RNA-Interference

Andrew Fire and Craig Mello 2006 (Nobel Prize in Physiology or Medicine of the Year 2006)

RNA interference, or RNAi for short, refers to an interruption of translation, i.e. the translation of the messenger RNA(mRNA) into a protein. The organism uses RNA interference and RNA silencing to regulate its gene expression, for example to ward off invading foreign nucleic acids (e.g. viruses). This "tool" is developed in all eukaryotic cells. RNA interference is therefore a form of gene regulation in which an already transcribed gene is not converted into a protein, or only to a small extent (gene silencing). As RNA interference usually occurs after transcription, it is also referred to as "post-transcriptional gene silencing" (PTGS).

During gene silencing, double-stranded RNA molecules are formed in the cell, which are cleaved by dicers (dsRNA-specific endonucleases from the RNase III family), into small RNAs with a length of 18-25 nucleotides. These molecules are also known as siRNAs (small interfering RNAs) or micro RNA (miRNA). The siRNAs are then incorporated as a single strand by a Dicer-associated protein into the RNA-induced silencing complex(RISC), which contains so-called Argonaute proteins and can degrade RNA that is complementary to the siRNA - the siRNA thus formally corresponds to an antisense mRNA.

RNA interference (RNAi) therapeutics mark a breakthrough in targeted gene regulation, with the potential to effectively treat a wide range of diseases. They use the natural cellular machinery to precisely shut down disease-causing genes. These include:

• Genetic diseases: RNAi therapeutics can treat genetic disorders caused by overactive or faulty genes. For example, RNAi can be used to reduce the production of an abnormal protein that plays a role in certain genetic diseases.
• Cancer: In some types of cancer, oncogenes or their products that promote tumor growth can be switched off. RNAi can be used specifically to suppress the expression of these genes in cancer cells, which can lead to slower tumor progression or even cell death.
• Infectious diseases: RNAi therapies can also be developed to suppress genes that are important for the replication of viruses within infected cells. This could be particularly useful in the treatment of viral infections such as HIV, hepatitis B and C or influenza.
• Eye diseases: RNAi can be used in the treatment of certain eye diseases, such as age-related macular degeneration (AMD), by switching off the genes that contribute to the harmful growth of blood vessels in the eye.
• Neurodegenerative diseases: In diseases such as Alzheimer's or Huntington's disease, RNAi could be used to reduce the production of toxic proteins associated with disease progression.
• Cardiovascular diseases: RNAi could help regulate genes involved in cardiovascular diseases, such as those that help regulate cholesterol levels.
• Metabolic disorders: There are potential applications for RNAi in the treatment of metabolic disorders, for example by regulating genes involved in glucose and lipid metabolism.

The best-known RNAi is rather short (only around 20 base pairs long) and combines with the Argonauts (special proteins) to regulate genes - in most cases to silence them. Actually, the Argonauts do all the work, they are just directed to the right place by the RNAi. The RNAi find their complementary mRNA, the Argonauts chop it up and render it useless.

1. Agrawal N et al. (2003) RNA interference: biology, mechanism, and applications. Microbiol Mol Biol Rev 67:657-685.
2. Han H (2018) RNA interference to knock down gene expression. Methods Mol Biol 1706:293-302.