User:Aayushh123/Small interfering RNA

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Small interfering RNA

DNA methylation, RNA-associated silencing, and histone modifications are 3 independent pathways that are thought to be involved in starting and/or maintaining epigenetic alterations. It has recently been evident that RNA regulates gene expression in human cells in a far more complicated and comprehensive manner. An RNA interference-based mechanism (RNAi) that is specifically mediated by small-interfering RNAs (siRNAs) can be used to achieve this regulatory effect through RNA-associated silence, which can be transcriptional in nature.

Intracellular delivery
There is great potential for RNA interference (RNAi) to be used therapeutically to reversibly silence any gene. For RNAi to realize its therapeutic potential, small interfering RNA (siRNA) must be delivered to the site of action in the cells of target tissues. But finding safe and efficient delivery mechanisms is a major obstacle to achieving the full potential of siRNA-based therapies. Unmodified siRNA is unstable in the bloodstream, has the potential to cause immunogenicity, and has difficulty readily navigating cell membranes. As a result, chemical alterations and/or delivery tools are needed to safely transfer siRNA to its site of action.

Transcriptional Gene Silencing
Many model organism, such as plants (Arabidopsis thaliana), yeast (Saccharomyces cerevisiae ), flies (Drosophila melanogaster) and worms (C. elegans), have been used to study small non coding RNA-directed Transcriptional gene silencing. In human cell, RNA-directed transcriptional gene silencing was observed a decade ago when exogenous siRNAs silenced a transgenic elongation factor 1 α promoter driving a Green Fluorescent Protein (GFP) reporter gene. The main mechanisms of transcriptional gene silencing (TGS) involving the RNAi machinery include DNA methylation, histone post-translational modifications, and subsequent chromatin remodeling around the target gene into a heterochromatic state.

Therapies
Alnylam Pharmaceuticals was the first industry to receive FDA approval for a siRNA therapy in 2018. Onpattro and Givlaaritm, have been approved for the treatment of Hereditary transthyretin amyloidosis. During hATTR amyloidosis, misfolded transthyretin (TTR) protein is deposited in the extracellular space. Under typical folding conditions, TTR tetramers are made up of four monomers. Hereditary ATTR amyloidosis is caused by a fault or mutation in the transthyretin (TTR) gene which is inherited. Changing just one amino-acid changes the tetrameric transthyretin proteins, resulting in unstable tetrameric transthyretin protein that aggregates in monomers and form insoluble extracellular amyloid deposits. Amyloid buildup in various organ systems causes cardiomyopathy, polyneuropathy, gastrointestinal dysfunction. Traditionally, liver transplantation has been the standard treatment for hereditary transthyretin amyloidosis, however its effectiveness may be limited by the persistent deposition of wild-type transthyretin amyloid after transplantation. Along with Onpattro, another RNA interference therapeutic drug has also been discovered (Partisiran) which has property of inhibiting hepatic synthesis of transthyretin. Target messenger RNA (mRNA) is cleaved as a result by tiny interfering RNAs coupled to the RNA-induced silencing complex. Patisiran, an investigational RNAi therapeutic drug, uses this process to decrease the production of mutant and wild-type transthyretin by cleaving on 3-untranslated region of transthyretin mRNA. So, silencing the TTR gene can undo the disease-causing effects of the TTR gene mutation.