RNA-based medicine is about to take a huge leap forward thanks to the discovery of extremely short RNA fragments with important anti-inflammatory properties.
Professor Michael Gantier's latest research, published in Nature Immunology, builds on the Nobel prize winning discoveries of microRNA (2024) and siRNAs (2006), except where those molecules contain around 20 bases, these very short RNA fragments can be as small as 1-3 bases.
So why are these tiny fragments of RNA so important? Prof Gantier explains.
"After systematic screening of hundreds of synthetic RNA molecules, we discovered that very short RNA fragments could bind to sensors of our immune system and block their activation," he said.
"This is the shortest class of RNAs ever reported to have a biological function (around 6 times shorter than Nobel Prize winning microRNAs!)".
RNA fragments potential for lupus and psoriasis
These findings have enormous significance for the development of new treatments for common autoimmune conditions, such as lupus, psoriasis, rheumatoid arthritis and more.
Prof Gantier's lab at Hudson Institute of Medical Research in Melbourne led an international team of experts from across Australia, as well as Japan, the UK and the USA.
But they didn't just identify RNA fragments binding to immune sensors; they also revealed for the first time that they play crucial roles in controlling dangerous inflammation, especially in autoimmune conditions.
Critical role protecting the body
With collaborators in Japan the Hudson Institute team solved the puzzle of how these RNA fragments bind to immune receptors at the molecular level.
This revealed something unexpected – the binding occurred in a new pocket in one of the receptors and blocked its activity. Critically, the team had previously discovered a rare mutation in the same pocket, which led to systemic autoimmunity known as lupus (published in Nature in 2022).
The team showed that the rare lupus mutation prevented binding of the short RNA fragments to the pocket of this receptor, meaning the receptor could not be blocked anymore. This suggests that autoimmunity in patients with this pocket mutation originates from an uncontrolled activation of the receptor, thereby revealing the importance of the short RNAs fragments to prevent disease.
"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," he said.
"That tells us that extremely short RNA fragments generated during RNA recycling have important anti-inflammatory functions no-one suspected."
Changing understanding of inflammation
"Our findings change the way we understand the initiation and maintenance of chronic inflammation driven by these receptors," said Prof Gantier. "They illustrate a mechanism which was entirely unknown – these receptors are constantly blocked by short RNA fragments and this is essential to maintain health."
The impact of these findings will only grow as they are further explored.
This work also has direct therapeutic applications for the management of autoimmune diseases, because these tiny RNA fragments can be manufactured to mimic the natural ones and thus prevent aberrant activation of these receptors.
"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.
"We are focusing on the skin because of the ease of use of our 3-base RNA fragments in this tissue, though we are also actively working with other companies to develop technologies to target other tissues where autoimmunity is prevalent."
