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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
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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
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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 which inhibits protein expression of another gene, lin-14, by binding its mRNA. Read More
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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
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First antisense drug is approved with fleeting success
In 1998, the United States Food and Drug Administration (FDA) approved the first antisense oligonucleotide drug, fomivirsen, for the treatment of cytomegalovirus (CMV) retinitis in individuals with AIDS. Read More
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Small RNAs trigger silencing in plants
Hamilton and Baulcombe identify 25-nucleotide antisense RNAs as the likely trigger for various types of post-transcriptional gene silencing. Read More
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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
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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
Lara Crow / Springer Nature Limited
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
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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
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Targeted siRNA delivery in vivo
Lieberman and her team provided 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
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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
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Gene editing by CRISPR–Cas
Foundational work in 2012 unveiled the function of CRISPR and the nuclease Cas9 in bacteria. Work by a number of research groups demonstrated that small guide RNAs recruit Cas9 to specific DNA sequences to enable gene editing. A year later, the CRISPR–Cas system was adapted to function in mouse and human cells paving the way to a number of genome engineering applications. Read More
Vicky Summersby / Springer Nature Limited
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
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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
Figure adapted with permission from Rigo, F. et al. J. Cell Biol. 199, 21–25 (2012)
A new dawn for RNAi drugs
The first therapeutic 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
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