A new experimental drug could finally turn multiple sclerosis (MS) from a disease that has no cure to one that can be successfully reversed with treatment. Researchers led by Jayakrishna Ambati at the University of Virginia School of Medicine showed that a newly developed chemical derivative of an old HIV drug restored movement and vision in a mouse model of the disease — a feat that no currently approved MS treatment is able to do.
The discovery came from an unexpected place. Several years ago, Ambati’s lab began analyzing large health insurance databases and realized that patients taking HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs) were at a much lower risk of developing the eye disease macular degeneration. Digging in to find out why, the scientists revealed that NRTIs block inflammasome activation that could inhibit the evolution of MS and other chronic diseases.
But NRTIs are known to have serious toxicities, so Ambati’s team created new chemical derivatives called kamuvudines that block inflammasomes without the harmful side effects. Now, their results treating mice with a kamuvudine called K-9 could portend an exciting new treatment strategy for MS.
“A discovery we made studying the eye, about an expected property of anti-HIV drugs, has now led to a possible new way of thinking about MS,” Ambati told DDN. “Going after the inflammasome, which may be what actually kills the nerve cells, and not only the immune cells upstream, potentially could be beneficial not just for MS but for many other neurodegenerative diseases. And that would be tremendously exciting.”
Blocking the inflammasome
The researchers found that K9 was able to reverse MS symptoms in mice by protecting the spinal cord nerve fibers and myelin insulation that the disease process of MS damages so heavily. They also found that the drug stopped the escalation of a known blood marker of nerve damage often used in clinical trials, called neurofilament light chain (NfL). Crucially, the mice treated with the approved MS drug, fingolimod, did not have their symptoms reversed.
“The reversal of disease was surprising. We expected K9 might protect animals from getting worse. We didn't expect animals that were already impaired to bounce back completely, both in their movement and their vision,” said Ambati. “It was dramatic to see an animal that couldn’t use its legs or see properly recover that function completely.”
The researchers believe that the drug works by blocking interactions between several proteins that join together to create inflammasomes that triggers inflammation in the body.
Next step: clinical trials for MS
The new drug could move quickly into clinical trials for MS, since Ambati and his collaborators have already been testing it in trials for eye diseases like diabetic macular edema and thyroid eye disease. Thus, there is already a wealth of safety data to build on in MS.
Ambati also co-founded Inflammasome Therapeutics in 2016 to study K9 in ALS.
“The next step in MS is a carefully designed clinical trial in people with MS, and NfL gives us an objective blood marker to see early whether the drug is doing what it did in animals,” said Ambati.
