RNA interference - Knowledge

1439: 1425: 12796: 5712: 3512: 619: 1083: 342: 2502:(IL-12) and tumor necrosis factor α (TNF-α). The innate immune system generates inflammation and antiviral responses, which cause the release pattern recognition receptors (PRRs). These receptors help in labeling which pathogens are viruses, fungi, or bacteria. Moreover, the importance of siRNA and the innate immune system is to include more PRRs to help recognize different RNA structures. This makes it more likely for the siRNA to cause an immunostimulant response in the event of the pathogen. 2868: 927: 1548:(HAO1) mRNA for breakdown. Lowering HAO1 enzyme levels reduces the oxidation of glycolate to glyoxylate (which is a substrate for oxalate). Lumasiran is administered subcutaneously by a healthcare professional with dosing based on body weight. Data from randomized controlled clinical trials indicate that the most common adverse reaction that was reported was injection site reactions. These reactions were mild and were present in 38 percent of patients treated with lumasiran. 1145:. This phenomenon has since been recognized as a feature of the plant immune system which allows the entire plant to respond to a virus after an initial localized encounter. In response, many plant viruses have evolved elaborate mechanisms to suppress the RNAi response. These include viral proteins that bind short double-stranded RNA fragments with single-stranded overhang ends, such as those produced by Dicer. Some plant genomes also express endogenous 33: 2942:

viral RNA sequences would show similar levels of protection. Researchers believed that viral RNA produced by transgenes could also inhibit viral replication. The reverse experiment, in which short sequences of plant genes were introduced into viruses, showed that the targeted gene was suppressed in an infected plant. This phenomenon was labeled "virus-induced gene silencing" (VIGS), and the set of such phenomena were collectively called

3070: 782: 198: 123:), are central to components to the RNAi pathway. Once mRNA is degraded, post-transcriptional silencing occurs as protein translation is prevented. Transcription can be inhibited via the pre-transcriptional silencing mechanism of RNAi, through which an enzyme complex catalyzes DNA methylation at genomic positions complementary to complexed siRNA or miRNA. RNAi has an important role in defending cells against parasitic 591: 2921:

decreased or became suppressed in a context-specific manner. This would later be explained as the result of the transgene being inserted adjacent to promoters in the opposite direction in various positions throughout the genomes of some transformants, thus leading to expression of antisense transcripts and gene silencing when these promoters are active. Another early observation of RNAi came from a study of the

3084: 177:, because synthetic dsRNA introduced into cells can selectively and robustly induce suppression of specific genes of interest. RNAi may be used for large-scale screens that systematically shut down each gene (and the subsequent proteins it codes for) in the cell, which can help to identify the components necessary for a particular cellular process or an event such as 2854:

large data sets is a fundamental challenge, requiring suitable statistics/bioinformatics methods. The basic process of cell-based RNAi screening includes the choice of an RNAi library, robust and stable cell types, transfection with RNAi agents, treatment/incubation, signal detection, analysis and identification of important genes or therapeutical targets.

166:(RISC). The RISC assembly then binds and degrades the target mRNA. Specifically, this is accomplished when the guide strand pairs with a complementary sequence in a mRNA molecule and induces cleavage by Ago2, a catalytic component of the RISC. In some organisms, this process spreads systemically, despite the initially limited molar concentrations of siRNA. 2607:, employing multiple approaches, including genetic engineering and topical application. Cells in the midgut of some insects take up the dsRNA molecules in the process referred to as environmental RNAi. In some insects the effect is systemic as the signal spreads throughout the insect's body (referred to as systemic RNAi). 291:, a miRNA-loaded RISC complex scans cytoplasmic mRNAs for potential complementarity. Instead of destructive cleavage (by Ago2), miRNAs rather target the 3′ untranslated region (UTR) regions of mRNAs where they typically bind with imperfect complementarity, thus blocking the access of ribosomes for translation. 915:(ADAR). It was originally proposed in 2000 that the RNAi and A→I RNA editing pathways might compete for a common dsRNA substrate. Some pre-miRNAs do undergo A→I RNA editing and this mechanism may regulate the processing and expression of mature miRNAs. Furthermore, at least one mammalian ADAR can sequester 2323:. These two vaccines use lipid nanoparticles to deliver antigen mRNA. Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key technical barriers in delivering the mRNA molecule into the host cell as distributed through 2920:

into petunia plants of normally pink or violet flower color. The overexpressed gene was expected to result in darker flowers, but instead caused some flowers to have less visible purple pigment, sometimes in variegated patterns, indicating that the activity of chalcone synthase had been substantially

2501:

siRNA is controlled by the innate immune system, which can be divided into the acute inflammatory responses and antiviral responses. The inflammatory response is created with signals from small signaling molecules, or cytokines. These include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12

1332:

enzyme starts to process siRNA. The end result of the process leads to degradation of mRNA and destroys any instructions needed to build certain proteins. Using this method, researchers are able to decrease (but not completely eliminate) the expression of a targeted gene. Studying the effects of this

2497:

The challenge between old pathogens and new has helped create a system of guarded cells and particles that are called safe framework. This framework has given humans an army of systems that search out and destroy invader particles, such as pathogens, microscopic organisms, parasites, and infections.

2452:

Compared with chemotherapy or other anti-cancer drugs, there are a lot of advantages of siRNA drug. SiRNA acts on the post-transcriptional stage of gene expression, so it does not modify or change DNA in a deleterious effect. SiRNA can also be used to produce a specific response in a certain type of

2240:

Currently, both miRNA and SiRNA are currently chemically synthesized and so, are legally categorized inside EU and in USA as "simple" medicinal products. But as bioengineered siRNA (BERAs) are in development, these would be classified as biological medicinal products, at least in EU. The development

1470:

While all of the current regulatory body approved RNAi therapeutics focus on diseases that originate in the liver, additional medications under investigation target a host of disease areas including cardiovascular diseases, bleeding disorders, alcohol use disorders, cystic fibrosis, gout, carcinoma,

1060:

Gene expression in prokaryotes is influenced by an RNA-based system similar in some respects to RNAi. Here, RNA-encoding genes control mRNA abundance or translation by producing a complementary RNA that anneals to an mRNA. However these regulatory RNAs are not generally considered to be analogous to

761:

to its mRNA target. Analysis of the inhibitory effect of mismatches in either the 5’ or 3’ end of the guide strand has demonstrated that the 5’ end of the guide strand is likely responsible for matching and binding the target mRNA, while the 3’ end is responsible for physically arranging target mRNA

2941:

working on improving plant resistance to viral diseases observed a similar unexpected phenomenon. While it was known that plants expressing virus-specific proteins showed enhanced tolerance or resistance to viral infection, it was not expected that plants carrying only short, non-coding regions of

2853:

discovery platforms. One major advantage of genome-scale RNAi screening is its ability to simultaneously interrogate thousands of genes. With the ability to generate a large amount of data per experiment, genome-scale RNAi screening has led to an explosion of data generation rates. Exploiting such

2436:

can effectively kill cancer cells, lack of specificity for discriminating normal cells and cancer cells in these treatments usually cause severe side effects. Numerous studies have demonstrated that RNAi can provide a more specific approach to inhibit tumor growth by targeting cancer-related genes

886:

that target subsequent transcripts. Heterochromatin maintenance has been suggested to function as a self-reinforcing feedback loop, as new siRNAs are formed from the occasional nascent transcripts by RdRP for incorporation into local RITS complexes. The relevance of observations from fission yeast

2456:

RNAi drugs treat cancer by silencing certain cancer promoting genes. This is done by complementing the cancer genes with the RNAi, such as keeping the mRNA sequences in accordance with the RNAi drug. Ideally, RNAi is should be injected and/or chemically modified so the RNAi can reach cancer cells

