Multiple Sclerosis Discovery -- Episode 61 with Dr. Yanming Wang

[intro music] Host – Dan Keller Hello, and welcome to Episode Sixty-One of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller. In this podcast, Dr. Yanming Wang of Case Western Reserve University in Cleveland, Ohio, discusses a solution to the vexing problem of how to track changes in myelin in the brain and spinal cord, a measurement believed to be especially important for new candidate drugs to restore this insulating sheathing around axons. First, here are some new items in the MS Discovery Forum. A new data visualization showcases the collaborations among authors who published papers reporting the results of clinical trials in progressive forms of multiple sclerosis in the last 30 years. You can find the network map on msdiscovery.org under “Research Resources.” You can mouse over circles in the graphic to find researchers' names. Click and drag the circles to animate the map and reveal connections. In research news, a Swedish team took the first steps toward finding potential disease markers in the immune cells of asymptomatic people with MS and with seasonal allergies. The study pinpointed three key proteins that may transform normally protective T cells into ones that attack myelin in the case of MS. The three proteins are transcription factors, which glom on to DNA and control which genes turn on and off. According to data from genome studies, the proteins are more common in genetic regions associated with disease, strengthening the case for their role in MS. Finally, the three proteins act differently in people with immune-related diseases, including multiple sclerosis, according to tests on blood samples. Ultimately, the researchers want to learn if they can detect multiple sclerosis and other autoimmune conditions much earlier. [transition music] And now to our interview. MSDF caught up with Dr. Yanming Wang last month at the 2015 World Congress of Neurology meeting in Santiago, Chile. We discussed his solution to what has been a missing link in MS research and practice; that is, how to image myelin -- not just lesions on an MRI, but how to tag the substance itself using a biomarker for molecular imaging called M-E-D-A-S, or "mee-das." Going beyond diagnosis, Dr. Wang told us it may eventually allow clinicians to get a better handle on disease progression and efficacy of treatments. Interviewer – Dan Keller You had referred to molecular imaging of myelin as the missing link. Why is this the missing link? Interviewee – Yanming Wang Because molecular imaging has really transformed how we practice medicine today, and it has become a standard care for virtually many neurological diseases. However, in multiple sclerosis, there's still no effective imaging technique in place that can help physicians to monitor not just for diagnosis, but also to monitor the disease progression. MSDF And would this be useful also in monitoring potential therapies? Dr. Wang Exactly. There's a lack of imaging technique that allow people to monitor the drug efficacy, particularly for those drugs that try to repair the myelin damage in the CNS. MSDF How would this differ from MRI imaging, what you see there, versus having a radioactive biomarker? Dr. Wang Currently, MRI is the commonly used imaging modality in MS, however MRI provides only anatomical information and also detect brain lesions. However, those lesions detected on MRI are not specific for myelin pathology. MSDF You do have a compound now, [11C]MeDAS, which would be specific for myelin. Is that right, is it very specific for myelin? Dr. Wang Exactly. It's very specific for myelin, because the advantage it has over MRI is that that is truly a molecular imaging modality which uses myelin-specific radiotracers that allow to quantitatively monitor the myelin damage and myelin distribution in the brain. So for this reason, we developed a specific radiotracer that can selectively bind to myelin with high affinity, so that we could directly image the myelin distribution. MSDF How quickly does it reach the CNS and you can image? Dr. Wang It takes minutes, literally, for the radiotracer to penetrate the BBB and enter the brain, and then the whole process takes only 60 minutes. MSDF Can you briefly describe your rat model where you're using lysolecithin as an MS model, and then what you did with your marker? Dr. Wang Lysolecithin model is an established model of focal demyelination in the brain, so we used that model to test our compounds to monitor the demyelination and remyelination. So after injection of MeDAS, the compounds could readily enter the brain and selectively bind to the myelin. And then at the peak of the disease, which is a peak of the demyelination, the brain uptake of the compounds is lowest, versus when the brain is recovered, then the brain uptake of the compounds is increased. So this demonstrated the in vivo specificity of the radiotracer for myelin. MSDF And you can image myelin on the way down and on the way up; you have this hepatocyte growth factor which causes some remyelination? Dr. Wang Right, exactly. In collaboration with my colleague, Bob Miller. So we'd use this imaging modality to see if we can monitor the drug efficacy for remyelination. So we'd give this HGF, which is a growth factor that promotes remyelination, and then we could use this imaging technique just to monitor the increase of remyelination after the drug treatment. MSDF Everything right now is in animals. Do you have plans for any human trials? Dr. Wang Yes, we are working on this paperwork required by FDA to put these compounds in humans. MSDF Is the compound so far nontoxic; it's diamino stilbene, is that right? Does it have any estrogenic effects or other toxic effects? Dr. Wang No. We have done systematic toxicity studies and there's any adverse effects in animal models so far. MSDF What do you see as the clinical utility of this if it enters the human realm? Dr. Wang It's going to be a very powerful tool for diagnosis and prognosis, and also particularly for evaluation of drug efficacy. As you know, currently pharmaceutical companies and academic investigators are all trying to develop new drugs that can repair myelin damage in order to restore the biological functions. However, there's a lack of imaging tools in place that allow them to monitor such myelin repair therapies, and this could provide the missing link for this endeavor. MSDF Does PET imaging with this compound correlate at all with what's seen on MRI, especially in a kinetic sense following time course? Dr. Wang Well, yes. In the wonderful publication in Annual Neurology a couple years ago, we did demonstrate that this PET imaging technique can be used as an imaging marker that correlates with the disease progression in terms of the severity of the symptoms in animal models, in the EAE models. The EAE rat, for example, its appearance, the relapsing or remitting stage, and that we could use this imaging marker to correlate nicely with the symptoms. And this is one of important application if we put this into clinical use. MSDF Is this compound the end-all and be-all, or are you developing others, or have some gone by the wayside for various reasons? Dr. Wang This compound, and also this imaging technique, could be used not just only in MS, but can also be used in many other neurological diseases, such as Alzheimer's disease, spinal cord injury, and stroke, for example, because all of these neurological diseases are associated to some degree with the myelin damage. MSDF Have we missed anything important, anything to add? Dr. Wang Again, I think the imaging technique, particularly molecular imaging technique based on positron emission tomography, is lagged behind in the field of neurological diseases because of the complexities of the brain and the lack of molecular probes that could advance our understanding, also facilitate the drug discovery. MSDF I appreciate it. Thank you. Dr. Wang Oh, thank you very much then. [transition music] MSDF Thank you for listening to Episode Sixty-One of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected]. For Multiple Sclerosis Discovery, I'm Dan Keller. [outro music]