I was an on-call intern late one night at the Johns Hopkins Hospital when I met a young woman who presented with weakness and pain in her legs. This was her third admission to the hospital in the past 6 months despite her doctor’s best effort to treat her for multiple sclerosis (MS).
“I don’t understand why these attacks keep coming,” she told me, wincing in pain. “I have done everything my doctor told me to do, taken every medication he told me to take. And still, I keep getting these attacks. Something is definitely not right.”
I stayed up with her that night trying to get to the bottom of this mystery. After scouring the medical literature, I found a new study published by the Mayo Clinic describing a potentially new blood test that distinguishes MS from a rare disease called neuromyelitis optica (NMO). That was 2004. Back then, NMO was not on the radar at most MS Centers around the country. I suspected that my patient that night was suffering from NMO, not MS, and I sent her blood to the Mayo Clinic for testing. It came back: POSITIVE.
This case had a profound impact on me. I wondered how many MS patients at Johns Hopkins actually had undiagnosed NMO. My mind wandered to the science around NMO – and the target of NMO, aquaporin-4. Could NMO patients have an abnormal aquaporin-4 that triggers the immune system to attack, or is aquaporin-4 just a naïve target of an aberrant immune system? For answers, I turned to Dr. Douglas Kerr who started the Transverse Myelitis Center at Johns Hopkins and probably knew more about Transverse Myelitis and NMO than anyone else in the world! Dr. Kerr invited me to work in his lab to develop a mouse model of NMO that could help us understand what causes NMO, and provide clues for the best ways to treat it.
I spent a few months in residency getting my project started but it was during my fellowship that I was able to spend most of my time in the lab. With funding from the American Academy of Neurology, I profiled the two different variations of aquaporin-4 found in the human brain and found that one of them was highly expressed in areas where NMO attacks occurred – especially in the spinal cord and optic nerves. With a grant provided by the Guthy-Jackson Charitable Foundation in 2009, I was hired on the faculty at Johns Hopkins to continue my work developing a mouse model of NMO. The NMO mouse proved to be more difficult to create than I originally envisioned, but with the help of the best colleagues and technicians I could find, we pressed on.
I finally had a breakthrough moment in 2012. Up to then, we were focused on the aquaporin-4 antibody. The aquaporin-4 antibody is a protein whose sole function is to bind to aquaporin-4 and trigger an immune attack. (By the way, the aquaporin-4 antibody is what is detected in the NMO blood test.) Many of us hypothesized that the antibody was harmful in NMO and caused the disease. We spent several years trying to understand how this antibody could be harmful, but in fact, it was not that harmful after all. The antibody may have contributed a little, but it was not the major player. Something else in the immune system was the cause of NMO. My breakthrough initially seemed like just another failure; I found yet more proof that the antibody was not the cause. In the course of proving that my hypothesis was wrong, I accidentally discovered that a different immune component was causing NMO—it was T cells reactive against aquaporin-4.
T cells are the thoughtful immune cells in your body. They go around and surveille for infections and cancers by communicating with each cell are carefully consider the context of any signal. Mature T cells are trained to look for a particular foreign protein, and we discovered that T cells directed to aquaporin-4 attack the optic nerves and spinal cord in mice, just like in patients with NMO. It took us 3 more years to prove definitively that these T cells were the cause of the disease and we published our results in 2015. Since then, two more labs in San Francisco and Germany confirmed our results.
Besides creating a mouse that develops NMO just like humans do, the more exciting news that comes from this discovery is the potential to cure NMO. Since we figured out exactly how to switch the immune system “on” to cause NMO, we had the capability to switch the immune system “off,” permanently. We successfully patented our findings – filed December 2016 – and applied for government funding to pursue a specific treatment for NMO based on our technology. The goal is to switch the immune system “off” to aquaporin-4, and to re-educate the immune system of NMO patients so that they will stop attacking the optic nerve and spinal cord.
As a field, we have significant progress in the understanding and treatment of NMO. We now have 3 worldwide clinical trials ongoing to treat a rare disease – this is quite a feat! It speaks to the progress we have all made in the lab towards finding treatment targets that can help patients in the acute and preventive treatment of NMO. For me, I am committed more than ever to achieve the goal I set out in 2004 – find the cure to NMO.
In fact, I believe NMO is a proof-of-concept disease that can demonstrate how re-educating the immune system can be an effective treatment for an autoimmune disease.
We’ve come a long way since I met my first patient with NMO in 2004. I hope everyone reading my story feels the same hope and optimism that we are closer than ever to finding a cure to NMO!
Published April 3,