1327:

is a method used to reduce the expression of an organism’s specific genes. This is accomplished by using the naturally occurring process of RNAi. This gene knockdown technique uses a double-stranded siRNA molecule that is synthesized with a sequence complementary to the gene of interest. The RNAi

1175:

The role of RNAi in mammalian innate immunity is poorly understood, and relatively little data is available. However, the existence of viruses that encode genes able to suppress the RNAi response in mammalian cells may be evidence in favour of an RNAi-dependent mammalian immune response, although

975:

of promoters targeted by RNAi; the new methylation pattern is copied in each new generation of the cell. A broad general distinction between plants and animals lies in the targeting of endogenously produced miRNAs; in plants, miRNAs are usually perfectly or nearly perfectly complementary to their

2493:

The human immune system is divided into two separate branches: the innate immune system and the adaptive immune system. The innate immune system is the first defense against infection and responds to pathogens in a generic fashion. On the other hand, the adaptive immune system, a system that was

495:

as well as for regulatory proteins. By binding to specific sites within the 3′-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript. The 3′-UTR also may have silencer regions that bind repressor proteins that

2272:

Lipid nanoparticles (LNPs) are based on liposome-like structures that are typically made of an aqueous center surrounded by a lipid shell. A subset of liposomal structures used for delivery drugs to tissues rest in large unilamellar vesicles (LUVs) which may be 100 nm in size. LNP delivery

2254:

is susceptible to several obstacles that reduce its therapeutic efficacy. Additionally, once siRNA has entered the bloodstream, naked RNA can be degraded by serum nucleases and can stimulate the innate immune system. Due to its size and highly polyanionic (containing negative charges at several

1446:

The technique of knocking down genes using RNAi therapeutics has demonstrated success in randomized controlled clinical studies. These medications are a growing class of siRNA-based drugs that decrease the expression of proteins encoded by certain genes. To date, five RNAi medications have been

270:

are then separated into single strands and integrated into an active RISC, by RISC-Loading Complex (RLC). RLC includes Dicer-2 and R2D2, and is crucial to unite Ago2 and RISC. TATA-binding protein-associated factor 11 (TAF11) assembles the RLC by facilitating Dcr-2-R2D2 tetramerization, which

275:

duplexes, whereas Dicer-2 the other less stable extremity. Loading is asymmetric: the MID domain of Ago2 recognizes the thermodynamically stable end of the siRNA. Therefore, the "passenger" (sense) strand whose 5′ end is discarded by MID is ejected, while the saved "guide" (antisense) strand

1345:

have been directed toward the design of successful dsRNA reagents that maximize gene knockdown but minimize "off-target" effects. Off-target effects arise when an introduced RNA has a base sequence that can pair with and thus reduce the expression of multiple genes. Such problems occur more

2966:

caused degradation of the par-1 message. It was thought that this degradation was triggered by single-stranded RNA (ssRNA), but two years later, in 1998, Fire and Mello discovered that this ability to silence the par-1 gene expression was actually triggered by double-stranded RNA (dsRNA).

1489:

membrane that facilitates crossover into the cytoplasm. Once inside the cell, the siRNA begins processing by the enzyme Dicer. Patisiran is administered by a healthcare professional through an intravenous infusion with dosing based on body weight. Warnings and precautions include risk of

1136:

that are specialized to react differently when the plant is exposed to different viruses. Even before the RNAi pathway was fully understood, it was known that induced gene silencing in plants could spread throughout the plant in a systemic effect and could be transferred from stock to

521:(affecting expression of several hundred genes). Friedman et al. estimate that >45,000 miRNA target sites within human mRNA 3′UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. 2391:

Antiviral treatment is one of the earliest proposed RNAi-based medical applications, and two different types have been developed. The first type is to target viral RNAs. Many studies have shown that targeting viral RNAs can suppress the replication of numerous viruses, including

3007:(siRNA), it was possible to target the silencing of specific sequences in a gene, rather than silencing the entire gene. Only a year later, McCaffrey and colleagues demonstrated that this sequence-specific silencing had therapeutic applications by targeting a sequence from the 2842:(HTS) technology. RNAi HTS technology allows genome-wide loss-of-function screening and is broadly used in the identification of genes associated with specific phenotypes. This technology has been hailed as a potential second genomics wave, following the first genomics wave of 704:

is less stably paired to its complement, but strand selection is unaffected by the direction in which Dicer cleaves the dsRNA before RISC incorporation. Instead, the R2D2 protein may serve as the differentiating factor by binding the more-stable 5′ end of the passenger strand.

1391:

lack this reaction to exogenous dsRNA and are therefore a common model system for studying mammalian gene-knockdown effects. Specialized laboratory techniques have also been developed to improve the utility of RNAi in mammalian systems by avoiding the direct introduction of

2350:

In addition to LNPs, RNAi therapeutics have targeted delivery through siRNA conjugates (e.g., GalNAc, carbohydrates, peptides, aptamers, antibodies). Therapeutics using siRNA conjugates have been developed for rare or genetic diseases such as acute hepatic porphyria (AHP),

2930:, although it was not immediately recognized as related. Further investigation of the phenomenon in plants indicated that the downregulation was due to post-transcriptional inhibition of gene expression via an increased rate of mRNA degradation. This phenomenon was called 2264:). Even after entering the cells, repeated dosing is required since their effects are diluted at each cell division. In response to these potential issues and barriers, two approaches help facilitate siRNA delivery to target cells: lipid nanoparticles and conjugates. 2453:

way, such as by downgrading suppression of gene expression. In a single cancer cell, siRNA can cause dramatic suppression of gene expression with just several copies. This happens by silencing cancer-promoting genes with RNAi, as well as targeting an mRNA sequence.

1533:

and enters into liver cells. The medication is administered subcutaneously by a healthcare professional with dosing based on body weight. Warnings and precautions include risk of anaphylactic reactions, hepatic toxicity, renal toxicity and injection site reactions.

524:

Direct experiments show that a single miRNA can reduce the stability of hundreds of unique mRNAs. Other experiments show that a single miRNA may repress the production of hundreds of proteins, but that this repression often is relatively mild (less than 2-fold).

773:(also cytoplasmic bodies or GW bodies), which are regions with high rates of mRNA decay; miRNA activity is also clustered in P-bodies. Disruption of P-bodies decreases the efficiency of RNAi, suggesting that they are a critical site in the RNAi process. 2801:

system and poison insects feeding on them. Another approach involves spraying dsRNA like a conventional pesticide. This would allow faster adaptation to resistance. Such approaches would require low cost sources of dsRNAs that do not currently exist.

11285:

Gilbert MK, Majumdar R, Rajasekaran K, Chen ZY, Wei Q, Sickler CM, et al. (June 2018). "RNA interference-based silencing of the alpha-amylase (amy1) gene in Aspergillus flavus decreases fungal growth and aflatoxin production in maize kernels".

271:

increases the binding affinity to siRNA by 10-fold. Association with TAF11 would convert the R2-D2-Initiator (RDI) complex into the RLC. R2D2 carries tandem double-stranded RNA-binding domains to recognize the thermodynamically stable terminus of

1280:

most likely already possessed an early RNAi pathway; the absence of the pathway in certain eukaryotes is thought to be a derived characteristic. This ancestral RNAi system probably contained at least one Dicer-like protein, one Argonaute, one

535:

The effects of miRNA dysregulation of gene expression also seem to be important in neuropsychiatric disorders, such as schizophrenia, bipolar disorder, major depression, Parkinson's disease, Alzheimer's disease and autism spectrum disorders.

