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Summer 2004 Progress Report
TO: All Supporters of The Myelin Project (TMP) FROM: Augusto Odone I. INTRODUCTION AND SUMMARY In mid-2004 we find ourselves with many pots simmering. In the transplantation area, the marmoset experiment by Dr. Gianvito Martino and Dr. Angelo Vescovi is proceeding according to plan. By year-end we should know whether the San Raffaele researchers have achieved in monkeys the same favorable results they obtained in rodents. If so, this would be the basis for the transition from animals to people, from monkeys to multiple sclerosis patients. Progress is being made in a parallel experiment, also in marmosets, by Dr. Anne Baron-Van Evercooren in France. Research is on target at the University of Wisconsin-Madison as well. Dr. Ian Duncan and Dr. Abdelmadjid Belkadi, building on their previous work in animals, have achieved remyelination in long tracts of the spinal cord of the myelin-deficient rat. For his part, Dr. Su-Chun Zhang has begun transplanting oligodendrocyte precursors, derived from embryonic stem cells, into shiverer mice. In the pharmaceutical area, TMP’s investment in preparatory work for the progesterone trial in postpartum women with MS is at last paying off; the trial is scheduled to commence at the end of this year. And Pfizer and Serono are planning with Dr. Inderjit Singh to launch a subset of their Lipitor plus Rebif study in MS, within the framework of an agreement brokered by TMP. The Myelin Project is extending its coverage of the leukodystrophies. The seminar we organized in record time for Pelizaeus-Merzbacher disease (PMD) has given impetus to research on this disease and promoted several collaborations between specialists. It has also led to new hopes that transplantation and pharmaceutical approaches may arrest the progression of PMD and possibly reverse its neurological damage. We are committing additional funds to Dr. Moser’s research on adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN), and plan to tackle metachromatic leukodystrophy in short order. Continued recession in the USA and Europe, coupled with the war in Iraq, have caused a decrease in our receipts, which have declined from $1.2 million in 2002 to $832,000 in 2003. Receipts should revive in the next several months, however, as a result of several initiatives. These include important fundraising events planned by our national branches in Britain, France and Canada; the acceptance of a popular actress to become the spokesperson for the Italian branch; and a BBC documentary in England on the Lorenzo’s Oil story and TMP. In the USA our miniscule office has been busy directing and coordinating research, evaluating the proposals received from researchers, answering patients’ queries and writing reports, such as the one you are now reading. This left little time to organize fundraising events or court firms for corporate donations. For the bulk of our receipts we rely almost exclusively on contributions from our U.S. supporters. II. RESEARCH On the transplantation front, experiments are proceeding well. The team at San Raffaele Scientific Institute in Milan, Italy, led by Dr. Gianvito Martino and Dr. Angelo Vescovi, is halfway through the second year of a two-year experiment involving transplantation of neural stem cells as a treatment for MS. As you may recall from our June 2003 report, this experiment seeks to achieve in monkeys the same positive results obtained in mice last year. In the current experiment, the researchers induced experimental autoimmune encephalomyelitis (EAE), a disease that mimics MS, in 15 marmosets, a species of monkey native to the New World. All animals receive daily treatment with cyclosporine, an immune-suppressing drug, to prevent rejection of the transplanted cells. Five of the animals received the cells intravenously, and four intrathecally (i.e., into the cerebrospinal fluid). The other six monkeys served as controls. The animals are monitored for three months; the experiment has not yet concluded, and the researchers cannot reveal any data until the analyses are completed, but thus far they have not seen any side effects from either the cell transplantation or the cyclosporine treatment. The donor cells, derived from a renewable cell line developed by Dr. Vescovi, were labeled by inserting in them a gene to express green fluorescent protein, which glows green under special light during laboratory examination. If cells in areas of the transplant glow, that is proof that the transplanted cells have survived. A parallel experiment continues in Paris, under the direction of Dr. Anne Baron-Van Evercooren. Her group at the Salpêtrière Hospital is also working with marmosets with EAE, but is pursuing transplantation of Schwann cells. Four marmosets were transplanted this spring, using Schwann cells derived from the