Tiny RNA fragments offer a giant opportunity for autoimmune diseases

Tiny fragments of RNA, once thought to be molecular waste, could spawn a new class of treatments for debilitating autoimmune and auto-inflammatory diseases.

This discovery, the culmination of eight years of research by Hudson Institute’s Professor Michael Gantier, could improve the lives of people with lupus, psoriasis, rheumatoid arthritis and other common conditions.

The key lies in very short RNA fragments (as small as 1-3 bases) generated during RNA recycling, which have important anti-inflammatory functions no-one suspected.

To put this in context, these are the shortest class of RNAs ever reported to have a biological function – around 6 times shorter than Nobel Prize winning microRNAs!

Blocking immune activation

Prof Gantier screened hundreds of synthetic RNA molecules and found these very short RNA fragments could bind to sensors of our immune system and block their activation.

His collaboration with The University of Tokyo, The Australian National University, St Vincent’s Institute of Medical Research, Western Sydney University, The UK’s Francis Crick Institute, CSIRO and other institutions offers insights into the design of targeted inhibitors that replicate nature’s own blueprint to control excessive immune activation.

The research, published in Nature Immunology, didn’t just identify RNA fragments binding to immune sensors; it also revealed for the first time that they play crucial roles in controlling dangerous inflammation, especially in autoimmune conditions.

One of the world’s foremost experts on oligonucleotides and the immune system, Professor Arthur Krieg, from UMass Chan Medical School RNA Therapeutics Institute (USA), called it a “tour de force” which “…has transformed our understanding of how immune sensors for viral infections are normally blocked to prevent autoimmunity. Their elegant and fundamental discovery provides a pathway to support the development of new medicines.”

“Our discovery shows that selected RNA fragments of only 1-3 bases help protect our bodies against misfiring of the immune system which mistakenly attacks the body – leading to autoimmunity,” Prof Gantier said.

Important anti-inflammatory functions

These findings change the way we understand the initiation and maintenance of chronic inflammation driven by these receptors, and the impact of these findings will only grow as they are further explored.

“They illustrate a mechanism which was entirely unknown – these receptors are constantly blocked by short RNA fragments and this is essential to maintain health,” Prof Gantier said.

Prof Gantier’s findings have recently progressed through their first clinical trial, thanks to Australian-based biotechnology company Noxopharm, whose topical cream has passed successfully through clinical safety trials.

“Currently, we are particularly targeting autoimmune diseases such as lupus, and its skin manifestation (cutaneous lupus), but we have reason to believe that our approach using short synthetic RNAs could work for many other skin diseases – including psoriasis,” Prof Gantier said.

See Prof Gantier discussing his research in this video

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