Local Researchers Dr. Brian Popko and Dr. Pedro Brugarolas Discuss Current Research on Drug Modification to Better Trace MS Development
Last October, funds from the Illinois State Lottery helped launch eight innovative local MS research projects which range from investigating the reduction of disease development and stimulation of myelin repair to original rehabilitation and physical exercise techniques. To get a better understanding of the research happening statewide, Greater Illinois Chapter marketing staff interviewed the lead researcher overseeing each pilot project.
Dr. Brian Popko is one of the National MS Society’s grant recipients for 2013. Dr. Popko holds a Ph.D. from the University of Miami School of Medicine and received postdoctoral training at the California Institute of Technology. After 13 years on the faculty in the Neuroscience Center at the University of North Carolina at Chapter Hill, Dr. Popko joined the University of Chicago in 2002 as the Jack Miller Professor in Neurological Sciences and Director of the Center for Peripheral Neuropathy and is currently researching the role that the immune response plays in the mechanisms and development of neurological disorders.
Dr. Pedro Brugarolas is a postdoctoral scholar in the laboratory of Dr. Brian Popko. Pedro completed his Ph.D. in Chemistry at the University of Chicago in 2011 and subsequently joined Dr. Popko’s laboratory to pursue novel ideas for therapeutics and diagnostics for MS.
Q: How did you both become involved in MS research?
Brian: Pedro’s story is probably the most interesting. He was a graduate student here working on a chemistry Ph.D. He has a friend with multiple sclerosis and was thinking about the disease and the problems that individuals with this disease are faced with. While still a graduate student, he came up with some ideas regarding confronting these issues and developed these ideas to the point where he wrote them up and showed them to me and other MS researchers around campus to see whether these ideas made sense. When I saw them, I thought they were actually very exciting and very novel, and so after meeting on and off for about six months, Pedro decided to join my lab to pursue these ideas.
Pedro: While I was working towards my Ph.D. in Chemistry at the University of Chicago, a person close to me was diagnosed with MS, this event lead me to seek information about the therapies available for MS patients and those in the pipeline. A few months later I became aware of a need for better diagnostics for MS and I thought that perhaps we could use chemistry to turn a recently approved drug for MS into a diagnostic. I discussed this idea with Brian, who is an expert on the mouse models needed to test the idea, and a few months later we decided to pursue the project together. For this project we also collaborate with Drs. Appelbaum and Chen from Radiology and Dr. Bezanilla from Biochemistry. I feel very fortunate to be able to work with these renowned professors on a project that could have a positive impact on MS patients.
Q: Pedro, what was your idea and how did it evolve into your current study that was awarded the grant funded by the Illinois State Lottery?
Pedro: The original idea consisted in taking an existing drug, radiolabeling it with a positron emitting isotope and using it as a diagnostic tracer for PET. If this drug selectively targets the lesions in MS, as we have reasons to suspect, this approach could offer new ways to image the lesions in MS patients, which would be very exciting because currently there are no PET tracers for MS available. A PET tracer for MS could provide a better way to assess the progression of the disease and perhaps even detect the disease earlier in the process. In addition, in order to make this drug suitable for radiolabeling we had to make some chemical modifications to the drug. During this process we realized that these modified versions of the drug had slightly different pharmacological properties and could potentially be useful therapeutics for people with MS.
Brian: To summarize, the gist of the project is to take an existing drug that has already been approved in MS patients, modify it in ways that Pedro has insight into because of his chemistry background that might both enhance its activity as a mobility drug and also perhaps to modify it in such a way that it may be used as a PET imaging tool to directly visualize the lesions that occur in MS patients.
Q: Currently, how is MS diagnosed, if not with a PET scan?
Brian: Primarily, MS is diagnosed based on a clinical evaluation aided by MRI. MRI is really an indirect assessment of the pathology of the disease. A PET scan would provide a much more direct diagnostic tool. There are currently no PET tracers for MS, so if we succeed we could create a very useful tool.
Q: Who might this drug benefit?
Pedro: The current drug works on about one third of patients, but at any stage of the disease. It works on those who have a mild disability to those who have severe disability. We hope that the drug we’re developing would continue to benefit patients at every stage and perhaps benefit a larger subset of patients, more than the one third that benefit from the current drug.
