THE STATUS OF REMYELINATION

   So, what’s taking so long? After all, the Apollo Project was announced in 1961 and met its goal of putting a man on the moon in 1969! The incredible achievement of a lunar landing was a marvel of what excellent planning, top-notch engineering, and a virtually unlimited budget can do to address a well-defined problem. That is, for the Apollo Project a series of steps could be clearly defined that, taken in a known sequence, ended with Neil Armstrong’s one giant step for mankind.

   Ah, if only remyelination were that simple (and only a fool would argue that the Apollo Project was simple). Re-myelination is an ill-defined problem, more like trying to drive from New York to Los Angeles without maps, road signs, a compass or even a highway system. The goal is well defined, but the means to achieve the goal are not quite so clear. That doesn’t mean that we can’t get there. By their nature, problems have solutions, and we have made significant progress toward that solution.

   Since the inception of The Myelin Project nearly 20 years ago, we have learned quite a lot about how myelin is formed. More to the point, we have been able to use this new knowledge to formulate better strategies to repair damaged myelin. Last summer, I asked nine Myelin Project Scientists to comment on the state of progress in myelin repair. I’ve summarized their answers here.

   Dr. Robin Franklin (Cambridge University, U.K.) has observed that the process of myelin repair was initially envisioned as linear. That is, there was thought to be one and only one specific sequence of events that culminated with replacement of lost myelin. We have now come to understand that the repair pathway is more like a web, with many possible branch points. Even more complicated, the specific pathway that yields myelin repair for one kind of insult may be quite different for a different lesion. However complicated it might sound, this may actually be good news. Dr. Franklin has re-stated the problem by comparing it to the children’s game of pick-up-sticks. As you will remember, the objective of this game is to remove sticks from a pile without making the remaining sticks move. In essence, the unnecessary sticks are removed, and by doing so, the necessary sticks are identified. In myelin repair, we want to identify those necessary sticks. That is, current research is focusing on those pathways that are common to all myelin repair.

   Dr. Anik Barone (Hopital Salpetrier, Paris, France) expanded on this theme, pointing out that oligodendrocytes, the cells that form brain myelin, have a very long life in normal neuronal tissue, so that myelin repair in normal brain is an infrequent event. However, even though infrequent, normal neuronal tissue is fully equipped to repair the occasional lesion. It is clear that the precursor cells are present even in demyelinating brains, such as from patients with MS. In the early stages of relapsing-remitting MS, it is thought that repairs are indeed made. In the later stages, however, repair fails, even though there are still demonstrable oligodendrocyte precursors. So the question is, what is stopping them from making the necessary repairs?

   Dr. Ian Duncan (University of Wisconsin, U.S.) noted some major advances in remyelination research. A few years ago, myelin-forming cells from outside the central nervous system were successfully transplanted into the brain of an MS patient. Although the procedure did not result in functional improvement, it did provide proof of principle that transplantation may be a reasonable method of myelin repair. Dr. Duncan also noted that limitations of this technique might be generating enough cells on a continuing basis, and determining how to direct them to the appropriate areas of the CNS.

   Dr. Gianvito Martino (San Rafael Institute, Milan, Italy) transplanted myelin-forming cells into the brains of rats with demyelinated lesions. When he examined the brains later, he was not surprised to discover that remyelination had occurred, but was surprised to discover that the new myelin was not from the transplanted cells. Dr. Martino has called this phenomenon the "bystander effect", where the transplanted cells "persuade" the stem cells already present in the brain to form new myelin. Even better, the transplanted animals showed significant functional improvement. If we can find out how the "persuasion" occurs, it might be possible to develop drugs that mimic the process.

   For Dr. Inderjit Singh (Medical University of South Carolina, U.S.) understanding the environment in which transplanted cells communicate with each other and with brain stem cells is a critical issue not yet addressed. Dr. Singh has found that statins (the same drugs that are used to treat high cholesterol) may be useful in controlling the inflammatory process in the brain. Along with Dr. Duncan, Dr. Singh has observed that not all inflammation is damaging, and that the inflammatory process is actually helpful in myelin repair. Dr. Singh’s studies with statins may help to lead us to drugs that will help to control inflammation in a helpful way, while limiting its harmful effects.

   Dr. William Blakemore (Cambridge University, U.K.) noted that one of the accomplishments of the past 20 years has been transplantation of cells into the brain in such a way as to provide a constant source of precursor cells for remyelination. This may be most important in treating the leukodystrophies, where the existing brain stem cells carry the defective gene. In that case, it becomes critical to discover which of several possible cell types has the greatest potential to remyelinate, and whether that cell type changes for different demyelinating diseases.

   Both Dr. Sam Ludwin (Queens University, Ontario, Canada) and Dr. Franklin have stressed that axonal preservation cannot be overemphasized, for without functional axons, remyelination is futile. Dr. Ludwin has observed that, in other tissues, the blood supply and the blood vessels themselves are critical to the inflammatory process. We are only beginning to understand how that relationship functions in the inflammatory process of demyelination and myelin repair.

   When I pause to think about where the research was just a few years ago, and look at where it is today, I realize that we are making progress, albeit slowly. We have a great deal more to do before achieving our goal of myelin repair for all of the demyelinating diseases. Like you, I am not satisfied with the pace of research. We can do better. With your continued generous support, we will.

We have now treated all of our intended six patients in Bristol in our phase one safety/feasibility study of autologous bone marrow cells in MS. All had longstanding disease which had resulted in some measure of persistent functional difficulty. We are now carefully and intensively examining and testing all these individuals over the next few months, with various types of scanning and clinical neurophysiological tests to help investigate function in different brain and spinal cord pathways. The results of this study will, we hope, be fully analyzed before the middle of 2008 - just a month or two after the last-treated patient completes their period of monitoring. We are, of course, very grateful indeed to these 6 individuals who have shown courage and enormous commitment in taking part in our study, and in complying with the really quite demanding schedule of repeated visits and tests. The study is currently being coordinated by a trainee neurologist currently doing this as a full time research project, funded generously for 12 months through The Myelin Project.

Our aims and hopes are that, when these results are completed, and of course assuming that safety is indeed confirmed, we will move on to a larger trial as soon as we can - though of course, the current study is primarily designed to look for unexpected adverse events, and if these should emerge, our plans would naturally have to alter significantly. The other major factor that could, of course delay our next trial is funding, which we know will represent a major hurdle.

Finally, our laboratory research is also making good progress - studying the same adult human bone marrow cells that patients are receiving, so as to understand better their basic properties and their capacity for contributing to tissue repair in MS. A Myelin Project-funded laboratory technician plays a key role in this.

These findings will have a significant impact on the design of our second clinical trial - our MS therapy work is therefore constantly and very closely integrated with our experimental laboratory research.

We remain of course extremely grateful to the Myelin Project for its invaluable support, and also for the encouragement it gives to our efforts.

Professor NJ Scolding, FRCP PhD

Neil Scolding trained in medicine in Cardiff, and in neurology in Cambridge and at Queen Square, London. He completed a PhD on the neurobiology of multiple sclerosis in Cardiff. In 2005 he was appointed Director of the Burden Neurological Institute (BNI), and developed new MS Stem Cell Laboratories in the BNI opening in 2007.   His clinical and research interests have always centered on inflammatory brain disease, and in particular on the biology and treatment of multiple sclerosis.  In addition to research papers, he has edited or co-edited three neurology or neuroscience textbooks.

We continue our work on myelin repair in the central nervous system in models of multiple sclerosis and the inherited myelin disorders of childhood. A major initiative is in the isolation of cells of oligodendrocyte lineage from human sources. We are working with both human embryonic stem cells and neural stem cells, studying their differentiation to oligodendrocytes. We will transplant such cells into animal models of acquired and inherited myelin disorders and study their remyelinating properties by contemporary imaging techniques. We are particularly interested in studying myelin repair in Krabbe’s disease and are exploring methods of supplying the missing enzyme to both central and peripheral nervous systems to prevent oligodendrocyte and Schwann cell death and subsequent demyelination.

SOS

The Myelin Project hopes to raise enough money to fund the development of a newborn screening test for adrenoleukodystrophy. Please give generously. No donation is too small.  We need your help to save our sons and daughters from the ravages of demyelinating diseases.

Please join us in Fort Worth, Texas October 28 – November 2, 2008 for the Annual Meeting of The Myelin Project. This meeting will be held at the famous Fort Worth Stockyards Hotel. The Stockyards Hotel was established in 1907 and is listed on the National Register of Historic Places.

"Step back in time by stepping into the Stockyard Hotel, the shining star of the Stockyards National Historical District in Fort Worth, Texas. Experience an era when cattle and cotton were common currency, outlaws were folk heroes and a single hotel was known around the world for Texas-style hospitality and comfort".

LORENZO’S OIL

 

The movie Lorenzo’s Oil is available from The Myelin Project office.