96:, which they published in 1998. Since the discovery of RNAi and its regulatory potentials, it has become evident that RNAi has immense potential in suppression of desired genes. RNAi is now known as precise, efficient, stable and better than 976:

target genes and induce direct mRNA cleavage by RISC, while animals' miRNAs tend to be more divergent in sequence and induce translational repression. This translational effect may be produced by inhibiting the interactions of translation

769:, translation of the mRNA target is not essential for RNAi-mediated degradation. Indeed, RNAi may be more effective against mRNA targets that are not translated. Argonaute proteins are localized to specific regions in the cytoplasm called 451:

derived from long dsRNA precursors differ from miRNAs in that miRNAs, especially those in animals, typically have incomplete base pairing to a target and inhibit the translation of many different mRNAs with similar sequences. In contrast,

11426:

Downie RC, Lin M, Corsi B, Ficke A, Lillemo M, Oliver RP, et al. (27 July 2021). "Septoria Nodorum Blotch of Wheat: Disease Management and Resistance Breeding in the Face of Shifting Disease Dynamics and a Changing Environment".

609:

further trims it to a ~20nt miRNA duplex (pre-siRNAs also enter the pathway at this step). This duplex is then loaded into Ago to form the “pre-RISC(RNA induced silencing complex)” and the passenger strand is released to form active

2887:

The process of RNAi was referred to as "co-suppression" and "quelling" when observed prior to the knowledge of an RNA-related mechanism. The discovery of RNAi was preceded first by observations of transcriptional inhibition by

841:

protein Chp1, and a protein called Tas3 of unknown function. As a consequence, the induction and spread of heterochromatic regions requires the Argonaute and RdRP proteins. Indeed, deletion of these genes in the fission yeast

2259:

must be used. If siRNA is transferred across the cell membrane, unintended toxicities can occur if therapeutic doses are not optimized, and siRNAs can exhibit off-target effects (e.g. unintended downregulation of genes with

2249:

To achieve the clinical potential of RNAi, siRNA must be efficiently transported to the cells of target tissues. However, there are various barriers that must be fixed before it can be used clinically. For example, "naked"

699:

kinetic analysis of RNAi in the presence and absence of ATP showed that ATP may be required to unwind and remove the cleaved mRNA strand from the RISC complex after catalysis. The guide strand tends to be the one whose

10414:

Rajput R, Khanna M, Kumar P, Kumar B, Sharma S, Gupta N, et al. (December 2012). "Small interfering RNA targeting the nonstructural gene 1 transcript inhibits influenza A virus replication in experimental mice".

442:(EBV). Thereafter, an increasing number of microRNAs have been described in viruses. VIRmiRNA is a comprehensive catalogue covering viral microRNA, their targets and anti-viral miRNAs (see also VIRmiRNA resource: 6967:"A putative RNA-interference-based immune system in prokaryotes: computational analysis of the predicted enzymatic machinery, functional analogies with eukaryotic RNAi, and hypothetical mechanisms of action" 503:. MREs are sequences to which miRNAs bind. These are prevalent motifs within 3′-UTRs. Among all regulatory motifs within the 3′-UTRs (e.g. including silencer regions), MREs make up about half of the motifs. 2241:

of the BERAs technology raises the question of the categorization of drugs having the same mechanism of action but being produced chemically or biologically. This lack of consistency should be addressed.

556:, that stimulates Dicer activity. This protein only binds long dsRNAs, but the mechanism producing this length specificity is unknown. This RNA-binding protein then facilitates the transfer of cleaved 390:. The phenomenon of RNAi, broadly defined, includes the endogenously induced gene silencing effects of miRNAs as well as silencing triggered by foreign dsRNA. Mature miRNAs are structurally similar to 6647:

DaRocha WD, Otsu K, Teixeira SM, Donelson JE (February 2004). "Tests of cytoplasmic RNA interference (RNAi) and construction of a tetracycline-inducible T7 promoter system in Trypanosoma cruzi".

2383:, nicotine-free tobacco, decaffeinated coffee, nutrient fortified vegetation and hypoallergenic crops. The emerging use of RNAi has the potential to develop many other products for future use. 517:

and annotations, listed 28,645 entries in 271 biologic species. Of these, 1,917 miRNAs were in annotated human miRNA loci. miRNAs were predicted to have an average of about four hundred target

2510:

RNAi has been used to genetically engineer plants to produce lower levels of natural plant toxins. Such techniques take advantage of the stable and heritable RNAi phenotype in plant stocks.

10792:

Singer O, Marr RA, Rockenstein E, Crews L, Coufal NG, Gage FH, et al. (October 2005). "Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model".

4613:

Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. (February 2005). "Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs".

158:

siRNAs. Each siRNA is unwound into two single-stranded RNAs (ssRNAs), the passenger (sense) strand and the guide (antisense) strand. The passenger strand is then cleaved by the protein

9816: 2781:

have been made to express dsRNA, carefully chosen to silence crucial genes in target pests. These dsRNAs are designed to affect only insects that express specific gene sequences. As a

2530:, a key enzyme in gossypol production, without affecting the enzyme's production in other parts of the plant, where gossypol is itself important in preventing damage from plant pests. 262:

studies on the genomes of multiple organisms suggest this length maximizes target-gene specificity and minimizes non-specific effects. These short double-stranded fragments are called

12992: 871:

in fission yeast, which may not be representative of activities in other genomic regions/organisms. In maintenance of existing heterochromatin regions, RITS forms a complex with

2498:

The mammalian safe framework has developed to incorporate siRNA as a tool to indicate viral contamination, which has allowed siRNA is create an intense innate immune response.

10336:

Li YC, Kong LH, Cheng BZ, Li KS (December 2005). "Construction of influenza virus siRNA expression vectors and their inhibitory effects on multiplication of influenza virus".

2379:

RNAi has been used for a variety of other applications including food, crops and insecticides. The use of the RNAi pathway has developed numerous products such as foods like

3015:

mice. Since then, multiple researchers have been attempting to expand the therapeutic applications of RNAi, specifically looking to target genes that cause various types of

882:. The formation of such a heterochromatin region, though not its maintenance, is Dicer-dependent, presumably because Dicer is required to generate the initial complement of 5825:

Irvine DV, Zaratiegui M, Tolia NH, Goto DB, Chitwood DH, Vaughn MW, et al. (August 2006). "Argonaute slicing is required for heterochromatic silencing and spreading".

5025:

Liu Q, Rand TA, Kalidas S, Du F, Kim HE, Smith DP, et al. (September 2003). "R2D2, a bridge between the initiation and effector steps of the Drosophila RNAi pathway".

2610:

Animals exposed to RNAi at doses millions of times higher than anticipated human exposure levels show no adverse effects. RNAi has varying effects in different species of

11844:

Huesken D, Lange J, Mickanin C, Weiler J, Asselbergs F, Warner J, et al. (August 2005). "Design of a genome-wide siRNA library using an artificial neural network".

5933:

Volpe T, Schramke V, Hamilton GL, White SA, Teng G, Martienssen RA, et al. (2003). "RNA interference is required for normal centromere function in fission yeast".

1481:. Patisiran uses the RNAi cascade to suppress the gene that codes for TTR (transthryetin). Mutations in this gene may cause the misfolding of a protein responsible for 434:. The dsRNA portion of this pre-miRNA is bound and cleaved by Dicer to produce the mature miRNA molecule that can be integrated into the RISC complex; thus, miRNA and 1176:

this hypothesis has been challenged as poorly substantiated. Evidence for the existence of a functional antiviral RNAi pathway in mammalian cells has been presented.

6682:

Robinson KA, Beverley SM (May 2003). "Improvements in transfection efficiency and tests of RNA interference (RNAi) approaches in the protozoan parasite Leishmania".

