An experimental treatment that uses tiny pieces of RNA to switch off an inflammation-related gene has been tested in people for the first time.
The inhaled drug, called ARO-RAGE, is designed to reduce the activity of RAGE, a receptor found on cells lining the lungs that can help set off inflammatory responses.
In a first-in-human study, the treatment was well tolerated and produced a substantial reduction in RAGE activity in the lungs. The researchers say the findings support further testing in asthma and other lung diseases, although the trial was not large enough to show whether the treatment actually improves symptoms or prevents attacks.
The Treatment Goes After Inflammation at Its Source
Asthma is not simply a problem of narrowed airways. Inflammation can make the airways swollen and overly sensitive, contributing to symptoms such as wheezing, coughing and difficulty breathing.
Most asthma treatments work by relaxing the airway muscles or suppressing inflammation after these processes are already underway.
The researchers behind ARO-RAGE took a different approach. They focused on RAGE, short for receptor for advanced glycation end-products, which sits on cells in the lungs and can respond to several signals associated with tissue stress and inflammation.
When RAGE is activated, it can trigger a chain of molecular signals that encourages further inflammation.
That makes the receptor an appealing target for researchers looking for a way to interrupt the process earlier.
Tiny RNA Molecules Switch Down the Target
ARO-RAGE uses small interfering RNA, or siRNA, to reduce the amount of RAGE the cells produce.
SiRNA molecules work by interfering with the genetic instructions used to make a particular protein. In this case, the treatment targets the messenger RNA carrying instructions for RAGE and causes those instructions to be broken down before the protein can be produced.
The drug is delivered by inhalation rather than injected into the bloodstream. That matters because the researchers want the treatment to reach the lungs directly while limiting exposure elsewhere in the body.
In earlier experiments, inhaled ARO-RAGE produced a deep and lasting reduction in RAGE activity in the lungs of animals. The researchers also saw reduced inflammatory responses in several models of lung disease before moving into human testing.
The First Human Study Showed the Drug Reached Its Target
The early clinical trial included healthy volunteers as well as people with asthma.
Researchers were primarily looking at safety and whether ARO-RAGE could actually suppress RAGE in the lungs, rather than testing whether it could treat asthma.
The treatment was well tolerated, with no major safety signal emerging from the study. More importantly, samples from the lungs showed that RAGE activity fell substantially after treatment.
That gave researchers evidence that the inhaled drug was reaching the part of the body where it was supposed to work and producing the biological effect it was designed to achieve.
The researchers describe this as an important step because RNA-based medicines can be difficult to deliver to a specific organ. The lungs offer an unusual advantage: a drug can be breathed in and delivered directly to the respiratory system.
It Is Still Too Early to Say It Treats Asthma
The encouraging laboratory results do not yet mean ARO-RAGE can control asthma.
The human study was an early-stage trial focused largely on safety and target engagement. It was not designed to determine whether people receiving the drug had fewer asthma attacks, better breathing, or fewer symptoms.
That question is now being tested more directly.
Researchers are studying whether suppressing RAGE can change the inflammatory response in people with asthma, particularly in forms of the disease that can be difficult to control with existing treatments. The researchers are also interested in whether the same approach could eventually be useful in other lung conditions in which RAGE is involved.
The appeal of the approach is that one inhaled treatment could potentially interfere with an inflammatory pathway before it produces the wider cascade of signals that damages or irritates the lungs.
But that possibility still needs to be demonstrated in patients.
For now, the study establishes something more specific: scientists have shown that an inhaled RNA drug can safely reach the lungs in people and substantially suppress a molecular target involved in inflammation. The next challenge is finding out whether silencing that target actually makes breathing easier for people with asthma.
