Small interfering RNA (siRNA) is a class of double-stranded RNA molecules, typically 20-25 base pairs in length.
siRNA molecules play a crucial role in the RNA interference (RNAi) pathway.
siRNAs are involved in post-transcriptional gene silencing by degrading mRNA transcripts.
siRNAs prevent the expression of specific genes.
siRNAs are processed down from longer double-stranded RNA precursors by the enzyme Dicer.
One strand of the siRNA duplex, known as the guide strand, is incorporated into the RNA-induced silencing complex (RISC).
The RISC, guided by the siRNA, binds to complementary mRNA sequences, leading to their cleavage and subsequent degradation.
siRNAs have shown potential in treating various diseases by targeting and silencing disease-related genes.
siRNA-based drugs like patisiran, givosiran, lumasiran, zerlasiran and inclisiran have been approved for conditions such as hereditary transthyretin-mediated amyloidosis, acute hepatic porphyria, primary hyperoxaluria type 1, and familial hypercholesterolemia, respectively.
Delivery systems, including lipid-based nanoparticles and polymer-based nanoparticles, have been developed to enhance the efficacy and specificity of siRNA therapeutics.
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded non-coding RNA molecules, typically 20–24 base pairs in length, similar to microRNA (miRNA), and operating within the RNA interference (RNAi) pathway.
They interfere with the expression of specific genes with complementary nucleotide sequences by degrading messenger RNA (mRNA) after transcription, preventing translation.
Naturally occurring siRNAs have a well-defined structure that is a short (usually 20 to 24-bp) double-stranded RNA.
The Dicer enzyme catalyzes production of siRNAs from long dsRNAs and small hairpin RNAs.
siRNAs can also be introduced into cells by transfection.
The mechanism by which natural siRNA causes gene silencing through repression of translation.
The siRNA-induced post transcriptional gene silencing is initiated by the assembly of the RNA-induced silencing complex (RISC).
ASP-RNAi is an innovative category of RNAi with the objective of suppressing the dominant mutant allele while sparing expression of the corresponding normal allele with the specificity of single-nucleotide differences between the two.
ASP-siRNAs are potential remedial alternative for the treatment of autosomal dominant genetic disorders especially in cases where wild-type allele expression is crucial for organism survival such as Huntington disease (HD),DYT1 dystonia, Alzheimer’s disease, Parkinson’s disease (PD), amyloid lateral sclerosis (ALS), and Machado–Joseph disease.
Their therapeutic potential has also been assessed for various skin disorders like epidermolysis bullosa simplex, epidermolytic palmoplantar keratoderma (EPPK), and lattice corneal dystrophy type I (LCDI).
Chemical modification of siRNA is employed to reduce in the activation of the innate immune response for gene function and therapeutic applications.
Genome-wide expression analysis, e.g., by microarray technology, can then be used to verify this and further refine the algorithms.
siRNAs transfection into cells typically lowers the expression of many genes, however, the upregulation of genes is also observed.
siRNAs delivered via lipid based nanoparticles have been shown to have therapeutic potential for central nervous system (CNS) disorders.
siRNAs that target and silence efflux proteins on the BBB surface have been shown to create an increase in BBB permeability.
siRNA delivered via lipid based nanoparticles is able to cross the BBB completely.
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.
Transfection Electroporation Viral-mediated delivery
Have been used.as drug delivery systems.
There are several advantages that this therapy has over small molecules and antibodies: It can be administered quarterly or every six months.
Almost all siRNA therapies administered in the bloodstream accumulates in the liver.
Onpattro (patisiran) was approved for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults.
hATTR is a rare, progressively debilitating condition.
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 forms insoluble extracellular amyloid deposits.
Amyloid buildup in various organ systems causes cardiomyopathy, polyneuropathy, gastrointestinal dysfunction.
It affects 50,000 people worldwide.
The siRNA is encased in a lipid nanoparticle.
The siRNA molecule halts the production of amyloid proteins by interfering with the RNA production of abnormal TTR proteins.
This prevents the accumulation of these proteins in different organs of the body and helps the patients manage transthyretin amyloidosis.
FDA has approved a second RNAi therapy, Givlaari (givosiran) used to treat acute hepatic porphyria (AHP).
Acute hepatic porphyria (AHP) is caused due to the accumulation of toxic porphobilinogen (PBG) molecules which are formed during the production of heme.
These molecules accumulate in different organs and this can lead to the symptoms or attacks of AHP.
Givosiran is an siRNA drug that downregulates the expression of aminolevulinic acid synthase 1 (ALAS1), a liver enzyme involved in an early step in heme production.
The downregulation of ALAS1 lowers the levels of neurotoxic intermediates that cause AHP symptoms.
Lumisiran (ALN-GO1) and inclisiran, are additional agents.
Zelsiran reduced time averaged lipoprotein (a) concentration by more than 80% during 36 weeks of treatment.