RNA interference

RNA interference: timeline of key events

Fire is a biologist, pathologist and geneticist. In 1998 he and other colleagues working at Carnegie Institute reported in an article in Nature the discovery of tiny snippets of double-stranded RNA (dsRNA) that appeared to silence specific genes which destroyed messenger RNA, a molecule involved in the production of proteins. They hypothesised that this was caused by a catalytic process. In 2006 he shared the Nobel Prize for Medicine for helping to show the mechanism that controlled the flow of genetic information. 1959-04-27T00:00:00+0000Mello is a biologist who shared the 2006 Nobel Prize for Physiology or Medicine for the discovery of RNA interference. This was based on work he carried out with colleagues to identify genes involved in regulating nematode development. He discovered that some nematode embryos injected with RNA to silence certain genes passed on the silencing effect to their offspring. On investigating further they found a double-stranded RNA was involved in the silencing phenomenon and that it is a defence mechanism against viral infection. The findings were published in 1998. 1960-10-19T00:00:00+0000Two independent teams demonstrate the phenomenon: Jonathan Izzant and Harold Weintraub; John Rubenstein and Jean-Francoise Nicolas.1984-01-01T00:00:00+0000Injections of a gene for pigment coloration in peturnias unexpectedly results in white flowers instead of purple flowers. US plant geneticists carrying out the experiment, Richard Jorgensen and Carolyn Napoli, call the phenomenenon 'cosuppression'.1986-01-01T00:00:00+0000Introduction of RNA into cells is shown to silence genes in the nematode worm Caenorhabditis elegans. This led to the coining of the rerm 'RNA interference'. A Fire, S Xu, M K Montgomery, S A Kostas, S E Driver, C C Mello, 'Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans', Nature, 391 (1998), 806–11.1998-02-01T00:00:00+0000Part of research to understand viral resistance in plants. A J Hamilton, D C Baulcombe, 'A species of small antisense RNA in posttranscriptional gene silencing in plants', Sciene, 29, 286/5441 (1999), 950-2.1999-01-01T00:00:00+0000Experiments conducted by Thomas Tuschl and colleagues show small interfering RNA (SiRNA) can be successfully used to induce short-term silencing of protein coding genes in mammalian cells. S M Elbashir, et al., 'Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells', Nature, 411 (2010) 494-8.2001-05-24T00:00:00+0000Drug developed by OPKO Opthalmologics.2004-01-01T00:00:00+0000Awarded to Andrew Fire and Craig C Mello for their work on RNAi in the nematode worm Caenorhabditis elegans published in 1998.2006-01-01T00:00:00+0000Merck gains access to potentially gate-keeping RNAi patents owned by Sima. Signals high hopes for RNAi technology.2006-10-01T00:00:00+0000Roche pays US$331 million for limited access to RNAi therapeutic platform.2007-01-01T00:00:00+0000Drug poor at preventing vision loss.2009-01-01T00:00:00+0000Sends shockwaves through RNAi drug development community.2010-11-01T00:00:00+0000Merck gained facility from Sima Therapeutics. Decision driven by company's need to cut costs.2011-07-29T00:00:00+0000Study conducted with 41 patients with advanced cancer. Led by Josep Tabernero, Institute of Oncology Department, Vall d'Hebron University together with Alnylam and other cancer research centres.2013-02-11T00:00:00+0000The drug, developed by Alynylam, aimed at lowering cholesterol. It was tested in 32 patients. 2013-10-03T00:00:00+0000Sanofi pays US$700 million for 12 percent stake in Alynlam. Signals renewed interest in RNAi therapeutics.2014-01-01T00:00:00+0000Roche agreed to pay US$148 million in upfront and milestone payments. Deal signals renewed optimism in RNAi therapeutics.2014-01-10T00:00:00+0000Novartis shut down its collaborative programme with Alynlam based on lingering problems associated with delivering RNAi therapeutics. It marked a major set back for the RNAi therapeutics field as a whole. 2014-04-14T00:00:00+0000The trials undertaken from 2013 used a drug that interferes with RNA. The drug was developed by Arrowhead Pharmaceuticals. The aim of the drug is to reduce the surface antigens (HBsAg) created by chronic hepatitis B infections. The trials showed the experimental drug was safe and effective enough to be tested in people. The drug is designed to deliver a molecule to the liver where it binds to a receptor, and then another molecule, derived from bee venom, helps break through the membranes in the liver cells to deliver the medicine directly into the cells. The drug interferes with the the expression of the hepatitis B messager RNA that produces HBsAg. 