marmosets themselves (autologous transplantation). In this experiment Dr. Baron also is labeling the cells with green fluorescent protein prior to transplantation. Dr. Baron is coordinating her study with Dr. Martino’s, which will allow the two researchers to compare the properties of neural stem cells and Schwann cells in the same animal model. In a separate experiment, Dr. Baron is developing a model in which lesions are targeted to the caudal cerebellar peduncle, an area of the brain that controls voluntary movement, in the macaca fascicularis monkey. In this model the animals should mimic the tremors experienced by MS patients. In cooperation with clinicians at Salpêtrière and a team at a national research center in Orsay, France, she will then transplant cells into these lesions, to ascertain whether they remyelinate the nerves and restore function in the monkeys. Dr. Ian Duncan of the University of Wisconsin-Madison and his research associate Dr. Abdelmadjid Belkadi report further progress in their experiment involving transplantation of oligodendrocyte progenitor cells (OPCs) into the myelin-deficient (md) rat, a strain that is born without myelin, and serves as a model for both PMD and some aspects of MS. After injecting OPCs into the spinal cord of 28 rats, the researchers found that the cells not only traveled up to 23 millimeters from the site of injection, as previously reported, but that they traveled in both directions along the spinal cord from the injection site, and that they integrated into the cord, producing extensive myelination. In a side experiment, the researchers transplanted OPCs into the brain and the cervical and thoracic areas of the spinal cord of six rats. Some animals transplanted at these sites showed the most widespread migration ever reported, with myelin-producing cells found along the upper and middle spinal cord, as well as in the sacral area. The researchers plan to confirm these results in a rat model that is longer-lived than the md strain; and to identify factors that influence the type of migration as well as the distance the cells migrate. Dr. Su-Chun Zhang from the same University is making progress as well with his stem cell experiment, notwithstanding some problems due to changes in laboratory personnel. Having succeeded in deriving oligodendrocyte precursors from embryonic stem cells, he has begun transplanting them into the shiverer mice. A laboratory test in two transplanted mice was positive for myelin. Dr. Zhang cautions that these results need to be verified in more animals with additional tests, but as an early indication, the finding is heartening. At Cambridge University in England, Dr. Robin Franklin has found that the olfactory mucosa is a readily accessible source of neural stem cells from which it may be possible to derive a plentiful supply of olfactory ensheathing cells (OECs). Although these cells do not normally make myelin, they are able to do so when transplanted to areas of demyelination in the brain or spinal cord, as shown by Dr. Franklin’s previous work in rats. One problem that impeded their use in humans, however, was finding an appropriate source. Deriving the cells from the olfactory bulb is difficult, since this lies inside the skull. Now Dr. Franklin reports that tissue from the olfactory mucosa, situated at the back of the nose but outside the cranium, may provide a viable alternative. This is an important finding since the stem cells obtained from this region may potentially provide a source not only of OECs but of other cells such as OPs. He plans a transplant study in rodents to demonstrate that stem cells from the olfactory mucosa can generate cells that will produce myelin. Dr. Franklin’s work will be funded by the U.K. Medical Research Council. Dr. Christian Confavreux in Lyon and Dr. Etienne-Emile Baulieu in Paris are getting close to launching a placebo-controlled trial of progestin a derivative of the sex hormone progesterone involving 300 post-partum women with MS (for the rationale of this experiment please refer to our preceding reports). Enrollment will be open to patients in those European countries where there are centers that participate in the European Database for Multiple Sclerosis (EDMUS), a cooperative network of MS clinicians headed by Dr. Confavreux. The study is estimated to cost $1 million. Le Projet Myéline/European Leukodystrophy Association has recently committed $300,000 to support the initial phase of the study. Other donors are expected to cover the balance of the estimated cost, once the study is under way and begins attracting attention. The use of statins in MS has received notice in the medical literature. Work Group members Dr. Inderjit Singh and Dr. Timothy Vollmer published a paper in the May 14 issue of The Lancet that illustrates the positive results of the clinical trial of simvastatin they conducted