RNAi Emerging Therapies

Ananthga Naik Nagappa, Rahul N, Anup Naha and Ajay Pise

Abstract: Small interference RNA (si RNA) is a promising therapeutic module which is making a big news due to its safe & efficus mode of action. SiRNA is offering better therapeutic interventions in the areas like AIDS, hepatitis, cancer, Hypertension etc. Its mode of action involves the blockade of protein synthesis which does not harm the treated organ but prevents key proteins mediating pathogenesis of the disease. There are products available for the treatment of age related macular degenerative disease for prevention of loss of vision. Here it is going to halt the production of a key pathogenic protein vegus (vascular endothelial growth factor). Many of the products are under various stages of clinical trial. There is a break through in medicine &therapeutics which is truly a biotechnological intervention.
The first hints of the existence of the gene silencing mechanism that is now called RNA interference emerged from work on the genetic modification of plants in the late 1980s. Attempts to deepen the violet hue of petunias by expressing higher levels of an enzyme involved in the synthesis of the pigment unexpectedly of extra copies of the gene had somehow caused a decrease in its expression rather than the anticipated increase. For some time this remained an unexplained oddity. It was soon joined by similar observations in the filamentous fungus Neurospora crassa and then the nematode worm Caenorhabditis elegans. Once the large community of developmental biologists working on the worm became involved, the pace quickened. In 1998 the key observation was made that led to the coining of term “RNA interference”. Fire and Mello showed that double standard RNA (mRNA) with sequence complementary to the antisense strand for which they won Nobel prize in medicine in 2006.
RNA interference or gene silencing is a phenomenon by which the double stranded RNAs mediated through siRNAs, elicit degradation of target mRNA containing homologous sequences thereby inhibiting the protein synthesis, in effect silencing the gene responsible for the same. Ease of application, cost effectiveness and possibilities for genome wide reverse genetics have quickly turned the approach into a widely accepted one. RNAi has been described in several eukaryotics organisms, both unicellular (Trypanosoma brucei) and multicellular (Caenorhabditis elegans, Drosophila melanogaster, planaria, hydra, plants, zebra fis, mice and humans). Transfection of dsRNA into animal cell results in the potent, long lasting, (typically several days) posttranscriptional silencing of homologous genes. As somatic mammalian cells exhibit an innate immune response (responding with interferon mediated defenses) when exposed to dsRNAs with more than 30bp, there was an initial confusion due to vigorous non specific shut down of transcription and translation, partly due to the activation of RNA dependent protein kinase activity (PKR). Later on studies proved that small interfering RNAs (siRNA) with 19-23 nucleotides length, work efficiently in silencing the gene. It is a robust method for lowering specific protein levels compared to traditional techniques such as antisense, ribozymes or microinjection of function blocking antibodies.


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