2015-01-01T00:00:00+0000Launched by Isis Pharmaceuticals (now Ionis) in partnership with Roche, the trial aimed to study the first therapy designed to silence the Huntingdon's disease gene and reduce the production of a protein responsible for the disease. 2015-07-21T00:00:00+00002016-11-09T00:00:00+0000The company's shares fell from a high of $6.18 on November 8, 2016, to an $1.20 on December 21, 2016. 2016-11-09T00:00:00+0000227 patient study showed drug from Alnylam Pharmaceuticals had benefits for rare hereditary disorder - ATTR amyloidosis with polyneuropathy, a rare disorder.2017-09-20T00:00:00+0000The aim of the drug is to mute hepatitis B genes to give the immune system a chance to fight the hepatitis B infection.2018-03-27T00:00:00+0000Developed by Arrowhead Pharmaceuticals, the drug, ARC-520, is administered with the antiviral entecavir. The treatment cleared the HBsAg from one patient and substantially reduced it in the remaining patients. The results were presented to the European Association for the Study of the Liver. 2018-05-02T00:00:00+0000The drug, patisiran, was approved for the treatment of a rare, progressive polyneuropathy caused by hereditary transthyretin-mediated, which affects approximately 50,000 people worldwide. Developed by Alynylam Pharmaceuticals, patisiran targets mRNAs for mutated transthyretin, which causes peripheral amyloidosis. The drugs works by delivering small interfering RNAs to the liver where they bind and degrade transthyretin messenger RNA. 2018-08-14T00:00:00+0000
Date Event People Places
27 Apr 1959Andrew Z Fire was born in Stanford CA, USAFire Carnegie Institute, Johns Hopkins, Stanford University
19 Oct 1960Craig C Mello was born in New Haven, CT, USAMelloUniversity of Massachusetts
1984Antisense RNA shown to inhibit gene activityIzzant, Weintraub, Rubenstein, NicolasFred Hutchinson Cencer Research Center, University of California San Francisco
1986Discovery of RNA interference (RNAi)Jorgensen, NapoliAdvanced Genetic Sciences
February 1998Double stranded RNA demonstrated to be potent mechanism for silencing genesFire, Mello, Xu, Montgomery, Kostas, Driver, Carnegie Institution of Washington, Johns Hopkins University, University of Massachusetts Cancer Center
1999Discovery of small interfering RNA (siRNA), very small stretches of double-stranded RNA, interfere with genesBaulcombe, Hamilton John Innes Centre
May 2001Small interfering RNA (siRNA) shown to be useful tool for switching off certain genesElbashir, Harborth, Lendecker, Yalcin, Weber, TuschlMax-Planck-Institute for Biophysical Chemistry
2004Phase I trial launched with RNAi treatment (Cand5) for wet age-related macular degeneration 
2006Nobel Prize awarded for RNA inteference workFire, MelloCarnegie Institution of Washington, University of Massachusetts
October 2006Merck acquires Sima Therapeutics for US$1.1 billion 
2007Roche signs alliance with Alynlam for RNAi therapeutics 
2009Phase III clinical trials for RNAi treatment (Cand5) for wet age-related macular degeneration halted 
November 2010Disappointment follows Roche's decision to pull out of RNAi therapeutics 
July 2011Merck closes down RNAi research facility 
11 Feb 2013RNAi treatment shown to be effective cancer treatment in phase I clinical trialsTaberneroVall d'Hebron University
3 Oct 2013RNAi drug was indicated to be safe and well-tolerated in a phase I trial 
January 2014Sanofi invests in Alynlam 
January 2014Roche entered RNAi therapeutics alliance with Santaris 
14 Apr 2014Novartis suddenly pulls plug on RNAi researchNovartis
2015Chimpanzee trials indicated that gene silencing drug could treat hepatitis B Arrowhead Pharmaceuticals
21 Jul 2015Phase 1 clinical trial launched with RNAi treatment for Huntingdon's diseaseIsis Pharmaceuticals, Roche
9 Nov 2016FDA halted phase II trials with RNA interference drug, ARC-520, due to multiple deaths of non-human primates treated with high dosesArrowhead Pharmaceuticals
9 Nov 2016 - 21 Dec 2016Arrowhead Pharmaceuticals shares fell following hold on clinical trials with RNAi drug to treat hepatitis BArrowhead Pharmaceuticals
20 Sep 2017Positive results reported from clinical trial with RNAi drugAlynlam
27 Mar 2018Dosing trial launched with humans to test use of RNA interference drug to treat hepatitis BArrowhead Pharmaceuticals
2 May 2018Positive results for RNAi drug for treating chronic hepatitis b reported from 8-person clinical trialArrowhead Pharmaceuticals
14 Aug 2018FDA approved first-ever drug based on RNAiAlynylam Pharmaceuticals