1018: 528:

The effects of miRNA dysregulation of gene expression seem to be important in cancer. For instance, in gastrointestinal cancers, nine miRNAs have been identified as

1156:

Although animals generally express fewer variants of the Dicer enzyme than plants, RNAi in some animals produces an antiviral response. In both juvenile and adult

1517:

designation for the treatment of acute hepatic porphyria (AHP) in November 2019. By 2020, givosiran received EMA approval. Givosiran is an siRNA that breaks down

765:

It is not understood how the activated RISC complex locates complementary mRNAs within the cell. Although the cleavage process has been proposed to be linked to

4166: 2987:

injections had an effect on protein production, but double-stranded RNA successfully silenced the targeted gene. As a result of this work, they coined the term

2494:

evolved later than the innate, is composed mainly of highly specialized B and T cells that are trained to react to specific portions of pathogenic molecules.

1371:

Depending on the organism and experimental system, the exogenous RNA may be a long strand designed to be cleaved by Dicer, or short RNAs designed to serve as

1301:. This study also suggests that the RNA-binding Argonaute protein family, which is shared among eukaryotes, most archaea, and at least some bacteria (such as 955:

Organisms vary in their ability to take up foreign dsRNA and use it in the RNAi pathway. The effects of RNAi can be both systemic and heritable in plants and

878:

to the local genes and stably binds local methylated histones, acting co-transcriptionally to degrade any nascent pre-mRNA transcripts that are initiated by

12239:

Romano N, Macino G (November 1992). "Quelling: transient inactivation of gene expression in Neurospora crassa by transformation with homologous sequences".

11380:

Katoch R, Thakur N (March 2013). "Advances in RNA interference technology and its impact on nutritional improvement, disease and insect control in plants".

7561:

Wilkins C, Dishongh R, Moore SC, Whitt MA, Chow M, Machaca K (August 2005). "RNA interference is an antiviral defence mechanism in Caenorhabditis elegans".

1172:, as Argonaute proteins are upregulated in response to viruses and worms that overexpress components of the RNAi pathway are resistant to viral infection. 597:

Biogenesis: primary miRNAs (pri-miRNAs) are transcribed in the nucleus and fold back onto themselves as hairpins that are then trimmed in the nucleus by a

13064: 4664:

Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N (September 2008). "Widespread changes in protein synthesis induced by microRNAs".

2327:(apoE) in the low-density lipoprotein receptor (LDLR). In December 2020, Novartis announced that positive results from phase III efficacy studies deemed 1544:(PH1) in pediatric and adult populations. The drug is designed to reduce hepatic oxalate production and urinary oxalate levels through RNAi by targeting 1153:. These effects may be part of a generalized response to pathogens that downregulates any metabolic process in the host that aids the infection process. 13061:

RNA interference (RNAi) experiments and bioinformatics in C. elegans for education. From the Dolan DNA Learning Center of Cold Spring Harbor Laboratory.

1540:

was approved as a siRNA-based medication in 2020 for use in both the European Union and the United States. This medication is used for the treatment of

13130: 7116:"Systemic acquired silencing: transgene-specific post-transcriptional silencing is transmitted by grafting from silenced stocks to non-silenced scions" 231:. When the dsRNA is exogenous (coming from infection by a virus with an RNA genome or laboratory manipulations), the RNA is imported directly into the 9064: 9009:"Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial" 867:

The mechanism by which the RITS complex induces heterochromatin formation and organization is not well understood. Most studies have focused on the

6137:"The assembly and maintenance of heterochromatin initiated by transgene repeats are independent of the RNA interference pathway in mammalian cells" 3325:

Macrae IJ, Zhou K, Li F, Repic A, Brooks AN, Cande WZ, et al. (January 2006). "Structural basis for double-stranded RNA processing by Dicer".

235:

and cleaved to short fragments by Dicer. The initiating dsRNA can also be endogenous (originating in the cell), as in pre-microRNAs expressed from

13098: 13065:

RNAi screens in C. elegans in a 96-well liquid format and their application to the systematic identification of genetic interactions (a protocol)

3384: 254:

protein Dicer, which binds and cleaves dsRNAs in plants, or short hairpin RNAs (shRNAs) in humans, to produce double-stranded fragments of 20–25

12696:

Elbashir S, Harborth J, Lendeckel W, et al. (2001). "Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells".

1297:

already possessed these components, which may then have had closer functional associations with generalized RNA degradation systems such as the

4106:

Sijen T, Steiner FA, Thijssen KL, Plasterk RH (January 2007). "Secondary siRNAs result from unprimed RNA synthesis and form a distinct class".

1229:

was shown to be involved in the regulation of several genes that control plant shape. In plants, the majority of genes regulated by miRNAs are

12483:"par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed" 10508:

Hu L, Wang Z, Hu C, Liu X, Yao L, Li W, et al. (2005). "Inhibition of Measles virus multiplication in cell culture by RNA interference".

10199:"Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference" 2416:. The other strategy is to block the initial viral entries by targeting the host cell genes. For example, suppression of chemokine receptors ( 3467:

Bernstein E, Caudy AA, Hammond SM, Hannon GJ (January 2001). "Role for a bidentate ribonuclease in the initiation step of RNA interference".

13069: 695:

separated these two strands, the process proved to be ATP-independent and performed directly by the protein components of RISC. However, an

74:. The detailed study of each of these seemingly different processes elucidated that the identity of these phenomena were all actually RNAi. 6533:"RNA-directed transcriptional gene silencing in plants can be inherited independently of the RNA trigger and requires Met1 for maintenance" 2445:, providing a combinatorial therapeutic approach with chemotherapy. Another potential RNAi-based treatment is to inhibit cell invasion and 500: 5618:

Jakymiw A, Lian S, Eystathioy T, Li S, Satoh M, Hamel J, et al. (2005). "Disruption of P bodies impairs mammalian RNA interference".

2292:

as a drug delivery mechanism began in 2018 with the siRNA drug patisiran, developed by Alnylam Pharmaceuticals. Dicerna Pharmaceuticals,

10379:

Khanna M, Saxena L, Rajput R, Kumar B, Prasad R (2015). "Gene silencing: a therapeutic approach to combat influenza virus infections".

6078:"RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production" 4286:

Gregory RI, Chendrimada TP, Shiekhattar R (2006). "MicroRNA biogenesis: isolation and characterization of the microprocessor complex".

2473:-producing genes (e.g. BACE1 and APP) by RNAi can significantly reduced the amount of Aβ peptide which is correlated with the cause of 2991:. This discovery represented the first identification of the causative agent for the phenomenon. Fire and Mello were awarded the 2006 1521:

1 (ALAS1) mRNA in the liver. Breaking down ALAS1 mRNA prevents toxins (responsible for neurovisceral attacks and AHP disease) such as

306:, that stimulates Dicer activity. The mechanism producing this length specificity is unknown and this protein only binds long dsRNAs. 1545: 227:

and is initiated by short double-stranded RNA molecules in a cell's cytoplasm, where they interact with the catalytic RISC component

2822:

libraries and to predict their likely efficiency at gene knockdown. Mass genomic screening is widely seen as a promising method for

13341: 9206:"Patient Perspective on Acute Intermittent Porphyria with Frequent Attacks: A Disease with Intermittent and Chronic Manifestations" 2883:

that induce suppression of both transgene and endogenous gene expression, giving rise to the unpigmented white areas of the flower.

12192:"Introduction of a Chimeric Chalcone Synthase Gene into Petunia Results in Reversible Co-Suppression of Homologous Genes in trans" 4327:

Pfeffer S, Zavolan M, Grässer FA, Chien M, Russo JJ, Ju J, et al. (April 2004). "Identification of virus-encoded microRNAs".

