Neuromyelitis Optica, Part 4: Unresolved Questions
And finally, a look at some unresolved questions, such as people diagnosed with NMO who don’t have the aquaporin antibody, and the funding situation
No antibody—but is it NMO?
A recent study that compared several antibody assays found that about a quarter of patients diagnosed with NMO lack the aquaporin-4 antibody (Waters et al., 2012). But perhaps some of them really don’t have the disease, Angela Vincent, MBBS, a neuroimmunologist at the University of Oxford, U.K., told MSDF: When she took a closer look at cases in her patient cohort who don’t carry the antibody, she found that some showed symptoms that were slightly different from NMO. They responded more quickly to treatment and didn’t seem to have relapses. Indeed, an Austrian group and Vincent’s group recently reported that some of these patients seem to have a different disease, caused by an autoantibody against a protein called MOG (myelin oligodendrocyte glycoprotein; Mader et al., 2011; Kitley et al., 2012).
Others are also trying to find out whether patients without the aquaporin 4 autoantibodies carry antibodies to different targets: Jeffrey Bennett, M.D., Ph.D., a neurologist at the University of Colorado School of Medicine in Aurora, for example, is studying what B cell types are especially common in such patients and wants to then identify the CNS targets of the antibodies these cells produce.
Perhaps eventually, most NMO patients without the aquaporin-4 antibody will turn out to have a different disease, Vincent said, adding that the same might turn out to be the case for some MS patients. “Maybe some of them do have an antibody,” she said. And indeed, researchers in Munich reported last year that about 50% of MS patients carry an antibody to KIR4.1, a potassium channel on oligodendrocytes and astrocytes in the brain (see “Channeling MS”; Srivastava et al., 2012). If more evidence along those lines becomes available, perhaps many of the lessons learned from studying NMO might eventually apply to MS as well.
A new funding source
Awareness of NMO as a disease, and research into finding treatments, has improved in recent years, in part because of Victoria Jackson, a cosmetics entrepreneur in Los Angeles. When she learned that her daughter had been diagnosed with NMO, she decided to invest her time and money into finding a cure. So with her husband, Bill Guthy, in 2008 she founded the Guthy-Jackson Charitable Foundation. “I was a mom on a mission,” she said in an interview with MSDF. “I decided at that moment that I would close the book on mascara and open the book on medicine and dedicate the rest of my life to finding a cure.”
Since then the foundation has invested more than $20 million into NMO research projects and is currently funding research of more than 70 scientists in 15 countries. It’s unclear how that compares with funding from the NIH, because the agency doesn’t track funding for NMO, according to Ursula Utz, Ph.D., a program director for MS at the National Institute of Neurological Disorders and Stroke, which is part of the NIH.
But Bennett, who receives funding from both the Guthy-Jackson Foundation and the NIH, said the Guthy-Jackson funding is critical. “The NIH isn’t going to invest a lot of money in a rare disease,” he said, adding that, without the Guthy-Jackson Charitable Foundation, “the field couldn’t have developed as it did. We couldn’t have done our work.” The foundation is also assembling a biorepository of patient samples that researchers can use for their studies, in collaboration with the Accelerated Cure Project, the content provider for MSDF.
By tying her funding to certain requirements, Jackson is also trying to change the way research is done in the NMO field. For example, she said, only researchers willing to collaborate are funded. “If you are being funded, you have to pick somebody else that you are working with,” she said. “Everyone has to work together or they are not funded.”
The foundation also helps patients directly. “They saved my life,” Long said, adding that when she was diagnosed with NMO, the foundation put her in touch with another NMO patient who helped her with questions she should ask her doctor.
And just weeks after her diagnosis, she attended the first “patient day” the foundation organized in California in November 2009 as part of its annual NMO meeting, which is attended by researchers as well. This event is unusual, because it allows patients to meet with researchers to learn about new treatments or get help when dealing with insurance companies.
But perhaps the most important aspect is that patients can talk to one another: At last year’s patient day, Long, herself a mother of three, met a woman who has young children and was very frightened because she had just been diagnosed with NMO and was in a wheelchair. “ 'Don’t think that this is here forever,’ ” she said she told her. “ 'I am not kidding you. Someone used to have to cut my food.’ ”
Key open questions
- What are the initial causes of NMO?
- Can scientists develop an animal model that simulates chronic NMO disease with high autoantibody titers in the blood and repeated attacks?
- What are the exact steps that lead from antibody binding to the damage that occurs in NMO lesions?
- It seems that NMO symptoms are largely restricted to the optic nerve and spinal cord. Does that mean that other organs such as the kidneys, which also have the aquaporin 4 water channel, are less affected? If so, why?
- Why do aquaporin antibody titers not always correlate with the severity of symptoms? Are all aquaporin-4 antibodies equally damaging?
- What causes the disease in patients that seem to have NMO but don’t carry the aquaporin antibody in their blood?
Thumbnail image on landing page. Jeffrey Bennett, University of Colorado, Denver.
- Jeffrey Bennett receives research support from the Guthy-Jackson Charitable Foundation and the NIH. He’s a consultant for MedImmune, Novartis, Abbott, Chugai, and Questcor.
- Hans Lassmann has received honoraria from Biogen Idec, Teva, and Novartis for giving lectures at meetings. He has consulted for Amgen and Baxter.
- Vanda Lennon is a named inventor on a patent and receives royalties for technologies related to aquaporin-4 antibodies in NMO diagnosis, and she receives research support from the Guthy-Jackson Charitable Foundation and the NIH.
- Claudia Lucchinetti is named on a patent related to NMO-IgG.
- Sean Pittock and the Mayo Clinic have a financial interest associated with several aquaporin-4 technologies. Dr. Pittock receives research support from Alexion, the Guthy-Jackson Charitable Foundation, and the NIH; he has consulted for Alexion, MedImmune, and Chugai but has received no compensation for these consulting activities.
- Richard Ransohoff serves as a consultant, speaker, or advisory board member for ChemoCentryx, Lundbeck, and Vertex.
- Alan Verkman is a named inventor on patents for anti-AQP4 blocking antibodies (aquaporumab) and enzymatic inactivation of NMO-IgG.
- Angela Vincent’s work on NMO is supported by the NHS National Commissioning Group for NMO.
- Scott Zamvil receives research support from the Guthy-Jackson Charitable Foundation, the Maisin Foundation, NIH, Biogen Idec, Teva, Five Prime, and Boehringer Ingelheim. He has served as a consultant and received honoraria from Biogen Idec, EMD Serono, Novartis, Roche, Genzyme, and Teva Pharmaceuticals Inc. He has served on Data Safety Monitoring Boards for Eli Lilly, BioMS, and Teva.
- Lawrence Steinman and Takashi Yamamura stated that they have no relevant financial ties.