An Overview

The Myelin Project aims to accelerate research on myelin repair. Myelin, the white matter insulating the nerves, allows the conduction of impulses from one part of the body to another. It can be destroyed by hereditary neurodegenerative disorders, such as the leukodystrophies, and by acquired diseases such as multiple sclerosis. All together, demyelinating diseases affect an estimated one million people in the industrialized countries alone.

Behind the Myelin Project is a multinational gathering of families struck by one demyelinating disease or another. Refusing to accept the conventional view that science cannot be hurried, they resolved to advance the moment when myelin could be restored. They have done this by creating a framework in which researchers can cooperate effectively, by giving scientists adequate, prompt financing and by continuously interacting with them. To counter researchers' endemic conservative stance, we at The Myelin Project constantly remind them of two aphorisms: “fortune favors the brave,” and “you never know until you try.” The founders of the Project are Augusto Odone and his late wife, Michaela Odone. Their only child Lorenzo is afflicted with adrenoleukodystrophy (ALD). Although not medical doctors, the Odones developed a therapy, now adopted on both sides of the Atlantic, that reverses the biochemical defect of ALD. The story of the Odones' struggle against ALD was dramatized in the 1992 Universal Studios release Lorenzo's Oil, starring Nick Nolte and Susan Sarandon.

The Myelin Project headquarters are in the Washington, D.C., metropolitan area, the location of NIH and other sophisticated research facilities, and one of the world's principal centers for medical research. The Myelin Project includes branches in Britain, France, Germany, Italy, Switzerland, and Dubai. Neither Project president Augusto Odone nor the other members of the Board receive compensation. In Britain, France, Germany, and Dubai, the Project officers are also volunteers.

Inspired by the great projects of the past (e.g., Project Apollo) which used a motivated, time-conscious approach to attain specific goals, The Myelin Project has set up a Work Group from among the top international laboratories specializing in myelin repair. The Work Group includes researchers from Yale University, Mount Sinai Medical Center, and the University of Wisconsin at Madison in the U.S., the Istituto Superiore di Sanitá and San Raffaele Scientific Institute in Italy, the Collège de France, the Hôpital de la Salpêtrière, and the Institut Pasteur in France, the Queen's University at Kingston in Canada, the University of Cambridge in the United Kingdom, and the Max-Planck-Institut in Germany.

With the Apollo Project, the Moon was the objective. With the Myelin Project, remyelination is the objective.

The Myelin Project targets its funds toward clinically oriented experiments on the cutting edge of remyelination research. Basic research and studies directed toward the advancement of science for science's sake are excluded from Project financing.

As of June 2002, The Myelin Project has financed 29 experiments for a total of approximately $4,000,000. The year 2001 marked a turning point for The Myelin Project, when Schwann cells were transplanted into the brain of an MS patient for the first time in medical history. Currently, several other promising research projects await our funding. In order to finance them, the Project needs increased resources.

We would be grateful if you would consider helping us. Supporting our work will not only be humanitarian, but will also make good business sense:

• Our administrative costs range from 11% to 15% of total receipts, depending on the year. We intend to continue to keep them within this range.

• Your donation will go toward financing practically oriented experiments conducted within the framework of a coherent overall plan, thus avoiding any dispersion or dilution effects.

Financing experiments is only one of the Project's features. As Dr. Ian Duncan, one of the Work Group's scientists, put it in an interview with People magazine, “The Myelin Project has given us more than money... it has given us inspiration... added a focus to our work and has provided us with a human context.”

Demyelinating Diseases In Brief

Demyelinating diseases are those in which myelin is the primary target. They fall into two main groups: acquired diseases and hereditary neurodegenerative disorders.

Acquired Diseases

The most common of these is multiple sclerosis (MS), which usually manifests itself between the 20th and 50th years of life. Current estimates are that approximately 2.5 million people worldwide have MS, with between 250,000 and 350,000 cases in the United States, 50,000 cases in Canada, 130,000 cases in Germany, 85,000 cases in the United Kingdom, 75,000 cases in France, 50,000 cases in Italy, and 11,000 cases in Switzerland.

An oligodendrocyte (center) is capable of myelinating several axons.
This illustration shows how myelin forms wrapped layers around the axon.