2526:, making them unsuitable for human consumption. RNAi has been used to produce cotton stocks whose seeds contain reduced levels of 864:. In some cases, similar processes associated with histone modification have been observed to transcriptionally upregulate genes. 6834: 5725:

Holmquist GP, Ashley T (2006). "Chromosome organization and chromatin modification: influence on genome function and evolution".

10586:"Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication, by Martínez et al" 9407: 9353: 6908:"Translational repression is sufficient for gene silencing by bacterial small noncoding RNAs in the absence of mRNA destruction" 2948:

After these initial observations in plants, laboratories searched for this phenomenon in other organisms. The first instance of

2577:, while virus-induced gene silencing (VIGS, a subtype of RNAi) was used by Scofield et al. 2005 to investigate the mechanism of 13181: 13123: 2726: 2720: 2708: 2698: 2339: 11649:"RNA interference in Lepidoptera: an overview of successful and unsuccessful studies and implications for experimental design" 11242:

Niggeweg R, Michael AJ, Martin C (June 2004). "Engineering plants with increased levels of the antioxidant chlorogenic acid".

749:(a process that allows more than one atom to share an electron by passing it back and forth) between the 5′ nucleotide in the 12328: 12064: 12037: 11939: 9781: 5133: 4303: 3923: 2992: 2565:

to improve photosynthesis. SBEIIa and SBEIIb genes in wheat have been targeted in wheat in order to produce higher levels of

2255:

sites) nature, unmodified siRNA molecules cannot readily enter the cells through the cell membrane. Therefore, artificial or

830: 491:

often contain regulatory sequences that post-transcriptionally cause RNAi. Such 3′-UTRs often contain both binding sites for

83: 11705: 9520:"RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European union legislation" 5442:

Sen G, Wehrman T, Blau H (2005). "mRNA translation is not a prerequisite for small interfering RNA-mediated mRNA cleavage".

11107:

Whitehead KA, Dahlman JE, Langer RS, Anderson DG (2011). "Silencing or stimulation? siRNA delivery and the immune system".

8335:"Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments" 2312: 1375:

substrates. In most mammalian cells, shorter RNAs are used because long double-stranded RNA molecules induce the mammalian

1266: 1048:, possibly due to the evolution of a novel pathway with similar function, or to the lack of selective advantage in certain 1044:

are missing RNAi pathways indicates that proteins required for RNA silencing have been lost independently from many fungal

891:

is not clear, as heterochromatin maintenance in mammalian cells may be independent of the components of the RNAi pathway.

12993:"Novartis receives EU approval for Leqvio(inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year" 10133:"Application of food and feed safety assessment principles to evaluate transgenic approaches to gene modulation in crops" 2261: 2256: 1203:

miRNAs, are most important in translational repression and in the regulation of development, especially on the timing of

875: 813:

Components of the RNAi pathway are used in many eukaryotes in the maintenance of the organization and structure of their

664: 11887:

Ge G, Wong GW, Luo B (October 2005). "Prediction of siRNA knockdown efficiency using artificial neural network models".

11438: 9475: 13013: 12446:

Ratcliff F, Harrison BD, Baulcombe DC (June 1997). "A similarity between viral defense and gene silencing in plants".

6590:"MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function" 13116: 11337:

Katoch R, Thakur N (March 2013). "RNA interference: a promising technique for the improvement of traditional crops".

4427:

Pillai RS, Bhattacharyya SN, Filipowicz W (2007). "Repression of protein synthesis by miRNAs: how many mechanisms?".

395: 12524:"Cosuppression in Drosophila: gene silencing of Alcohol dehydrogenase by white-Adh transgenes is Polycomb dependent" 1346:

frequently when the dsRNA contains repetitive sequences. It has been estimated from studying the genomes of humans,

1237:

during development by modulating the expression of key regulatory genes, including transcription factors as well as

4052:

Pak J, Fire A (January 2007). "Distinct populations of primary and secondary effectors during RNAi in C. elegans".

2810:

Approaches to the design of genome-wide RNAi libraries can require more sophistication than the design of a single

2785:, in 2009 a study showed RNAs that could kill any one of four fruit fly species while not harming the other three. 13092:: a database of phenotypes from RNA interference screening experiments in Drosophila melanogaster and Homo sapiens 11608:"Corn rootworm-active RNA DvSnf7: Repeat dose oral toxicology assessment in support of human and mammalian safety" 12056:

Optimal High-Throughput Screening: Practical Experimental Design and Data Analysis for Genome-scale RNAi Research

11647:

Terenius O, Papanicolaou A, Garbutt JS, Eleftherianos I, Huvenne H, Kanginakudru S, et al. (February 2011).

11203:"Design of tomato fruits with reduced allergenicity by dsRNAi-mediated inhibition of ns-LTP (Lyc e 3) expression" 10625:

Fuchs U, Damm-Welk C, Borkhardt A (August 2004). "Silencing of disease-related genes by small interfering RNAs".

9371: 9082: 2442: 1556: 484: 479: 12671: 10053:"Targeted gene suppression by RNA interference: an efficient method for production of high-amylose potato lines" 4874:"Micro spies from the brain to the periphery: new clues from studies on microRNAs in neuropsychiatric disorders" 2896:

plants, and more directly by reports of unexpected outcomes in experiments performed by plant scientists in the

247:, then exported to the cytoplasm. Thus, the two dsRNA pathways, exogenous and endogenous, converge at the RISC. 104:

produced intracellularly by an expression vector may be developed and find utility as novel therapeutic agents.

5534:

Sen G, Blau H (2005). "Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies".

3003:

Just after Fire and Mello's ground-breaking discovery, Elbashir et al. discovered, by using synthetically made

2850: 13054: 5334:

Tomari Y, Matranga C, Haley B, Martinez N, Zamore PD (November 2004). "A protein sensor for siRNA asymmetry".

5287:"Short interfering RNA strand selection is independent of dsRNA processing polarity during RNAi in Drosophila" 3058:

received EMA approval in 2020 for the treatment of high cholesterol and is currently under review by the FDA.

62:, through translational or transcriptional repression. Historically, RNAi was known by other names, including 13270: 7925: 3097: 2335: 1065:

systems in prokaryotes are analogous to eukaryotic RNAi systems, although none of the protein components are

798: 611: 224: 163: 8629:"Absence of non-specific effects of RNA interference triggered by long double-stranded RNA in mouse oocytes" 13398: 10976:"RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model" 9100:

Gonzalez-Aseguinolaza G (11 June 2020). "Givosiran — Running RNA Interference to Fight Porphyria Attacks".

1518: 1286: 977: 584: 330: 11606:

Petrick JS, Friedrich GE, Carleton SM, Kessenich CR, Silvanovich A, Zhang Y, et al. (November 2016).

10662:"RNA interference is a functional pathway with therapeutic potential in human myeloid leukemia cell lines" 6037:"RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing" 923:

strains indicating that A→I RNA editing may counteract RNAi silencing of endogenous genes and transgenes.

13455: 13209: 13045: 11779: 9835: 3028: 1273: 671:. As the fragments produced by Dicer are double-stranded, they could each in theory produce a functional 10884:

Piedrahita D, Hernández I, López-Tobón A, Fedorov D, Obara B, Manjunath BS, et al. (October 2010).

9580:

Kanasty R, Dorkin JR, Vegas A, Anderson D (November 2013). "Delivery materials for siRNA therapeutics".

8384:"dsCheck: highly sensitive off-target search software for double-stranded RNA-mediated RNA interference" 3956:"RDE-4 preferentially binds long dsRNA and its dimerization is necessary for cleavage of dsRNA to siRNA" 215:

domains are colored green, the PAZ domain yellow, the platform domain red, and the connector helix blue.