27 Apr 1959

Andrew Z Fire was born in Stanford CA, USA

19 Oct 1960

Craig C Mello was born in New Haven, CT, USA

1984

Antisense RNA shown to inhibit gene activity

1986

Discovery of RNA interference (RNAi)

Feb 1998

Double stranded RNA demonstrated to be potent mechanism for silencing genes

1999

Discovery of small interfering RNA (siRNA), very small stretches of double-stranded RNA, interfere with genes

May 2001

Small interfering RNA (siRNA) shown to be useful tool for switching off certain genes

2004

Phase I trial launched with RNAi treatment (Cand5) for wet age-related macular degeneration

2006

Nobel Prize awarded for RNA inteference work

Oct 2006

Merck acquires Sima Therapeutics for US$1.1 billion

2007

Roche signs alliance with Alynlam for RNAi therapeutics

2009

Phase III clinical trials for RNAi treatment (Cand5) for wet age-related macular degeneration halted

Nov 2010

Disappointment follows Roche's decision to pull out of RNAi therapeutics

Jul 2011

Merck closes down RNAi research facility

11 Feb 2013

RNAi treatment shown to be effective cancer treatment in phase I clinical trials

3 Oct 2013

RNAi drug was indicated to be safe and well-tolerated in a phase I trial

Jan 2014

Sanofi invests in Alynlam

Jan 2014

Roche entered RNAi therapeutics alliance with Santaris

14 Apr 2014

Novartis suddenly pulls plug on RNAi research

2015

Chimpanzee trials indicated that gene silencing drug could treat hepatitis B

21 Jul 2015

Phase 1 clinical trial launched with RNAi treatment for Huntingdon's disease

9 Nov 2016

FDA halted phase II trials with RNA interference drug, ARC-520, due to multiple deaths of non-human primates treated with high doses

9 Nov 2016 - 21 Dec 2016

Arrowhead Pharmaceuticals shares fell following hold on clinical trials with RNAi drug to treat hepatitis B

20 Sep 2017

Positive results reported from clinical trial with RNAi drug

27 Mar 2018

Dosing trial launched with humans to test use of RNA interference drug to treat hepatitis B

2 May 2018

Positive results for RNAi drug for treating chronic hepatitis b reported from 8-person clinical trial

14 Aug 2018

FDA approved first-ever drug based on RNAi

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