MS attacks the white matter of the central nervous system (CNS). In its classic manifestation (90% of all cases), it is characterized by alternating relapsing/remitting phases with periods of remission growing shorter over time. Its symptoms include any combination of spastic paraparesis, unsteady gait, diplopia, and incontinence.

Hereditary Neurodegenerative Disorders

This category includes the eight identified leukodystrophies:metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus-Merzbacher disease and Alexander's disease. The first six are storage disorders. The lack or the malfunctioning of an enzyme causes a toxic buildup of chemical substances. In Pelizaeus-Merzbacher disease myelin is never formed (dysmyelination) because of a mutation in the gene that produces a basic protein of CNS myelin. The etiology of Alexander's disease remains largely unknown.

The clinical course of hereditary demyelinating disorders, which usually tend to manifest themselves in infancy or early childhood, is tragic. Previously normal children are deprived, in rapid progression, of sight, hearing, speech, and ambulation. Equally tragic is their prognosis: death within a few years.

A number of government agencies and private foundations currently support research on various myelin diseases. Some efforts focus on identifying the cause of individual diseases; others are directed toward developing therapies for arresting disease progress or preventing onset.

In contrast, little attention is being given to the problems of repairing damage already done by the disease and of restoring lost function. Laboratories working on remyelination are relatively few in number and their programs are under-funded. In addition, rivalry among researchers is intense. Laboratories tend to work in isolation, learning of each other's progress through medical journal articles which are usually published a year or two after experiments are completed. This fragmented approach is clearly unsuitable to regenerating CNS myelin, a complex task which requires multi-disciplinary skills.

Scope and Strategies

Scope

Since myelin loss leads to the reduction or blockage of nerve impulse conduction, myelin regrowth would logically restore conduction in diseases for which therapies capable of halting demyelination have already been found (e.g., phenylketonuria, Refsum's disease, which are treatable, mainly through restricted diets). But regenerating myelin may also be beneficial in demyelinating diseases for which no effective treatment has been developed (e.g., multiple sclerosis). Indeed, the new myelin may well be able to withstand attack by the primary demyelinating agent, either permanently or for a long period of time.

Strategies To attain its objectives, The Myelin Project relies on three major strategies: prompting researchers to work as a team and coordinating their research efforts, promoting interaction between researchers and laypeople, and rapid financing of practically oriented experiments.

The annual meetings of the Work Group as well as several teleconferences during the year provide a forum for exchanging information on member laboratories' respective work programs. They also serve to establish or strengthen personal ties among participating researchers, who now have come to see themselves as teammates rather than rivals. Today researchers visit each other's laboratories and join forces to conduct Project-financed experiments. They also exchange papers on the progress of their experiments continuously, even before publication.

2001 Work Group Meeting

Interaction between researchers and laypeople has been achieved at different levels. The presence of informed representatives of the families at scientific meetings (a quiet reminder that the objective of medical research is to save human lives) has served to provide researchers with increased motivation and focus. In some instances, we have helped researchers solve practical problems (e.g., assistance in locating and obtaining rare animal models; providing for quick transport of brain tissue from one laboratory to another).

The Myelin Project staff makes it a point to process requests for experiment funding rapidly—in a matter of weeks, rather than years. Two factors contribute to cutting down processing time:

Proposals are reviewed within the Work Group, rather than by external committees, with the occasional addition of one outside reviewer. Reviewers are given a 3-week deadline for sending in their comments. The Myelin Project is managed in a businesslike, "no red tape" fashion. Being victims themselves, or relatives of victims of a demyelinating disease, the members of our boards of directors are naturally committed to moving research along at the fastest possible pace.

The Myelin Project Progress Report

December 9, 2002

Dear Friend of The Myelin Project,

We are pleased to report in the following paragraphs the progress we made over the last year.

The 13th Annual Meeting of The Myelin Project Work Group took place Nov. 7-9 in Bal Harbour, Florida, with the participation of thirty-six scientists and a similar number of laypersons. The scientists included several prominent clinicians, a sign that our efforts to move research to the clinical stage are coming to fruition.