13407: 13095: 11788: 11722: 8672:, Agami R (April 2002). "A system for stable expression of short interfering RNAs in mammalian cells". 3571:"RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals" 13024: 7200:"Suppression of post-transcriptional gene silencing by a plant viral protein localized in the nucleus" 3392: 239:

in the genome. The primary transcripts from such genes are first processed to form the characteristic

13440: 13040: 11713: 7981:"The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14" 7296:

Katiyar-Agarwal S, Morgan R, Dahlbeck D, Borsani O, Villegas A, Zhu JK, et al. (November 2006).

5665:(2000). "An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells". 4772:

Palmero EI, de Campos SG, Campos M, de Souza NC, Guerreiro ID, Carvalho AL, et al. (July 2011).

2839: 2815: 1567: 1482: 1352: 1126:, especially in plants where it may also prevent the self-propagation of transposons. Plants such as 844: 12795: 10837:"Allele-specific RNAi mitigates phenotypic progression in a transgenic model of Alzheimer's disease" 7065:

Blevins T, Rajeswaran R, Shivaprasad PV, Beknazariants D, Si-Ammour A, Park HS, et al. (2006).

5711: 3511: 3428: 3230:"Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes" 2983:. In investigating the regulation of muscle protein production, they observed that neither mRNA nor 1566:

Other investigational drugs using RNAi that are being developed by pharmaceutical companies such as

1360:

have substantial off-target effects. A multitude of software tools have been developed implementing

13450: 13139: 11922:

Janitz M, Vanhecke D, Lehrach H (2006). "High-Throughput RNA Interference in Functional Genomics".

11429: 9425:

Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O'Riordan WD, Cochat P, et al. (1 April 2021).

8960:

Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O'Riordan WD, Cochat P, et al. (1 April 2021).

7710:

Cullen BR (June 2006). "Is RNA interference involved in intrinsic antiviral immunity in mammals?".

2578: 2289: 1486: 1012: 826: 11152:"Engineering cottonseed for use in human nutrition by tissue-specific reduction of toxic gossypol" 9007:

Adams D, Tournev IL, Taylor MS, Coelho T, Planté-Bordeneuve V, Berk JL, et al. (March 2023).

8854:

Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. (5 July 2018).

8482:"siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference" 8333:

Munkácsy G, Sztupinszki Z, Herman P, Bán B, Pénzváltó Z, Szarvas N, et al. (September 2016).

7355:

Fritz JH, Girardin SE, Philpott DJ (June 2006). "Innate immune defense through RNA interference".

6326:

Yang W, Chendrimada TP, Wang Q, Higuchi M, Seeburg PH, Shiekhattar R, et al. (January 2006).

930:

Illustration of the major differences between plant and animal gene silencing. Natively expressed

13262: 13197: 7249:"Double-stranded RNA binding may be a general plant RNA viral strategy to suppress RNA silencing" 2952:

silencing in animals was documented in 1996, when Guo and Kemphues observed that, by introducing

2759: 2527: 1571: 1478: 1430: 458: 394:

produced from exogenous dsRNA, but before reaching maturity, miRNAs must first undergo extensive

10537:"VIRmiRNA: a comprehensive resource for experimentally validated viral miRNAs and their targets" 8116:

Jones-Rhoades MW, Bartel DP, Bartel B (2006). "MicroRNAS and their regulatory roles in plants".

4380:"VIRmiRNA: a comprehensive resource for experimentally validated viral miRNAs and their targets" 2793:

Alternatively dsRNA can be supplied without genetic engineering. One approach is to add them to

1438: 1333:

decrease in expression may show the physiological role or impact of the targeted gene products.

13416: 13366: 11494:

Ivashuta S, Zhang Y, Wiggins BE, Ramaseshadri P, Segers GC, Johnson S, et al. (May 2015).

8578:

Reynolds A, Anderson EM, Vermeulen A, Fedorov Y, Robinson K, Leake D, et al. (June 2006).

8020:

Palatnik JF, Allen E, Wu X, Schommer C, Schwab R, Carrington JC, et al. (September 2003).

5387:"Structural basis for 5'-end-specific recognition of guide RNA by the A. fulgidus Piwi protein" 3603:

Vermeulen A, Behlen L, Reynolds A, Wolfson A, Marshall WS, Karpilow J, et al. (May 2005).

3423: 3032: 2962: 2767: 2478: 2474: 1308: 806: 766: 688: 598: 546: 439: 419: 296: 284: 92: 13253: 12029: 12022: 9764:

Leung AK, Tam YY, Cullis PR (2014). "Lipid Nanoparticles for Short Interfering RNA Delivery".

8792:

Ventura A, Meissner A, Dillon CP, McManus M, Sharp PA, Van Parijs L, et al. (July 2004).

6776:

Drinnenberg IA, Weinberg DE, Xie KT, Mower JP, Wolfe KH, Fink GR, et al. (October 2009).

2477:. In addition, this silencing-based approaches also provide promising results in treatment of 2307:

Other recent applications include two FDA approved COVID-19 vaccines: mRNA-1273, developed by

971:(channels in the cell walls that enable communication and transport). Heritability comes from 12344:

Covey S, Al-Kaff N, Lángara A, Turner D (1997). "Plants combat infection by gene silencing".

11120: 9493: 9143: 8129: 6201: 3004: 2819: 2811: 2574: 2482: 2356: 2251: 1541: 1405: 1393: 1372: 1365: 1357: 1342: 1146: 964: 935: 919:

from RNAi pathway components. Further support for this model comes from studies on ADAR-null

916: 883: 872: 790: 758: 750: 709: 672: 668: 580: 576: 572: 568: 557: 467: 456:

typically base-pair perfectly and induce mRNA cleavage only in a single, specific target. In

453: 448: 435: 391: 387: 326: 322: 318: 314: 288: 280: 272: 267: 263: 120: 116: 12937:"Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles" 12850:

Wall NR, Shi Y (October 2003). "Small RNA: can RNA interference be exploited for therapy?".

1412:

vector systems allowing the inducible activation or deactivation of transcription, known as

13322: 13314: 13279: 13018: 12948: 12760: 12705: 12628: 12617:"Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans" 12400: 12353: 12144: 11730: 11660: 11560: 11295: 10987: 9672:

De-Souza EA, Camara H, Salgueiro WG, Moro RP, Knittel TL, Tonon G, et al. (May 2019).

9589: 9389: 8805: 8746: 8681: 8033: 7937: 7880: 7823: 7766: 7625: 7570: 7517: 7460: 7309: 6919: 6849: 6789: 6730: 6601: 6544: 6089: 5989: 5889: 5834: 5781: 5676: 5398: 5343: 5298: 5034: 4728: 4673: 4622: 4336: 4115: 4061: 3864: 3658: 3534: 3476: 3334: 3289: 3132: 3024: 2654: 2515: 1506: 1290: 1230: 1225: 1208: 1180: 1128: 746: 567:

this initiation response is amplified through the synthesis of a population of 'secondary'

313:

this initiation response is amplified through the synthesis of a population of 'secondary'

17: 11989: 7506:"Animal virus replication and RNAi-mediated antiviral silencing in Caenorhabditis elegans" 2553:

fungal growth in maize which would have otherwise contaminated the kernels with dangerous

1179:

Other functions for RNAi in mammalian viruses also exist, such as miRNAs expressed by the

438:

share the same downstream cellular machinery. First, viral encoded miRNA was described in

8: 13357: 13333: 13080: 10289:"A retrovirus-based system to stably silence hepatitis B virus genes by RNA interference" 10002:

Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel U, et al. (11 June 2020).

