RNA interference: Therapy by switching off genes

RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults (© Alnylam)

RNA interference (RNAi) is the natural gene-silencing process that arises in numerous organisms ranging from plants to mammals. This mechanism controls the expression of individual genes in a cell. The expression or conversion of genes into proteins can be influenced with the help of the RNAi procedure developed by Thomas Tuschl and colleagues at the Max Planck Institute for Biophysical Chemistry in Göttingen. This enables the switching off of specific genes so that the information they contain is not passed on. The procedure thus represents a very promising approach to the treatment of various diseases, such as metabolic disorders and cancer. Since 2018 Alnylam´s ONPATTRO©is the first RNAi drug on the market worldwide. In 2019 Alnylam received another FDA approval for its drug Givlaari© (Givosiran). In 2020, Oxlumo© (Lumasiran) was approved as the third drug in the USA and Europe. In 2022 finally an approval for AMVUTTRA™ (vutrisiran) followed.

RNA interference (RNAi) was first observed in plants and some invertebrate animals (e.g. fruit flies). However, Thomas Tuschl and his colleagues from the Max Planck Institute for Biophysical Chemistry in Göttingen were the first to succeed in establishing the functioning of RNAi in mammalian cells as well. In the RNAi procedure developed by Thomas Tuschl, synthetically manufactured RNA strands are inserted into a cell. These bind themselves to complementary messenger RNAs (mRNAs), which are then removed or destroyed through a complex cellular mechanism. This reduces or prevents the implementation of genes in proteins. Due to RNAi, it is possible to specifically deactivate individual genes so that the information contained in the gene is not passed on and the protein concerned is not produced. The discovery of this “switch” represents an extremely promising approach to the treatment of a very wide range of diseases, some of which are currently still not accessible to treatment by drugs. Consequently, RNAi therapeutics constitutes a significant new class of drugs. In future, they could be used for the treatment of viral diseases, metabolic diseases and cancers, and could be of similar importance as monoclonal antibodies already today.

Alnylam, a leading company in the development of RNAi therapeutics, is out licensee. In 2018, Alnylam announced the worldwide very first FDA approval of an RNAi therapeutic - ONPATTRO ™ (Patisiran) - for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. In 2019, the second RNAi drug Givlaari® was approved in the USA for the treatment of acute liver porphyria. The third siRNA drug was approved in the USA and Europe in November 2020. The very rare genetic disease “primary hyperoxaluria type 1” can be treated with Oxlumo®. In 2022 Alnylam announced the US and EU approval of AMVUTTRA™ (vutrisiran), an RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated Amyloidosis in Adults.

  • The RNA interference process (© Alnylam)
  • The therapeutic RNAi mechanism (© Alnylam)
  • Inhibition of the miRNA function through a microRNA antagonist (© Alnylam)
  • Prof. Dr. Thomas Tuschl (© EPO)
  • RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults (© Alnylam)
  • GIVLAARI™ (givosiran) product and packaging (picture: Business Wire)
  • The very rare genetic disease “primary hyperoxaluria type 1” can be treated with Oxlumo (© Alnylam)

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