Milestone |
Nature Milestones in Antisense RNA
The discovery of antisense RNA phenomena has profoundly altered our understanding of gene regulation and revolutionized the way biological research is conducted. The potency, specificity and ease of synthesis of antisense RNAs have made them ubiquitous and therapeutically-attractive agents in biomedical research.
This Milestone charts the history of antisense RNA breakthroughs on an interactive Timeline and provides key articles and relevant reviews from Nature Research journals. We hope you will enjoy the read!
Milestones
Collection
Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model
Spinal muscular atrophy (SMA) is a motor neurone disease caused by a mutation in a gene called SMN1 that is necessary for the survival of motor neurons. Humans have a duplicate gene, SMN2, but that is barely expressed. One promising form of therapy involves increasing SMN2 expression. It has been assumed that it would be necessary to increase the expression of SMN2 in spinal cord motor neurons to achieve a therapeutic effect. Not so. In a mouse model of SMA, subcutaneous, peripheral administration of an antisense oligonucleotide that corrects a splicing defect in SMN2 is shown to provide a much more powerful therapy than direct delivery to the brain. Surprisingly, peripheral rescue is found to be essential for long-term rescue of SMA, and biomarkers suggest that the liver has an important role of the liver in SMA pathogenesis.
Regulation of microRNA function in animals
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.
Tapping the RNA world for therapeutics
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.
Further Reading
A germline-specific class of small RNAs binds mammalian Piwi proteins
In RNA interference, small RNAs (siRNAs or miRNAs) act to regulate gene expression. They serve as specificity factors that direct the RISC (RNA-induced silencing) complex to the complementary mRNA targets. A major component of RISC is a protein of the Argonaute family. Two groups have now identified 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 small RNAs. The function of the piRNAs is not yet known, but they might be involved in sperm production.
A novel class of small RNAs bind to MILI protein in mouse testes
In RNA interference, small RNAs (siRNAs or miRNAs) act to regulate gene expression. They serve as specificity factors that direct the RISC (RNA-induced silencing) complex to the complementary mRNA targets. A major component of RISC is a protein of the Argonaute family. Two groups have now identified 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 small RNAs. The function of the piRNAs is not yet known, but they might be involved in sperm production.
PIWI-interacting RNAs: small RNAs with big functions
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.
The chemical evolution of oligonucleotide therapies of clinical utility
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.
The next generation of CRISPR–Cas technologies and applications
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.
Antisense oligonucleotides: the next frontier for treatment of neurological disorders
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 current state and future directions of RNAi-based therapeutics
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.
