Milestones | 15 November 2019

Milestones in antisense RNA research

  • 1970
  • 1980
  • 1990
  • 2000
  • 2010
  • 2020
Milestone 01: 1970s

First signs of antisense RNA activity

In the mid-1970s, researchers isolated cellular antisense RNA species that affected mRNA translation measured in cell-free in vitro reconstituted translation systems. Exogenous plasmid DNA fragments were shown to have similar effects, and shortly thereafter, Paul Zamecnik and Mary Stephenson reported synthetic DNA oligonucleotides capable of inhibiting Rous sarcoma viral RNA translation in cells. Read More

Photograph of garden artwork called ‘Waltz of the polypeptides’ by Mara G. Haseltine at Cold Spring Harbor Laboratory, NY, USA. Ivanka Kamenova / Springer Nature Limited
Milestone 02: 1990

Patterns of co‑suppression in plants

Experiments designed to create new pigmentation patterns in petunias yielded the first observations of post-transcriptional gene silencing caused by a transgene homologous to an endogenous sequence. Read More

Garden petunia (Cultivar Picotee Purple) in bloom blickwinkel / Alamy Stock Photo
Milestone 03: 1993

microRNAs emerge as potent post-transcriptional gene regulators

The role of microRNAs as post-transcriptional regulators of gene expression emerges from studies carried out by two research groups independently in 1993. Both groups were studying larval development of the nematode C. elegans, when they found evidence that the gene lin-4 expresses a non-coding RNA that inhibits protein expression of another gene, lin-14, by binding to its mRNA. Read More

Graphic of microRNAs in light bulbs Vicky Summersby / Springer Nature Limited
Milestone 04: 1998

Exogenous dsRNA silences genes in C. elegans

First study to show that, in nematodes, the administration of double-stranded RNA leads to sequence-specific mRNA targeting and gene silencing, through a processes termed ‘RNA interference’. Read More

Illustration of a double helix Yustyna-Olha Shevchuk / Alamy Stock Photo
Milestone 05: 1998

First antisense drug is approved with fleeting success

In 1998, the United States Food and Drug Administration approved the first antisense oligonucleotide drug, fomivirsen, for the treatment of cytomegalovirus retinitis in individuals with AIDS. Read More

Medical syringe, close up Westend61 GmbH / Alamy Stock Photo
Milestone 06: 1999

Small RNAs trigger silencing in plants

Hamilton and Baulcombe identify 25-nucleotide antisense RNAs as the likely trigger of various types of post-transcriptional gene silencing. Read More

3D graphic of the RNA-induced silencing complex BSIP SA / Alamy Stock Photo
Milestone 07: 2000

Mechanism of RNA interference discovered

RNA interference is achieved through the conversion of double-stranded RNA into small interfering RNAs, which guide the RNA-induced silencing complex to specifically cleave complementary mRNAs. Read More

Axe on a log, stacked firewood at the back imageBROKER / Alamy Stock Photo
Milestone 08: 2001

Small interfering RNAs silence genes in mammals

Small interfering RNAs are shown to be powerful tools for gene silencing in mammalian cells, and are subsequently harnessed to prevent and treat hepatitis in mice. Read More

Cartoon of a librarian looking cross and signaling shhh! Lara Crow / Springer Nature Limited
Milestone 09: 2001

piRNAs — guardians of the germline

Research in the 2000s led to the identification of piRNAs — small RNA species that act in a transposon surveillance pathway in the germline and protect genome integrity and fertility. Read More

Guardian figures, Mausoleum of Emperor Khai Dinh, in Hue, Vietnam imageBROKER / Alamy Stock Photo
Milestone 10: 2002

pSUPER start to large-scale RNA interference screening

Use of a retroviral vector that stably expresses short hairpin RNAs strongly and specifically silences genes and enables the generation of vector libraries for large-scale loss-of-function genetic screens. Read More

Four female athletes on athletics track, leaving starting blocks Cultura Creative (RF) / Alamy Stock Photo
Milestone 11: 2005

Targeted siRNA delivery in vivo

Lieberman and colleagues provide a first proof-of-principle demonstration of the therapeutic potential of siRNA in 2005. The researchers used antibody-mediated siRNA delivery to obtain efficient gene silencing in specific target cells in vivo in mice. Read More

Graphic of drones delivering orders on a cityscape background Feodora Chiosea / Alamy Stock Vector
Nobel prize:2006

The Nobel prize in physiology or medicine is awarded to Andrew Fire and Craig Mello for their discovery of RNA interference — gene silencing by double-stranded RNA (Milestone 4). Announcement

Graphic of drones delivering orders on a cityscape background Editorial / Alamy Stock Photo
Milestone 12: 2012

Gene editing by CRISPR–Cas

Foundational work in 2012 demonstrated that small guide RNAs hybridize to and recruit the nuclease Cas9 to specific DNA sequences to enable gene editing. A year later, the CRISPR–Cas system was adapted to function in mammalian cells, thereby enabling the development of numerous genome engineering applications. Read More

Cartoon of the CRISPR–Cas genome editing tool depicted as the Star Trek starship Enterprise Vicky Summersby / Springer Nature Limited
Milestone 13: 2014

Chemical optimization improves oligonucleotide delivery

In 2014, Manoharan and colleagues conjugated siRNA to N‑acetylgalactosamine, a ligand for the asialoglycoprotein receptor present on the surface of hepatocytes. This chemical modification enabled targeted delivery of siRNAs to the liver, resulting in efficient gene silencing in vivo by subcutaneous administration. These conjugates are currently a promising platform for the development of siRNA drugs targeting liver-expressed genes. Read More

Medically accurate illustration of the liver within a transparent human body Sebastian Kaulitzki / Alamy Stock Photo
Milestone 14: 2016

An antisense oligonucleotide splicing modulator to treat spinal muscular atrophy

The United States Food and Drug Administration approves the first antisense oligonucleotide drug that affects splicing for the treatment of a devastating neuromuscular disease. Read More

Diagram showing the mechanism by which antisense oligonucleotides can alter pre-mRNA splicing Figure adapted with permission from Rigo, F. et al. J. Cell Biol. 199, 21–25 (2012)
Milestone 15: 2018

A new dawn for RNAi drugs

The first therapeutic agent that acts via an RNA interference-based mechanism is approved by the United States Food and Drug Administration; the drug is used to treat polyneuropathy caused by hereditary transthyretin (hATTR) amyloidosis, a progressive degenerative disease. Read More

Abstract design of lipid nanomicelles GiroScience / Alamy Stock Photo