RNA interference

General description

RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS), is a conserved biological response to double-stranded RNA (dsRNA) that mediates resistance to both endogenous and exogenous dsRNA.
The RNAi process begins with the presence of a dsRNA molecule. It can be introduced by a virus or a researcher. The dsRNA is recognized by the DICER enzyme that cuts it in small fragments (21-25pb long) named small interfering RNA (siRNA). Each of these siRNA bind to a protein complex called RISC (RNA Induced Silencing Complex) that removes one of the RNA strands. The RISC-RNA complex recognizes the target mRNA and cleaves it, leading to the inhibition of protein synthesis. The fragments of mRNA are then degraded by other enzymes. It's important to notice that a single siRNA can lead to the silencing of hundreds or thousands of mRNA strands.
This process was observed in many eukariotic cells, including mammalian cells like, mice and human cells.
Scientists have great interest in the ability of turning down genes. This ability can be used to determine a gene function and can also be used in the treatment of some diseases caused by the production of harmful proteins.



The RNA interference phenomenon was first discovered in Caenorhabditis elegans (a nematode worm) by Andrew Fire and Craig Mello in 1998. During a study of the response of C. elegans to the injection of double-stranded RNA (dsRNA), Fire and Mello observed that it resulted in a sequence-specific silencing.
Later on, in 2000, Zamore discovered that RNase III (Dicer) was envolved in the cleavage of the dsRNA.
In 2001, Tuschl described RNAi in mammalian cells.
Song reported the possible therapeutical use of small interference RNA (siRNA) in whole animals in 2003.
In 2004, Acuity Pharmaceuticals started the first phase of clinical trials of a siRNA drug for age-related macular degeneration.
Fire and Mello won the Nobel Prize in Physiology or Medicine in 2006.
Nowadays many pharmaceutical companies are investing in this revolutionary technology in order to create new effective pharmaceuticals.

Products and Companies

RNA reagent vendors

Ambion: provide pre-designed siRNAs, vectors for siRNA expression in mammalian cells, reagents optimized for the transfection in mammalian cells, purification and detection of siRNAs.

RNA therapeutics

Acuity Pharmaceuticals: developing treatments for age-related macular degeneration (AMD) and diabetic retinopathy (DR);
Alnylam Pharmaceuticals: developing treatments for respiratory syncytial virus (RSV), liver cancers, TTR amyloidosis, Huntington's disease and hypercholesterolemia;
Silence Therapeutics: among others, this companie is developing therapies for macular degeneration (AMD), acute kidney injury, delayed graft function, solid tumors, acute lung injury and acute hearing loss;
Calando Pharmaceuticals: developing the siRNA delivery system RONDEL (RNAi/Oligonucleotide Nanoparticle Delivery);
CytRx: focused on metabolic and inflamatory diseases, this company is developing siRNA based drugs for prostate, pancreatic and stomach cancer, neurodegeneration, diabetes complications, acute promyelocytic leukemia and soft tissue sarcomas;

Further information

Resource Center of RNA interference technology: http://www.rnaiweb.com/
Howard Hughes Medical Institute powerpoint presentation: http://www.hhmi.org/biointeractive/rna/rna_interference/01.html
Review: RNA interference and the use of small interfering RNA to study gene function in mammalian systems, Bantounas et al, Journal of Molecular Endocrinology (2004), 545-55
Nobel Prize: http://nobelprize.org/nobel_prizes/medicine/laureates/2006/adv.html
Nature Publishing Group RNAi animations: http://www.nature.com/focus/rnai/animations/index.html
RNAi Database: http://www.rnai.org/

Ana Teresa Estevens MEBiol

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