various subject domains.

FIGURE 3

Patents published/granted on oligonucleotide by different agencies in the last 5 years.

FIGURE 4

Selected milestones in the historical development of OT; 2′-O-Me: 2′-O-methylation, 2′F: 2′ fluoro, PS, phosphorothioated; PNA, peptide nucleic acid; PMO, phosporodiamidate morpholino; ASO, antisense oligonucleotide; GAPMER, short DNA ASO with RNA segments; FHCol, familial hyperchloestromia; GalNAc, N-acetylgalactosamine.

FIGURE 5

Mechanism of antisense oligonucleotides. ASOs bind to pre-mRNA/mRNA and act in four ways to inhibit protein synthesis (A) Inhibition of 5′ capping and polyadenylation of the tail, (B) Modulation of RNA splicing, (C) Translational repression, and (D) RNase H induced degradation.

FIGURE 6

Mechanism of siRNA by assembly and activation of RNA- RISC. Formation of RISC followed by siRNA-RISC complex induced recognition and binding to mRNA target resulting in mRNA cleavage and sequence-specific gene silencing.

FIGURE 7

Mechanism of aptamers showing sequence folding into 3D structure formation (functional aptamer) and binding to the target.

FIGURE 8

Chemical modifications of Oligonucleotides- 2′-OMe: 2′-O-methyl, 2′-MOE: 2′-O-methoxyethyl, LNA, locked nucleic acid; cEt, constrained ethyl bridged nucleic acid; PMO, phosphorodiamidate morpholino-oligonucleotide; PNA, peptide nucleic acid.