in 30 patients with relapsing-remitting MS. Dr. Singh, Serono and Dr. Gary Birnbaum of the University of Minnesota have joined forces for the next step: a clinical trial of Lipitor plus Rebif in 45 patients. Leukodystrophies In our last newsletter, we reported on the study of Lorenzo’s Oil as a preventive treatment for asymptomatic ALD boys conducted by Dr. Hugo Moser of the Kennedy Krieger Institute in Baltimore. Since then, Dr. Moser has re-analyzed the data from the trial, and found that the conclusions he presented at our 14th annual meeting last September overestimated the reduction of risk, or hazard, associated with Lorenzo’s Oil. A revised draft of the study will soon be submitted to a major neurology journal for publication. In other news from Baltimore, Dr. Moser is planning a larger clinical trial of Lorenzo’s Oil, this time in adrenomyeloneuropathy (AMN), the adult form of ALD. The proposed trial will involve 200 patients, 100 men and 100 women (female carriers also tend to develop symptoms in the later decades of life). While several public agencies will provide the bulk of the funds, the Kennedy Krieger Institute and TMP have agreed to join forces to seek complementary financing with money raised from private donors.
In March of this year, The Myelin Project convened a workshop on Pelizaeus-Merzbacher disease (PMD), a leukodystrophy for which so far no remedy has been developed. We sponsored the meeting jointly with the PMD Foundation of the U.S. and the European Leukodystrophy Association. Participants in the meeting included 12 doctors from several countries specializing in PMD and as many parents of boys struck by the disease. The meeting reviewed possible approaches to therapy in light of the advances in the understanding of the cellular and molecular bases of PMD, a disease that is characterized by abnormalities in the formation of myelin. While the meeting did not come up with any magic therapeutic suggestion, putting researchers in a room together did achieve some positive results. Thus the meeting served to reinforce existing relationships between researchers and to establish new ones. After some spirited discussions, a general consensus appeared to take form on research priorities. Most importantly, the meeting gave rise to specific collaborations. For example, Dr. Odile Boespflug-Tanguy, the head of an INSERM unit in Clermont-Ferrand, France, and Dr. James Garbern of Wayne State University in Detroit, Michigan, decided to harmonize the collection of key PMD clinical data, such as MRI scans. Lastly, Dr. Klaus-Armin Nave of the Max-Planck Institute in Germany will submit a proposal to The Myelin Project for a study of a pharmacological gene therapy, aimed at affecting gene expression in a murine model of PMD.
It may be too soon to declare a victory for gene therapy, but the news so far is good: In the clinical trial of gene therapy for Canavan disease led by Dr. Paola Leone of Robert Wood Johnson Medical School in Camden, N.J., four of the seven treated patients are showing an increase in markers for brain myelin. This study represents the first success of gene therapy for a neurodegenerative disorder. The four youngest patients in the trial have markedly improved both biochemically and neurologically. As for the three oldest, they too experienced clinical improvement, albeit to a lesser extent. All the treated children were between 2 and 5 years old when treatment began. In collaboration with researchers at Children’s Hospital of Philadelphia and the University of North Carolina at Chapel Hill, Dr. Leone will continue the trial this summer with five additional patients between 12 and 24 months of age. Dr. Joanne Kurtzberg, of Duke University Medical Center in North Carolina, has for some time transplanted umbilical cord blood stem cells into the bloodstream of children with leukodystrophies, such as Krabbe disease, generally with favorable results. While these children show language and cognitive improvement, some still have serious deficits in lower motor functions, such as walking. One reason may be that the donor cells do not reach, or reach too slowly, the brain area that controls those functions. The recent isolation ex vivo in Dr. Kurtzberg’s lab of oligodendrocytes from human cord blood prompted a new strategy to address this issue: expansion of the cells in culture followed by direct injection into the ventricular fluid or into brain tissue. Dr. Kurtzberg is now seeking FDA permission for a Phase I safety trial of the new cells, involving their transplantation into the brain in six children with advanced leukodystrophies. If the cells prove safe, Dr. Kurtzberg and colleagues will conduct a second trial to prove their potential efficacy in 20 children who have already undergone cord blood transplants but still have deficits, using oligodendrocytes isolated from their cord blood donor.
