RNA interference (RNAi) technology is one of the most exciting discoveries of the past decade in functional genomics and a next step in the molecular revolution, redefining drug discovery and target validation. Significantly, the technology has the potential to fundamentally change the drug discovery and development process.
RNAi is a mechanism used by cells to regulate the expression of genes and replication of viruses. The RNA interference mechanism uses short interfering RNA (siRNA) to induce the destruction of target RNA using naturally occurring cellular protein machinery. Harnessing the natural phenomenon of RNAi holds potential for the development of a new class of drugs with specificity towards a wide range of diseases that result from undesirable protein production or viral replication.
Although the phenomenon was first observed in plants, the term 'RNAi' was coined in 1998 after Andrew Fire and colleagues at the Carnegie Institute in Washington found that injecting double stranded RNA into the nematode worm Caenorhabditiselegans caused gene silencing.
A major stumbling block for the technology was that RNAi could not be used in mammals due to induction of the toxic interferon response by dsRNA. However, with the discovery by Thomas Tuschl and colleagues at the Max Planck Institute in Germany in 2001, that gene silencing could be induced in mammalian cells by short, 21-22 nucleotide long dsRNAs, so-called 'short interfering' (si) RNAs, without causing the interferon response.
The mediators of RNA interference are 21- and 23-nucleotide small interfering RNAs (siRNA). In a second step, siRNAs bind to a ribonuclease complex called RNA-induced silencing complex (RISC) that guides the small dsRNAs to its homologous mRNA target. Consequently, RISC cuts the mRNA approximately in the middle of the region paired with the antisense siRNA, after which the mRNA is further degraded. In essence, once inside the cell RNAi is processed into short 21-26 nucleotide RNAs termed siRNAs that are used in a sequence-specific manner to recognize and destroy complementary RNA.
As every cell contains the RNAi machinery and any gene can be targeted with a good deal of specificity, the prospect of specifically suppressing the expression of disease-causing genes has generated a lot of enthusiasm for developing RNAi-based therapies. Because RNAi is an endogenous and ubiquitous pathway, the effectiveness of gene silencing achieved with RNAi surpasses what has been possible in the past using other small nucleic acids, such as antisense oligonucleotides or ribozymes. In one head-to-head comparison, siRNAs knocked down gene expression about 100–1000 fold more efficiently than antisense oligonucleotides.
The development of RNAi technology was voted by the journal, Science, as the 'breakthrough of the year' in 2002.
Monoclonal antibody therapy is the use of monoclonal antibodies (or mAb) to specifically bind to target cells. This may then stimulate the patient's immune system to attack those cells. It is possible to create a mAb specific to almost any extracellular/ cell surface target, and thus there is a large amount of research and development currently being undergone to create monoclonals for numerous serious diseases (such as rheumatoid arthritis, multiple sclerosis and different types of cancers). There are a number of ways that mAbs can be used for therapy. For example: mAb therapy can be used to destroy malignant tumor cells and prevent tumor growth by blocking specific cell receptors.