Q: What is the importance of mouse models?
Brian: MS is a very complex disease. You have an immune component, a CNS component, a clinical component. You have an immune response that attacks myelin, you have infiltration of immune cells in the CNS, you have demyelination, you have loss of oligodendrocytes and in certain situations you have recovery from that, the immune system dampens down, you have remyelination and repopulation of myelinating cells. There’s a lot going on, and scientists like to reduce things down to their simplest possible configurations. What we try to do with our mouse models is to dissect out all of these complexities so that we can focus in on one aspect of MS. We have one mouse model in which we cause the oligodendrocytes to die. We have other mouse models that have focal demyelination events and can be used for imaging lesions for this project. We have mouse models in which we can induce an immune response. Any one mouse model is not going to get you very far, but the combination of the models really allows you to put each aspect of MS into a bigger context.
Q: You mentioned that MS is a complex disease. What do you think the biggest challenge that MS research faces?
Brian: MS is a relapsing-remitting disease. In the early stages where you have infiltration of the immune system into the CNS you have demyelination, but you also get recovery. But over time, those relapses become worse and the recovery becomes less. So MS switches from a relapsing-remitting disorder to a progressive disease, where you don’t recover from the neurological failure. There are drugs on the market that are very good at limiting or completely blocking the immune response and so are very good at managing the relapsing-remitting forms, but the long-term, progressive form of the disease is really quite an unknown entity. I think that as we go down this road more research needs to be focused on the chronic stages of MS.
Pedro: One challenge that I think research commonly faces is that it’s difficult to translate the basic discoveries in the lab to the patient. We are hoping that because we are starting with a drug that is already being used and only modifying it to make to better and to add an application, we can perhaps bypass this challenge.
Q: How have you seen research in the field of MS change in the past 10 years?
Brian: The past 10 years have seen tremendous advancements. Ten years ago there was one drug on the market, interferon beta, which provides only marginal benefit. Now there are a number of drugs that have a dramatic effect on the disease course. So, as far as management of the disease, the neurologists have a much better capacity to ameliorate the significant clinical symptoms. As far as the science aspects of it, we know a lot more, we have better animal models today than we did a decade ago, we have a much better understanding of the remyelination process, although we still need to know much more. When you demyelinate an axon, you do two things: One, you prevent it from conducting its electrical signal and secondly that axon becomes much more prone to degeneration. Although the central nervous system has the capacity to remyelinate the axon, it doesn’t have the capacity to regenerate the axon. So with that understanding it became absolutely clear that efforts to enhance remyelination are critical because not only are you restoring the physiological function of the neuron, you’re protecting it. It’s generally believed that the chronic progression of this disease is due to the accumulated loss of axons. We have generated a mouse model in which we can kill all of the oligodendrocytes and eliminate all of the CNS myelin from the mouse and although the mouse gets very sick, it has the capacity to regenerate all of its oligodendrocytes, remyelinates its axons and clinically it recovers to the point where you aren’t able to distinguish this mouse from a mouse that hadn’t gone through the disease process. Using this mouse model among others, we are learning a lot about the remyelination process which is something that we didn’t talk about 10 years ago.
Q: Obviously a lot of progress has been made in the last decade. What are your hopes from the next 10 years of MS research?
Pedro: I’m going to speak more from my personal interest here, it would be great if the causes were better understood so that we can prevent the disease from happening and I really hope there will be therapies that will stop progression completely or, even better, therapies that will reverse the disease. In the meantime, I hope that work like ours will help people manage the disease better.
Q: Why is it taking longer to develop drugs that promote remyelination versus drugs that suppress the immune system?
Brian: The immune system has been studied for a very long time and drugs that inhibit or dampen the immune system have been developed for lots of reasons. For example, transplant patients need such drugs so that they can accept donor organs. Drugs that will enhance remyelination are much more difficult to think about because our understanding of the myelination and remyelination processes is less than that of the immune system. It’s a much more difficult question and hasn’t received the same amount of focus. But recently this question of remyelination has received increased interest and we are seeing progress.
Q: And do you think with this recent focus on remyelination, we will see advancements in drugs that will not just stop inflammation but target the root of the disease?
Interview conducted by Talia Weiss, Greater Illinois Chapter Intern, Marketing Department - Winter 2013