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Discovery opens up new RNA therapies for diseases driven by auto-inflammation

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RNA therapeutics comprise a rapidly expanding category of drugs that have the potential to revolutionise treatments for many diseases, including those currently deemed undruggable.

Key points

  • RNA therapeutics can modulate our immune system’s response.
  • Research into how this operates has so far focused on how to stop immune responses, but more is needed to fully understand how
  • RNAs affect our immune system, whether inhibiting it or activating it.
  • This research provides opportunities to create RNA therapeutics with anti-inflammatory effects to target and help diseases driven by auto-inflammation such as lupus.

However, one challenge scientists face when getting these therapies into the human cell, is that they can, in some cases, suppress key immune system sensors which normally alert our body to infections – until now.

A study led by Associate Professor Michael Gantier published in the Nucleic Acid Research has created the most comprehensive description of how chemical modifications of RNA therapeutics interact with the body’s immune system.

“By informing scientists about how RNA therapeutics exhibit anti-inflammatory effects, this research will help the design of more specific molecules and inform new treatments for diseases driven by auto-inflammation.” Gantier said.

Present in every form of life, as well as pathogens such as bacteria and viruses, nucleic acids are used by our immune system to detect infections. Understanding how the recognition of nucleic acids by the immune system operates is essential to make safe RNA therapeutics aim at providing new ways to treat disease.

“RNA therapeutics need to be modified to prevent strong immune responses, such as flu-like symptoms. So far, research in this field has focused on how to stop immune responses, but we have discovered that some modifications could lead to profound immune suppression, something that has been discounted to date,” Gantier said.

Associate Professor Gantier’s research also provides added opportunities to create molecules with anti-inflammatory effects that target diseases driven by auto-inflammation such as lupus.

What is RNA and why is it important?

DNA and RNA are a class of molecules called nucleic acids (the ‘NA’ in DNA and RNA), which are essential to all forms of life. They contain and access the genetic information that controls which cells do what in our bodies.

While most people know about DNA, our understanding of RNA – or its most familiar form, mRNA or messenger RNA – is far more limited and has only recently become part of the popular lexicon due to mRNA COVID-19 vaccines (such as Pfizer or Moderna).

In a cell, the main job of RNA is to convert the information stored in DNA – our genetic blueprint or instruction – into proteins. This task is carried out by a specific type of RNA called ‘messenger’ RNA, or mRNA.

In addition to carrying the information from our DNA, mRNA fine-tunes it, allowing a further level of control of what the genetic information bears, while also vastly expanding its repertoire.

The most well-known example of RNA therapeutics to the public are mRNA COVID-19 vaccines. These vaccines supply the body with mRNA that instructs our cells to make a protein resembling the SARS-CoV-2 spike protein, subsequently promoting the synthesis of specific antibodies to neutralize it. However there are many other classes of RNA therapeutics in clinical development to help fine-tune gene function, such as the hypercholesterolemia treatment inclisiran, approved last December in the European Union.

Collaborators | Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Western Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria 3168, Australia; Integrated DNA Technologies Inc., Coralville, IA 52241, USA

Funders | Australian National Health and Medical Research Council; Quebec Fonds de Recherche du Québec; Fielding Foundation Innovation Award

Story Source: Materials provided by Hudson Institute of Medical Research. Note: Content may be edited for style and length.

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