Journal Article

RNA therapeutics: beyond RNA interference and antisense oligonucleotides

Altman, Sidney, Kole, Ryszard, Krainer, Adrian R.

2012

Overview

Key Points All RNA-targeted therapeutic technologies exploit oligonucleotides that bind to target RNA, but they differ in their mechanism of action and produce different effects. Small interfering RNAs, antisense oligonucleotides and external guide sequences lead to enzyme-dependent degradation of targeted mRNA. Drugs involving these approaches are designed to reduce the level of harmful gene products such as viral or bacterial proteins or disease-promoting cellular proteins. They could be useful against cancer as well as viral and bacterial infections, or used to prevent the accumulation of high levels of cholesterol in the bloodstream. Steric-blocking oligonucleotides block the access of cellular machinery to pre-mRNA and mRNA without degrading RNA. Splice-switching oligonucleotides are discussed in detail in this Review; these oligonucleotides redirect alternative splicing, repair defective RNA or restore the production of proteins that are missing because of genetic defects. Splice-switching oligonucleotide-based drugs should be useful for the treatment of genetic diseases such as Duchenne muscular dystrophy, spinal muscular atrophy and β-thalassaemia. Compared to classical small-molecule drugs, it is much more difficult to achieve intracellular delivery with oligonucleotides; this is still a major issue for this class of drugs. The advantage of oligonucleotides is their high specificity, which results from sequence-specific base pairing to target RNA. The oligonucleotide-based drug fomivirsen was approved by the US Food and Drug Administration in 1998 for the treatment of viral retinitis in patients with AIDS. Oligonucleotide-based drugs are now in advanced clinical trials for the treatment of cancer and Duchenne muscular dystrophy as well as for lowering high cholesterol levels. Here, the authors highlight how RNA-blocking oligonucleotides can redirect alternative splicing, repair defective RNA, restore protein production or downregulate gene expression, and so may be useful for treating disorders such as Duchenne muscular dystrophy, spinal muscular atrophy and β-thalassaemia. Here, we discuss three RNA-based therapeutic technologies exploiting various oligonucleotides that bind to RNA by base pairing in a sequence-specific manner yet have different mechanisms of action and effects. RNA interference and antisense oligonucleotides downregulate gene expression by inducing enzyme-dependent degradation of targeted mRNA. Steric-blocking oligonucleotides block the access of cellular machinery to pre-mRNA and mRNA without degrading the RNA. Through this mechanism, steric-blocking oligonucleotides can redirect alternative splicing, repair defective RNA, restore protein production or downregulate gene expression. Moreover, they can be extensively chemically modified to acquire more drug-like properties. The ability of RNA-blocking oligonucleotides to restore gene function makes them best suited for the treatment of genetic disorders. Positive results from clinical trials for the treatment of Duchenne muscular dystrophy show that this technology is close to achieving its clinical potential.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/51/1914 / 631/92/436 / Alternative splicing / Alternative Splicing - drug effects / Alternative Splicing - genetics / Animals / Anti-Bacterial Agents - therapeutic use / Antisense oligonucleotides / Antiviral Agents - therapeutic use / beta-Thalassemia - drug therapy / beta-Thalassemia - genetics / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Clinical trials / Duchenne's muscular dystrophy / Gene expression / Gene Expression - drug effects / Gene Expression - genetics / Health aspects / Humans / Medicinal Chemistry / Messenger RNA / Molecular Medicine / Morpholinos - genetics / Morpholinos - therapeutic use / Muscular Dystrophy, Duchenne - drug therapy / Muscular Dystrophy, Duchenne - genetics / Myotonic Dystrophy - drug therapy / Myotonic Dystrophy - genetics / Oligodeoxyribonucleotides, Antisense - pharmacology / Oligodeoxyribonucleotides, Antisense - therapeutic use / Oligonucleotides / Pharmacology/Toxicology / Phosphorothioate Oligonucleotides - genetics / Phosphorothioate Oligonucleotides - therapeutic use / Physiological aspects / Recovery of function / review-article / RNA Interference - drug effects / RNA, Messenger - genetics / RNA, Small Interfering - genetics / RNA-mediated interference / Therapeutic applications