In an update of the Schwann cell transplantation trial at Yale, Dr. Timothy Vollmer reported that his team is still reviewing the results of the biopsies taken from the second and third transplanted MS patients. Dr. Vollmer said that he has not seen evidence of either cell survival or new myelin formation so far, but cautioned that no final assessment could be made before the ongoing review is completed. Assuming that no positive result emerges from this review, the question then arises as to whether we should go ahead with transplanting the remaining two patients according to the current protocol or whether we should modify the trial design, for instance by planning to use other cell types. We agreed with Dr. Vollmer that we would cross that bridge when we have the final biopsy results. Dr. Vollmer also reported that none of the three patients transplanted so far suffered complications from the operation, confirming the safety of the procedure, an important achievement in itself. Although Dr. Vollmer has recently moved to the Barrow Neurological Institute in Phoenix, Arizona, he continues to oversee the Yale trial.

Dr. Gianvito Martino and his collaborator Dr. Fulvio Mavilio, both of the San Raffaele Scientific Institute in Milan, presented their progress report after the first year of a three-year experiment sponsored by The Italian Branch of the Myelin Project.

The researchers are employing a two-pronged approach in MS: transplantation (via injection) of neural stem cells; and gene therapy using a viral vector, to deliver anti-inflammatory and neural growth factors into the brain. These approaches do not involve neurosurgery, as the cells are injected by either intravenous or intrathecal (i.e., into the cerebrospinal fluid) routes. Dr. Martino has been working so far with adult neural stem cells in the mouse model of experimental allergic encephalomyelitis (EAE), a condition similar to MS. In the course of their work, the researchers found that the injected cells were able to enter the brain, home in on demyelinated areas, appear to differentiate into oligodendrocytes (the myelin-producing cells in the brain), and remyelinate axons. The injected cells were also shown to rescue native oligodendrocyte progenitors through a “bystander” effect that restrains the production of two growth factors that normally appear following injury, and which prevent oligodendrocyte progenitors from repairing damaged myelin. The transplanted cells' neuroprotective effects were sustained, lasting up to 100 days. Dr. Martino also reported that the treated mice showed significant remission of EAE neurological deficits as compared to untreated control animals.

For his part, Dr. Mavilio has been working on developing an enhanced vector, in which researchers remove the pathogenic “guts” of a virus but leave the shell, and use it to carry beneficial genes into cells in the body. In particular he succeeded in engineering a vector capable of carrying genes that code for growth and anti-inflammatory factors. In 2003, the San Raffaele team will begin experimenting in monkeys. If those studies are successful, they intend to move to human trials.

Dr. Anne Baron-Van Evercooren has submitted a proposal for a new experiment with monkeys. Working with clinicians at the Salpêtrière Hospital in Paris, she plans to transplant Schwann cells into monkeys with EAE, which closely mimics the inflammatory demyelinating environment of MS in humans. In particular, the researchers intend to implant the cells into focal lesions in the cerebellar peduncle, a site at the rear of the brain. Demyelination in this site often results in impaired movements and tremor in MS. In contrast to the Yale trial, which uses cells extracted from the patients one day prior to the operation, Dr. Baron-Van Evercooren will implant cells that have been expanded with a mix of growth factors in the lab over a period of several weeks. Working first in rats, the researchers will try several techniques with regard to: labeling the cells; the route of delivery (surgical implantation or injection); and MRI imaging. The optimal methods will be selected for the subsequent monkey experiments, at the end of which the researchers will verify the MRI images with extensive laboratory analyses of the monkey tissue. This last step will allow in-depth examination of Schwann cell survival and remyelination potential. The two-year study is designed as a prelude to a clinical trial. We are circulating Dr. Baron-Van Evercooren's proposal to the Myelin Project Work Group for review; if the response is positive, we intend to finance the study.

In yet another international collaboration promoted by The Myelin Project, Dr. Baron-Van Evercooren is considering joining forces with Dr. Martino and his colleagues; both groups' monkey experiments have aspects in common and have recently received European Union approval.