9902:

Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V (January 2017).

8913:

Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel U, et al. (11 June 2020).

8580:"Induction of the interferon response by siRNA is cell type- and duplex length-dependent" 8531:"siVirus: web-based antiviral siRNA design software for highly divergent viral sequences" 6328:"Modulation of microRNA processing and expression through RNA editing by ADAR deaminases" 4513:"Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways" 2714: 2642: 2570: 1522: 1062: 1045: 912: 849: 652: 635: 349: 283:

base-pair to their target mRNA and cleave it, thereby preventing it from being used as a

147: 59: 13035: 12952: 12764: 12709: 12632: 12404: 12357: 12148: 11664: 11564: 11299: 10991: 10935:"Viral-based modelling and correction of neurodegenerative diseases by RNA interference" 9593: 8809: 8750: 8685: 8037: 7941: 7884: 7827: 7770: 7629: 7574: 7521: 7464: 7313: 6923: 6853: 6793: 6734: 6605: 6548: 6093: 5993: 5893: 5838: 5785: 5680: 5402: 5347: 5302: 5038: 4732: 4677: 4626: 4340: 4119: 4065: 3868: 3662: 3538: 3480: 3414:

Bagasra O, Prilliman KR (August 2004). "RNA interference: the molecular immune system".

3338: 3293: 3194: 3169: 3136: 3054:

later won FDA approval for the treatment of AHP and PH1 in 2019 and 2020, respectively.

1096:

Please help update this article to reflect recent events or newly available information.

13345: 13074: 12969: 12936: 12875: 12784: 12729: 12652: 12597: 12369: 12304: 12283: 12264: 12252: 12002: 11869: 11826: 11813: 11796: 11774: 11750: 11583: 11544: 11520: 11495: 11476: 11405: 11362: 11319: 11267: 11201:

Le LQ, Lorenz Y, Scheurer S, Fötisch K, Enrique E, Bartra J, et al. (March 2006).

11178: 11151: 11132: 11059: 11034: 10910: 10885: 10861: 10836: 10817: 10561: 10536: 10485: 10458: 10361: 10318: 10264: 10239: 10170:

Berkhout B (April 2004). "RNA interference as an antiviral approach: targeting HIV-1".

10033: 9979: 9952: 9928: 9903: 9879: 9854: 9817:"Big Pharma's Turn On RNAi Shows That New Technologies Don't Guarantee R&D Success" 9792: 9773: 9746: 9721:

Li W, Szoka FC (24 March 2007). "Lipid-based nanoparticles for nucleic acid delivery".

9698: 9673: 9649: 9624: 9554: 9519: 9456: 9330: 9305: 9281: 9254: 9230: 9205: 9186: 9125: 8895: 8715: 8604: 8579: 8555: 8530: 8408: 8383: 8359: 8334: 8226: 8201: 8141: 8057: 7961: 7901: 7868: 7844: 7811: 7787: 7754: 7735: 7646: 7613: 7594: 7538: 7505: 7481: 7448: 7429: 7400:"RNAi is an antiviral immune response against a dsRNA virus in Drosophila melanogaster" 7380: 7332: 7297: 7273: 7248: 7140: 7115: 7091: 7066: 7042: 7017: 6993: 6966: 6942: 6907: 6873: 6810: 6777: 6624: 6589: 6570: 6508: 6481: 6452: 6427: 6403: 6376: 6352: 6327: 6300: 6275: 6210: 6185: 6161: 6136: 6012: 5977: 5958: 5915: 5858: 5802: 5769: 5750: 5700: 5643: 5559: 5511: 5486: 5467: 5419: 5386: 5367: 5226: 5175: 5150: 5058: 4951: 4924: 4900: 4873: 4849: 4822: 4798: 4773: 4749: 4716: 4697: 4646: 4590: 4565: 4404: 4379: 4360: 4240: 4227: 4202: 4183: 4175: 4139: 4085: 4031: 3980: 3955: 3888: 3832: 3807: 3783: 3758: 3731: 3706: 3679: 3646: 3629: 3604: 3558: 3500: 3449: 3358: 3207: 2979:

paper reported a potent gene silencing effect after injecting double stranded RNA into

2782: 2682: 2648: 2550: 2301: 1424: 1165: 1133: 1066: 1003:

lack the RNAi pathway entirely. Most or all of the components are also missing in some

868: 721: 514: 399: 162:(Ago2). The passenger strand is degraded and the guide strand is incorporated into the 12893:

Sah D (2006). "Therapeutic potential of RNA interference for neurological disorders".

12863: 12540: 12523: 12216: 12191: 12167: 12132: 12108: 12081: 11980: 11010: 10975: 10459:"Advancements in Nucleic Acid Based Therapeutics against Respiratory Viral Infections" 9174: 8828: 8793: 8769: 8734: 8506: 8481: 8457: 8432: 8311: 8275: 8250: 7224: 7199: 7176: 7067:"Four plant Dicers mediate viral small RNA biogenesis and DNA virus induced silencing" 6881: 6695: 6557: 6532: 6251: 6234: 6112: 6077: 5768:

Verdel A, Jia S, Gerber S, Sugiyama T, Gygi S, Grewal SI, et al. (January 2004).

5262: 5245: 4529: 4512: 4488: 4463: 3587: 3570: 3525:

Siomi H, Siomi MC (January 2009). "On the road to reading the RNA-interference code".

2441:). It has also been proposed that RNAi can enhance the sensitivity of cancer cells to 2273:

mechanisms have become an increasing source of encasing nucleic acids and may include

1477:

is the first double stranded siRNA-based medication approved in 2018 and developed by

13151: 12974: 12932: 12910: 12867: 12832: 12776: 12721: 12644: 12589: 12545: 12504: 12499: 12482: 12463: 12428: 12423: 12388: 12324: 12256: 12221: 12172: 12113: 12060: 12033: 11994: 11945: 11935: 11904: 11861: 11830: 11818: 11800: 11742: 11734: 11686: 11629: 11588: 11525: 11480: 11468: 11460: 11397: 11354: 11311: 11259: 11224: 11219: 11202: 11183: 11124: 11064: 11015: 10974:

Harper SQ, Staber PD, He X, Eliason SL, Martins IH, Mao Q, et al. (April 2005).

10956: 10915: 10866: 10809: 10724: 10683: 10642: 10607: 10602: 10585: 10566: 10517: 10490: 10432: 10396: 10353: 10310: 10269: 10220: 10179: 10152: 10113: 10108: 10091: 10072: 10037: 10025: 9984: 9933: 9884: 9797: 9777: 9738: 9703: 9654: 9605: 9559: 9541: 9460: 9448: 9335: 9286: 9235: 9190: 9178: 9129: 9117: 9046: 9038: 8989: 8981: 8942: 8934: 8899: 8887: 8833: 8774: 8707: 8650: 8609: 8560: 8511: 8462: 8413: 8364: 8315: 8280: 8231: 8182: 8133: 8098: 8049: 8002: 7997: 7980: 7953: 7906: 7849: 7792: 7753:

Maillard PV, Ciaudo C, Marchais A, Li Y, Jay F, Ding SW, et al. (October 2013).

7727: 7692: 7651: 7586: 7543: 7486: 7421: 7416: 7399: 7372: 7337: 7278: 7229: 7180: 7145: 7096: 7047: 6998: 6947: 6865: 6815: 6758: 6753: 6718: 6699: 6664: 6660: 6629: 6562: 6513: 6457: 6408: 6357: 6305: 6256: 6215: 6166: 6117: 6058: 6017: 5976:

Li LC, Okino ST, Zhao H, Pookot D, Place RF, Urakami S, et al. (November 2006).