III. FINANCIAL OVERVIEW In 2003 we devoted $700,000 to research, of which approximately $475,000 was disbursed directly to researchers for their experiments. Additional research expenditures included costs for the 14th annual Work Group meeting last September in Acqui Terme, Italy. Communication costs also accounted for a significant share of research expenditure, particularly at our Headquarters office just outside Washington, D.C. In line with its function as TMP’s nerve center, Headquarters held several teleconferences with researchers to coordinate their work and make rapid decisions. Although administrative costs declined somewhat in absolute terms from last year, they were higher as a percentage of receipts (18.8% in 2003 versus 13.1% in 2002). This is explained by the sizable decline in receipts from 2002 to 2003, as mentioned in the introduction, rather than by a ballooning of our costs. On the other hand, administrative costs as a percentage of expenditures remained essentially unchanged from 2002.
IV. PLANS AND STRATEGIES As in recent years we intend to concentrate our funding on human trials or animal experiments that will lead directly to the clinic. In line with our increased focus on the leukodystrophies, we will direct a larger share of our resources to research on these diseases. We have thus earmarked funds for Dr. Moser’s clinical study of Lorenzo’s Oil in AMN and for Dr. Nave’s experiment involving pharmacological gene therapy in a mouse model of PMD. We also stand ready to finance research on new therapies for metachromatic leukodystrophy. This focus on leukodystrophies in no way means that we have diminished our interest in MS, however. We have already committed a sizable amount to the international clinical trial of progesterone by Dr. Confavreux and Dr. Baulieu. We are also prepared to make additional grants out of our contingency funds to Dr. Martino for a potential trial of neural stem cells in MS patients, and we will consider supporting Dr. Bert ‘t Hart’s intriguing project on increasing the immune system’s tolerance to myelin in monkeys.
V. FUNDRAISING Canada The Myelin Project of Canada has planned its first major fundraising event, Motorcycles 4 Myelin, for May 29, which just happens to be Lorenzo Odone’s 26th birthday. The Canadian branch has made great strides in the unglamorous but necessary business of establishing its organizational structure, which includes recruiting and voting in a board of directors and officers and registering with the appropriate government agencies. A two-on-two basketball tournament is planned for later this year, to be underwritten by corporate sponsors. The Canadian branch also is moving to increase awareness of myelin diseases and The Myelin Project by distributing a study guide for the film Lorenzo’s Oil to high school and university science teachers. France The European Leukodystrophy Association (ELA) continues to build on its solid base of successful fundraising with the assistance of stars from the worlds of sports, music, and the movies. We have a stake in ELA’s fundraising activities, since every year ELA transfers substantial amounts to The Myelin Project. On May 4 ELA held its annual television fundraiser, broadcasting in prime-time, and with no fewer than 80 celebrities on hand to answer the phones and take donations from callers. ELA also showed a 30-second TV spot featuring soccer hero and ELA patron Zinédine Zidane. The French branch also conducts fundraising and awareness campaigns throughout the year, in schools as well as among the general public. This fall, ELA/Le Projet Myéline will host the 15th annual meeting of The Myelin Project Work Group, in Nice. Germany Spencer Ryan took over as vice-president from Regina Frerks-Steinke, who will remain as the leukodystrophy representative. In May the German branch established a subsidiary, The Myelin Projekt gGmbH. This will free the branch from the inflexible regulations that encumber charities in Germany. Heike Drechsler, an Olympic Gold medal long-jumper, has accepted to become the spokesperson for the German Myelin Project after this year’s Summer games in Athens in which she will participate. In June the branch will hold a concert with the German army band, and a second benefit concert is set for July. Parent associations are pressuring the German government to classify Lorenzo’s oil as a prescription drug, a prerequisite for having medical insurance cover its cost.
