siRNA therapeutics

Published on March 20, 2022   18 min

A selection of talks on Genetics & Epigenetics

Hi. My name is John Rossi. I'm a professor at City of Hope National Medical Center in Los Angeles, California. Today's presentation is about small interfering RNAs or siRNAs, their mechanism of action and development as human therapeutics. Co-presenting with me today is Daniel Rossi, a Clinical Project Associate at Duet BioTherapeutics.
Small interfering RNAs, known commonly as siRNAs, are small strands of RNA which can completely alter the expression of genes through a process known as RNA interference or RNAi. This is a process by which double stranded RNA molecules produce sequence-specific suppression of gene expression via translational or transcriptional repression. The end result being the suppression of a given protein. It's thought to have originally evolved as a defense mechanism against the invasion of exogenous genes, such as those from viruses, making its original purpose something akin to an intracellular immune system. In a biologist's hands, it offers a powerful research tool and method to treat currently undruggable diseases, allowing the suppression of proteins which have yet evaded effective inhibition by traditional pharmaceutical drugs. In particular, it shows great promise in genetic diseases, infectious diseases, and cancer.
Now, for a quick primer on how siRNA functions at the level of molecular biology. The production of siRNA to achieve gene silencing, begins with long double stranded RNAs formed from a hairpin or from complementary RNAs, which are cleaved by an endoribonuclease called Dicer, which cuts the long double stranded RNA molecule to form small interfering RNA, or siRNA. This shorter strand of RNA is capable of getting incorporated with a number of proteins to form the RNA induced silencing complex or RISC, where the strand is unwound to form a single stranded siRNA with the strand less thermodynamically stable at the five prime end chosen to remain part of the complex. This single siRNA strand can now guide the RISC to its complementary mRNA target. Once RISC binds to its target and induces mRNA cleavage, the cut mRNA strand will be degraded, and in turn, will never be able to be translated into protein.