5950: 5907: 5878:"Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi" 5850: 5807: 5742: 5692: 5635: 5600: 5551: 5516: 5459: 5455: 5424: 5359: 5316: 5267: 5218: 5180: 5129: 5122: 5099: 5050: 5007: 4956: 4905: 4854: 4803: 4754: 4689: 4638: 4595: 4534: 4493: 4444: 4409: 4352: 4309: 4299: 4268: 4232: 4158: 4131: 4077: 4023: 3985: 3929: 3919: 3880: 3837: 3788: 3736: 3684: 3634: 3592: 3562: 3550: 3492: 3441: 3350: 3307: 3251: 3199: 3150: 2926: 2913: 2823: 2466: 1498: 1200: 999: 713: 358: 97: 13108: 12879: 12601: 12387:

Kumagai MH, Donson J, della-Cioppa G, Harvey D, Hanley K, Grill LK (February 1995).

12373: 12268: 11873: 11754: 11706:"Bugs Are Not to Be Silenced: Small RNA Pathways and Antiviral Responses in Insects" 11409: 11366: 11271: 11136: 10835:

Rodríguez-Lebrón E, Gouvion CM, Moore SA, Davidson BL, Paulson HL (September 2009).

10365: 10322: 8719: 8145: 7965: 7739: 7433: 7384: 6877: 6574: 5962: 5862: 5754: 5647: 5471: 5371: 5230: 5120:

Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, et al. (2004).

5062: 4789: 4364: 4244: 4089: 4035: 3892: 3855:

Ahlquist P (May 2002). "RNA-dependent RNA polymerases, viruses, and RNA silencing".

3362: 3110: 1578:, and Sylentis. These medications cover a variety of targets via RNAi and diseases. 39:

delivery of designed shRNAs and the mechanism of RNA interference in mammalian cells

13385: 13029: 12964: 12956: 12902: 12859: 12822: 12788: 12768: 12713: 12656: 12636: 12579: 12535: 12494: 12455: 12418: 12408: 12361: 12299: 12248: 12211: 12203: 12162: 12152: 12103: 12093: 12006: 11984: 11976: 11927: 11896: 11853: 11808: 11792: 11726: 11676: 11672: 11668: 11619: 11578: 11568: 11515: 11507: 11450: 11442: 11389: 11346: 11323: 11303: 11251: 11214: 11173: 11163: 11150:

Sunilkumar G, Campbell LM, Puckhaber L, Stipanovic RD, Rathore KS (November 2006).

11116: 11054: 11046: 11005: 10995: 10946: 10905: 10901: 10897: 10856: 10848: 10821: 10801: 10772: 10714: 10673: 10634: 10597: 10556: 10548: 10480: 10470: 10424: 10388: 10345: 10300: 10259: 10251: 10210: 10144: 10103: 10064: 10015: 9974: 9964: 9923: 9915: 9874: 9866: 9787: 9769: 9750: 9730: 9693: 9685: 9644: 9636: 9597: 9549: 9531: 9438: 9325: 9317: 9276: 9266: 9225: 9217: 9170: 9109: 9028: 9020: 8973: 8926: 8877: 8867: 8823: 8813: 8764: 8754: 8697: 8689: 8640: 8599: 8591: 8550: 8542: 8501: 8493: 8452: 8444: 8403: 8395: 8354: 8346: 8307: 8270: 8262: 8221: 8213: 8172: 8125: 8088: 8041: 7992: 7945: 7896: 7888: 7839: 7831: 7782: 7774: 7719: 7682: 7641: 7633: 7614:"The interplay between virus infection and the cellular RNA interference machinery" 7598: 7578: 7533: 7525: 7476: 7468: 7411: 7364: 7327: 7317: 7268: 7260: 7219: 7211: 7172: 7163:

Voinnet O (August 2001). "RNA silencing as a plant immune system against viruses".

7135: 7127: 7086: 7078: 7037: 7029: 6988: 6978: 6937: 6927: 6857: 6805: 6797: 6748: 6738: 6691: 6656: 6619: 6609: 6552: 6503: 6493: 6447: 6439: 6398: 6388: 6375:

Yang W, Wang Q, Howell KL, Lee JT, Cho DS, Murray JM, et al. (February 2005).

6347: 6339: 6295: 6287: 6246: 6205: 6197: 6156: 6148: 6107: 6097: 6048: 6035:

Noma K, Sugiyama T, Cam H, Verdel A, Zofall M, Jia S, et al. (November 2004).

6007: 5997: 5942: 5919: 5897: 5842: 5797: 5789: 5734: 5704: 5684: 5667: 5627: 5590: 5563: 5543: 5506: 5498: 5451: 5414: 5406: 5351: 5306: 5257: 5210: 5170: 5162: 5089: 5042: 4997: 4992: 4987: 4975: 4946: 4936: 4895: 4885: 4844: 4834: 4793: 4785: 4744: 4736: 4701: 4681: 4650: 4630: 4585: 4577: 4524: 4483: 4475: 4464:"Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways" 4436: 4399: 4391: 4344: 4291: 4260: 4222: 4214: 4150: 4143: 4123: 4069: 4015: 3975: 3967: 3911: 3872: 3827: 3819: 3806:

Liang C, Wang Y, Murota Y, Liu X, Smith D, Siomi MC, et al. (September 2015).

3778: 3770: 3726: 3718: 3674: 3666: 3624: 3616: 3582: 3542: 3504: 3484: 3453: 3433: 3342: 3297: 3241: 3211: 3189: 3181: 3140: 3123: 2778: 2324: 1303: 1254: 1138: 1049: 1024: 993: 108: 12733: 12459: 10886:"Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer's mice" 10068: 9024: 8669: 8061: 7892: 7637: 7504:

Lu R, Maduro M, Li F, Li HW, Broitman-Maduro G, Li WX, et al. (August 2005).

3031:. Four years later the first-in-human Phase I clinical trial was started, using a 13288: 13102: 13058: 12616: 12098: 11573: 11446: 11350: 9321: 9033: 6719:"Lineage-specific loss and divergence of functionally linked genes in eukaryotes" 5876:

Volpe TA, Kidner C, Hall IM, Teng G, Grewal SI, Martienssen RA (September 2002).

3823: 3302: 3277: 2843: 2736: 2692: 2670: 2592: 2588: 2412:, respiratory syncytial virus (RSV), SARS coronavirus (SARS-CoV), adenovirus and 2409: 2368: 1526: 1510: 1380: 1298: 1216: 1184: 1161: 1119: 981: 972: 822: 717: 708:

The structural basis for binding of RNA to the Argonaute protein was examined by

383: 174: 55: 11624: 11607: 10703:"CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo" 10052: 9969: 9674:"RNA interference may result in unexpected phenotypes in Caenorhabditis elegans" 8914: 8645: 8628: 8177: 8160: 8093: 8076: 7687: 7670: 4251:

Zhao Y, Srivastava D (April 2007). "A developmental view of microRNA function".

3915: 3910:. Advances in Experimental Medicine and Biology. Vol. 887. pp. 15–30. 3759:"Anatomy of RISC: how do small RNAs and chaperones activate Argonaute proteins?" 2826:

and has triggered the development of high-throughput screening methods based on

2664:

are models that have been widely used to learn how RNAi works within particular

1529:(PBG) from accumulating. To facilitate entry into the cytoplasm, givosiran uses 833:(RITS), and is carried out by a complex of proteins called the RITS complex. In 618: 544:

Exogenous dsRNA is detected and bound by an effector protein, known as RDE-4 in

294:

Exogenous dsRNA is detected and bound by an effector protein, known as RDE-4 in

13233: 12748: 12393: