Nature Milestones in Antisense RNA

MicroRNAs (miRNAs) are key regulators of biological processes. Recent discoveries have expanded our understanding of the control of miRNA function in animals, through alternative processing, miRNA-sequence editing, post-translational modifications of Argonaute proteins, subcellular localization and regulation of miRNA–target interactions.

Developments in basic RNA biology have spawned RNA-based strategies to generate new types of therapeutics. Judy Lieberman reviews RNA-based drug design and discusses barriers to more widespread applications and possible ways to overcome them.

One of two studies that identifies a new class of small RNAs that interact with one Argonaute subfamily, the Piwi class. These testis-specific small RNAs, called 'piRNAs', are slightly longer than the previously described siRNAs and miRNAs.

One of two studies that identifies a new class of small RNAs that interact with one Argonaute subfamily, the Piwi class. These testis-specific small RNAs, called 'piRNAs', are slightly longer than the previously described siRNAs and miRNAs.

PIWI-interacting RNAs (piRNAs) have numerous crucial biological roles, particularly transposon silencing in the germ line. In this Review, the authors describe our latest understanding of piRNA biogenesis and functions across diverse species, highlighting how, despite the universal importance of transposon control, different species have evolved intriguingly distinct mechanistic routes to achieve this.

Refinements in the chemistries employed in oligonucleotide therapeutics have galvanized clinical progress. The complex interplay between chemical modifications and integration into sequence architecture is discussed in the context of antisense and small-interfering RNA drugs.

CRISPR–Cas systems have revolutionized genome editing, and the CRISPR–Cas toolkit has been expanding to include single-base editing enzymes, targeting RNA and fusing inactive Cas proteins to effectors that regulate various nuclear processes. Consequently, CRISPR–Cas systems are being tested for gene and cell therapies.

Two decades after antisense oligonucleotides (ASOs) were initially identified as agents capable of modulating RNA processing and protein expression, the first antisense oligonucleotide (ASO) therapies have now been approved for the treatment of neurological disease. Here, Rinaldi and Wood discuss our current understanding of ASO pharmacology, and the future prospects for ASO-mediated treatment of neurological disease

The recent approval of the first RNA interference (RNAi)-based therapy has generated considerable excitement in the field. Here, Rossi and colleagues discuss key advances in the design and development of RNAi drugs leading up to this landmark achievement, assess the current clinical pipeline and highlight future opportunities and challenges for RNAi-based therapeutics.