Italy Just as ELA in France has Zinédine Zidane, in Italy the Comitato Italiano Progetto Mielina now has a star: this year actress Anna Maria Barbera stepped forward to become the “madrina” (godmother) of the Italian Myelin Project. Also this year, the Comitato Italiano moved to enlarge its governing body and prepare new strategies for future fundraising. One victory the Italian branch celebrated this spring was a bureaucratic one: gaining government approval to become a registered non-profit organisation (ONLUS), allowing donors to make tax-deductible contributions. Other ventures included a fund drive based around The Myelin Project Work Group’s 14th annual meeting, held last fall in Acqui Terme, in northern Italy; a charity lottery in L’Aquila, in central Italy, and the sale of Valentine chocolate hearts. Italian board member Massimo Panattoni, who owns optician shops in Acqui Terme and Canelli, is behind a new initiative to raise awareness of MS among his 450 colleagues throughout Italy, since the first symptom of this disease often presents as optic neuritis.
United Kingdom With a mixture of profound regret and best wishes, we thanked Diana McGovern for all her service as she retired earlier this year after more than 10 years as Honorable Secretary of the British Trust for The Myelin Project. Mrs. McGovern remains a trustee and an advisor. Belle, an American and doctor, now living in the U.K., has taken the helm, and brought in a flurry of ideas and momentum. The British Trust revamped and renamed its web site (www.myelinproject.co.uk); it now offers families a chance to interact via a message board. In April a number of runners participated in the London Marathon on the Trust’s behalf; in May was the first annual Myelin in the Moors Walkathon, which Belle described as “a resounding success,” with walkers from all over the U.K. A few individuals have taken strides on their own on behalf of The Myelin Project: One man, retracing the route his father took in World War II, is walking from Bury, near Manchester, to Bremen, Germany, while another is riding on horseback from Edinburgh to London to help raise awareness and funds for The Myelin Project. In July, the BBC will be air a new documentary about The Myelin Project, Lorenzo, and the invention of Lorenzo’s Oil. And in August, borrowing from the commonwealth country of Canada, the British Trust will host its own Motorcycles for Myelin event, to be held in Manchester. Instead of “Live To Ride,” the motto will be “Ride So That Others May Live.”
Switzerland The Swiss branch, in addition to conducting mailings to its members and friends, held a benefit concert in a church at Christmastime, set up an information booth at a neurology conference in Bern, inserted posters about Das Myelin Projekt Schweiz in a regional weekly newspaper, and plans to try telemarketing, in concert with a firm that specializes in this method of fundraising.
VI. CONCLUSION We have embarked on an ambitious research program pursuing several approaches to the treatment of myelin diseases, including MS and the leukodystrophies, with the hope that one or more will eventually work out. As you know, The Myelin Project is based on a spirit of private initiative—most of our funds are contributed from families struck by one myelin disease or another. Unlike other charities, we do not receive or seek funding from public agencies, which usually comes with strings attached. Our modus operandi has enabled us to process research proposals quickly, so that our scientists don’t have to fill out interminable questionnaires, as most public agencies require, and then having to wait a long time for an acceptance/rejection decision. We would like to follow through with the implementation of our research program while maintaining our private initiative philosophy. But to do this we need your help. Please be generous with your (tax-deductible) donations! This will help us fuel research on treatments for the children of the leukodystrophies as well as for the adults with MS. Please accept our gratitude for your generous donation in advance. Thank you!!! As many of you understand, we are so very grateful for each and every penny or pound that is donated to The British Trust for The Myelin Project. The responses in the past to our fundraisers have been overwhelming and we want to continue the successful campaigns. Please note however, unless it is specifically requested, we will be unable to send thank yous to all who have donated. The postal charges would be enormous. So, please accept our gratitude, in advance, on behalf of all our families here in the UK and around the world, who shall benefit from your kind donation. To make a donation, click here.
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