In the past we have sponsored studies by Drs. Etienne-Emile Baulieu and Michael Schumacher on the remyelinating abilities of steroidal hormones in MS. At the annual meeting, Dr. Baulieu and colleagues elaborated on a proposal for a clinical trial to examine the use of progestin (a synthetic form of progesterone), in 200 post-partum women with MS. Pregnant women with MS generally experience a decline in relapses during the third trimester of pregnancy, followed by a sharp increase in the three months post-partum. The trial, which aims to prevent relapses, will be randomized, double-blind, and placebo-controlled. For three months after giving birth, women will be administered progestin and estradiol, a form of estrogen. Trial participants will be evaluated at several points during pregnancy, and at one, three, and six months post-partum. Drs. Baulieu, Schumacher, and trial coordinator Dr. Martine El-Etr are from the Bicêtre Hospital in Paris; they will be collaborating with neurologist Dr. Christian Confavreux of the Hôpital Neurologique in Lyon.

The only problem with this study is its cost—approximately $1 million. Whether we might finance part of this cost depends on the volume of donations we receive in the coming months.

Two of our Work Group members, Dr. Inderjit Singh (who could not come to the meeting) and Dr. Vollmer, have conducted a multicenter trial of the cholesterol drug simvastatin in MS patients (see our previous reports), funded by Merck & Co. Dr. Vollmer will report results of the trial when analysis of the data is completed. Simvastatin's potential as a therapy for MS was highlighted in a study published last month in the journal Nature and echoed in the New York Times. The authors included some renowned MS researchers on the West Coast of the U.S.

Earlier this year we had given Dr. Ian Duncan and neuroradiologist Dr. Aaron Field, both of the University of Wisconsin-Madison, a grant to study the feasibility of repairing spinal cord lesions in MS via cell transplantation. A significant subset of MS patients have lesions in their spinal cord that account for most or all of their symptoms. Part of the grant was for MRI studies aimed at gauging the size of the lesions and at determining whether axons had survived. As a prelude to scanning MS patients, the researchers used advanced MRI techniques to image the brain of the shaking pup, an animal model for Pelizaeus-Merzbacher disease. The data showed low levels of myelin, but bundles of relatively intact axons available for remyelination. In the next few months, they will verify these findings by microscopic examination of the tissue in the lab. The next step will be to use the MRI techniques to characterize spinal cord demyelinating plaques in MS; Dr. Field reported that a group of 10 MS patients has now been selected to undergo MRI scanning.

Last year we awarded a grant to Dr. Su-chun Zhang, of the University of Wisconsin-Madison, to develop cells that can repair or replace damaged myelin. One year into the program, Dr. Zhang reports that he has succeeded in guiding undifferentiated embryonic stem cells to become neural cells. He also has figured out a method of inducing a proportion of these cells to differentiate into oligodendrocyte progenitors (OPs). Next year his task will be to refine the process so as to increase the number of OPs produced, and then to see if they produce myelin. To verify this latter point, Dr. Zhang intends to transplant the cells into both congenitally dysmyelinated shiverer mice and chemically demyelinated mice.

Dr. Evan Snyder of Harvard Medical School talked about his experiment with neural stem cells in twitcher mice, an animal model of Krabbe disease in which the accumulation of psychosine causes cell death. Following transplantation of the cells, he could observe a significant reduction in psychosine levels—a result that indicates that cell replacement therapies with neural stem cells are possible. He mentioned that even better results in demyelinated animals could be obtained by transplanting stem cells engineered to express growth factors-an approach he is currently trying in shiverer mice. Lastly, he reported that, surprisingly, stem cells did not appear to transdifferentiate into native neurons, oligodendrocytes, or astrocytes, but remained undifferentiated. Nevertheless, they promoted remyelination, and produced a host of beneficial neurotrophic factors.

It is not very often that we can report good news in the leukodystrophies, but this time we are.

