RNA interference as a therapeuticRNA interference (RNAi) is a highly-conservedbiological gene silencing process in which mediates resistance to bothendogenous and exogenous pathogenic nucleic acids, as a result regulates theexpression of protein coding genes (Chin,Ang and Chu, 2017). In 1996, first RNAi type of phenomenon was reported byNapoli and Horgensen from observation of lighted and even white petunias wheninjected color producing gene to the flowers (Jorgensen et al.
, 1996). Fire andMello revealed that introduction of double stranded RNA in Caenorhabditis elegans lead to gene silencing. Subsequently, RNAirelated events were described in almost all eukaryotic organisms. Various categoriesof small double strand RNA have been found.
Generally, RNAiinvolves three main steps, production of small RNAs by specialized ribonucleaseIII-like enzyme named Dicer, formation of an effector complex (RISC), andsequence specific binding and silencing gene either by degradation of targetedmRNA or translational inhibition (Carthew andSontheimer, 2009). There are someexceptions. Recently was found biogenesis of unusual miR-451 could use AGOenzyme process into mature miRNA instead of using Dicer (Herrera-Carrillo and Berkhout, 2017).
The discovery of RNAi facilitated the study of functionalcharacterization of genes and proteins interactions in the pathway. What’smore, with the aid of many new developed tools as bioinformatics andgenome-wide reagents, RNAi has enormous potential to develop therapeuticeffects for the diagnosis and treatment of viral infection, dominant disorders,neurological disorders and many types of cancers (Ultimo et al., 2017). It has been found certain miRNAsoverexpressed to downregulate tumor suppressors contribute to oncogenesis whichcould be used to diagnosis of certain cancers (Chen et al.
, 2016). Mature miRNAs are 20-25nt small noncoding RNA moleculeswhich primarily bind to the 3′ untranslated region of mRNAs, resulting in adownregulation of target proteins through the degradation of target mRNAs whenperfectly bind or through translational inhibition when imperfectly bind (Tye et al., 2014). Different miRNA havedifferent expression pattern. Some kinds of miRNA expressed in all stages whileothers have a more restricted spatial and temporal expression pattern (Nagalakshmiet al., 2014).
miRNA expression level has been demonstrated correlates withboth the type of leukemia and the prognosis of patients from a microarray study(Mashreghi andAbolhassani, 2017). Therefore, the expression file of miRNA can be used asbiomarkers in diagnosis, differential diagnosis, prognosis and therapy ofhematologic cancer (Wang,Chen and Sen, 2015). RNAi Therapeutics is the branch of science that focus oncontrol of gene activity at RNA level that target the specific mRNA to increaseor decrease production of proteins involved in a disease to eradicate diseases (Aagaard and Rossi, 2007). The combination ofincreasing numbers of identified genetargets and the efficiency that comes from RNAi drug discovery puts science atthe forefront of the potential pharmaceutical leaders of the next decade. RNAi-based therapy works via delivery of small RNAduplexes, including micro RNA (miRNAs) mimics, short interfering RNAs (siRNAs),short hairpin RNAs (shRNAs) and Dicer substrate RNAs (dsiRNAs) in clinicaltrials. It is a promising and attractive new class of therapeutic, especiallyagainst undruggable targets for the treatment of cancer and other diseases.Several RNAi cancer therapeutic clinical trials have beencarried out by targeting a variety of cancers (Bobbin and Rossi, 2016).
Oncogenes, mutated tumorsuppressor genes and several other genes involved in tumor progression are goodtargets for gene silencing by RNAi-based therapy (Behzad, 2014). RNAi cansimultaneous target multiple genes of various cellular pathways involved intumor progression which could be an advantage compared to other methods ofcancer therapy. RNAi cancer therapy might also allow the development ofpersonal drug for specific patients. APN401is one of the several cancervaccines using cbl-b siRNA to treat refractory solid tumors.
Cbl-b siRNA was uptakeand loaded with tumor antigens by multiple cell types present in Peripheralblood-derived monocytes (PBMCs) via ex vivo electroporation treatment. Apeironhopes this strategy could be used to enhance the antitumor immune reactivityand improve T cell activation with the knockdown cbl-b (Bobbin and Rossi, 2016). Gradalis developed a cancer vaccine FANG which use twodownstream bifunctional shRNAs to target furin. As a result, maturatedimmunosuppressant protein TGF-B will be decrease in overian cancer patients. GIneuroendocrine tumors, HCC, an adrenocortical carcinoma was treated usingTKM-PLK1 RNAi therapeutic. Polo-like kinase (PLK) is often overexpressed incancer cell, LNPs delivered siRNA knockdown PLK gene will reduce cancer celldivision. Additionally, many cancer cells dependent on MYC for growth.
Clinicaltrials use RNAi therapeutic targeting the MYC oncogene was studied by Dicerna. Thereare lots of other RNAi therapeutic in clinical trials are in development ofcancer as well other kind of diseases (Bobbinand Rossi, 2016). Although there are lots of clinical trialsfor different diseases have been carried out by lots of different companies,there is no RNAi based drugs have been put on the market.
During the design ofRNAi-based therapeutics, there are lots of challenges and issues. Those areincluding off-target effects, efficacy of silencing targets, delivery of siRNAsto target tissues, generate natural immune response and toxicity to the targetcells (Ozcan et al., 2015). Design of siRNA, selection of strand andchoice of targets as well as the number of targets plan an important role inthe effectiveness of RNAi and off-target effects (Chin, Ang and Chu, 2017). Biodistrubution of RNAi drugs includes both technicaland scientific challenges (Dolly). Delivery of siRNAs to target tissues isimpeded by many barriers(Ozcan et al., 2015).During the development of RNAi in cancer therapy, various kinds of nano-basedcarriers are used to delivery RNAi molecule and has been shown some advantagescompared to viral vectors, lipids, peptides and other delivery methods (Xin et al.
, 2017). Dysfunctional TTR protein will cause notonly disable transport vitamin A but also accumulated of amyloid deposits thatattack the heart and nerve system (Rizk and Tuzmen,2017). Patisiran is a drug that uselipid nanoparticle enriching small interfering RNAs to target mutatedtransthyretin (TTR) gene showed extremely positive results during first andsecond trials (Rizk and Tuzmen, 2017). Althoughnanoparticles have been shown some efficiencies, immunogenicity and toxicitycaused by this technique limit their applications (Xin et al., 2017).Withthe development bioinformatics, sequencing technology, and delivery technology,RNAi as a therapeutic technique can be developed and approved at a faster rate.
It can be applied in wide range of diseases diagnosis and genetic medicinesdesign. Nowadays, several clinical trials are in Phase III development andmight be approved by FDA within the next few years (Bobbin and Rossi, 2016). In the future, RNAi therapeutics is promising and evencould be used to design personal drugs of specific diseases for differentpopulations.
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