RNA interference (RNAi) is a natural cellular defense mechanism that is activated in response to the invasion of exogenous genes, such as viral DNA or RNA. RNAi therapeutics, taking advantage of this natural mechanism, are designed to use double-stranded RNA oligonucleotides, small interfering RNA (siRNA), or single-stranded RNA oligonucleotides such as microRNA (miRNA), to activate an intracellular enzyme complex, referred to as the RNA-Induced Silencing Complex, or RISC. The oligonucleotides are designed as a copy of a short region of the mRNA for a gene that has been targeted for silencing. Once delivered to the relevant tissues or cells, siRNA are loaded into RISC. Although single-stranded, miRNA oligonucleotides double-back on themselves forming a double-stranded region, and are first processed to yield a double-stranded RNA oligonucleotide that is then loaded into RISC. RISC then processes the double-stranded oligonucleotide to release one strand, usually the so-called “sense” strand that has the same sequence as the corresponding target gene mRNA. RISC uses the antisense strand as a guide to locate the mRNA with the complementary sequence that is targeted for silencing, ultimately leading to cleavage of the entire target mRNA. The consequence of the cleavage of the target mRNA is that the protein that would have been translated and produced from target mRNA is not translated and produced, thereby “silencing” the gene.
RNAi therapeutics employing siRNA or miRNA formulated into drugs have the potential to form a third major class of drugs, in addition to conventional small molecule and antibody drugs. Unlike small molecules or antibodies that must act by neutralizing the function of proteins implicated in disease through physical interaction with the protein, RNAi therapeutics prevent those proteins from being made in the first place. RNAi therapeutics are designed based on the genetic sequence of the target protein, and thus are capable of inhibiting disease-causing proteins once considered undruggable. The sequence-level targeting allows potential for protein isoform-specific knockdown. Drug discovery is also significantly faster using RNAi therapeutics, since developing a new product is based on design and synthesis of oligonucleotides rather than screening small molecules or generating antibodies against the protein.