Dr. Hugo Moser of the Kennedy Krieger Institute in Baltimore presented the results of 10-year international study on the preventive efficacy (or lack thereof) of Lorenzo's Oil in adrenoleukodystropy (ALD). The study involved 104 presymptomatic ALD boys under six years of age, from both the US and Europe. Two groups emerged in the course of the study: the first included those boys who followed the Lorenzo's Oil regime scrupulously, and normalized their very long chain fatty (VLCFA); in the second were those boys who were less strict with the regime and whose VLCFA remained at abnormally high levels. A comparison of the two groups showed that the odds of developing the childhood form of the disease for the boys who adhered strictly to the regime were significantly lower than those of noncompliant boys. The oil's preventive effect was not complete, however: some boys who lowered their VLCFA levels still developed the childhood form of ALD. In addition, boys who escape childhood ALD (onset is generally between 6 to 10 years of age) are still at risk of developing the adult form, adrenomyeloneuropathy (AMN), which usually manifests itself in the late 20s or early 30s. Along with the main finding, another merit of the study was to demonstrate for the first time that the VLCFA indeed have a role in the pathogenesis of ALD. We have committed to award a $50,000 grant to Dr. Moser for a staff person to: follow up the boys who did not come down with symptoms within the time frame of the study; reinforce historical statistics on ALD; and prepare all data required by the U.S. Food and Drug Administration for approval of Lorenzo's Oil as a therapy for this disease. The funds will originate from donations made to The Myelin Project that are restricted to ALD research.

We are also encouraged by word from Germany about the effects of Lorenzo's Oil in AMN. Although it progresses more slowly than the childhood form, AMN is still a serious debilitating disease. Dr. Wolfgang Köhler of Saxonian State Hospital in Hubertusburg has nearly completed a clinical trial of 47 patients, and early observations suggest the oil may help arrest the progress of the disease in this disorder. All patients were subjected to an extensive annual evaluation using clinical, neuropsychological, neurophysiological and MRI techniques over a mean study period of eight years to confirm the oil's clinical efficacy. Dr. Köhler intends to publish the results of his study when it is completed, hopefully before the end of the year.

Dr. Paola Leone of the Robert Wood Johnson Medical School in New Jersey presented a progress report on a gene therapy trial for Canavan disease. She now has continuous data for one year on three patients who underwent the treatment. Dr. Leone reported that there was no neurological deterioration, no regression in developmental skills, and no significant change in gross motor function. In addition, at three to six months after treatment, she observed MRI improvement as well as a decrease in n-acetyl aspartate, the offending metabolite accumulating in Canavan's. She emphasized the importance of delivering the gene as early as possible, since this treatment yields better results in younger patients. At the end of her presentation, Dr. Leone announced that the trial will continue with a second cohort of six Canavan children.

Umbilical cord blood stem cell transplantation can be an effective treatment for several leukodystrophies, including Krabbe disease, metachromatic leukodystrophy, and ALD. Dr. Joanne Kurtzberg of Duke University Medical Center in Durham, North Carolina, presented results on transplantation in 25 Krabbe's patients, three of whom received bone marrow and the rest umbilical cord blood cells. The fatality rate due to transplantation in this group was 10%, of which half was due to graft-versus-host disease. Overall, children do not improve much in the first year, and some continue to deteriorate, Dr. Kurtzberg said. In the second through fifth years after the procedure, the deterioration stops, and some children improve slightly. Dr. Maria Escolar, a collaborator of Dr. Kurtzberg's from the University of North Carolina at Chapel Hill, reported that transplantation success depends on disease progression: the earlier, the better. Development in children transplanted under two months of age was in the normal range, while in those transplanted later, it was far below the norm.

On the promotion and fundraising front, the presentation of Dr. Moser's ALD study launched a blitz of media coverage by newspapers, magazines, radio and television outlets in Europe, North America, and Australia.

Our efforts to carry this media interest over to The Myelin Project have been strenuous, and we will continue to advance the Project whenever the opportunity arises.

In another welcome development, Susan Sarandon, the co-star of the film Lorenzo's Oil, has agreed to be our spokesperson and to promote The Myelin Project in her future public appearances.

We have worked hard on strengthening the management of the Italian and German branches of The Myelin Project, by attracting new people who have both influence and charisma. We hope that this flourishing of activities will serve to spread awareness of our project among the general public.

We count on the friends of The Myelin Project, both new and old, to expand our research program and increase our chances of arriving soon at new treatments for MS patients and leukodystrophy children alike.

Please be generous with your donations!

I would like to take this opportunity to extend to you and your family my personal wishes, as well as those of my staff, for a merry holiday season and a Happy New Year.

Augusto Odone

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We are grateful to all who helped us during the latter half of this year-too many to mention individually. However, we would like to acknowledge several whose generosity and efforts were especially helpful: