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I. Introduction and Summary
In the six months since our last progress report, The Myelin Project has continued to provide "start-up" money for experiments directed at translating research from the laboratory to the clinic. Confirming this trend is the commencement of two human trials of pharmaceutical therapies for multiple sclerosis.
The first will consist of a small-scale, multicenter clinical study calling for the enrollment of approximately 20 MS patients. Its aim will be to investigate whether the cholesterol drug atorvastatin (Lipitor) in combination with Rebif, a type of interferon-beta made by Swiss biotechnology company Serono, would be more effective as a therapy for MS than either drug alone.
The proposed trial is based on a protocol conceived by Dr. Inderjit Singh of the Medical University of South Carolina; it will be conducted by Dr. Singh and colleagues in South Carolina and by Dr. Timothy Vollmer of Barrow Neurological Institute in Phoenix, Arizona. Funding for the trial will come from The Myelin Project and Serono.
The co-financing of this trial by Serono is the result of our efforts over the past year to involve the pharmaceutical industry in our research. With a view to leveraging our research dollars, we will continue in our efforts to attract the interest and financial resources of pharmaceutical and biotechnology companies to trials conceived by Work Group members.
The second study will test the ability of progesterone to keep post-partum women with MS relapse-free (for details, please see our previous progress reports). The trial will be coordinated by Dr. Etienne-Emile Baulieu of HÙpital BicÍtre in Paris and Dr. Christian Confavreux of HÙpital Neurologique in Lyon. The full plan calls for a placebo-controlled study of 300 participants, but the trial will commence with an initial sub-group of 30 to 40 patients.
II. RESEARCH
Following the 14th Annual Meeting of The Myelin Project Work Group, held September 14-16 in Acqui Terme, Italy, The Myelin Project Headquarters and Le Projet MyÈline decided to provide $300,000 toward this first phase of the trial, with additional funding to come from other sources.
At the Annual Meeting, Dr. Hugo Moser of the Kennedy Krieger Institute in Baltimore and Dr. Wolfgang Köhler of Saxonian State Hospital Hubertusburg in Wermsdorf, Germany, presented the latest developments of their research on ALD and AMN, respectively.
Specifically, Dr. Moser reported on the new, stronger data from the follow-up of the international study of Lorenzo's Oil as a preventive treatment for asymptomatic ALD boys. The main conclusion of the follow-up was that lowering the levels of very long chain fatty acids (VLCFA) in asymptomatic boys dramatically reduces the risk of their developing the childhood form of the disease-the deeper the VLCFA reduction, the lower the risk.
Not only does this new study validate the conclusions of the international study, but advances its earlier findings by describing in quantitative terms the association between the VLCFA and the risk of developing the disease. In the best-case scenario, an asymptomatic ALD boy who succeeds in bringing down his plasma VLCFA levels from 0.8 micrograms per milliliter to 0.2 (i.e., the level prevailing in healthy persons) can expect a 93% drop in his risk of developing ALD symptoms. "It's absolutely astounding," Dr. Moser said. Among other things, these findings put to rest the long-debated issue of whether the VLCFA are a byproduct of ALD or whether they play a key role in the pathogenesis of the disease. They do.
Dr. Moser cautioned, however, that Lorenzo's Oil's protective effect is not absolute. The data show reduction, rather than total elimination, of the risk: Some asymptomatic boys will thus go on to develop ALD even with the Oil.
On his part, Dr. Kohler reported the results of a study he conducted on 50 patients with adrenomyeloneuropathy (AMN) who took Lorenzo's Oil for a mean period of 6.3 years. Patients were considered compliant with the Oil regimen if they lowered their VLCFA levels to normal within six months after starting the Oil, and maintained that level for at least two years. At last follow-up, 84% of the patients were found to be clinically better than what may have been expected on the basis of the natural course of the disease, while a subgroup of 48% remained stable or improved.
The clinical trial of gene therapy for Canavan disease continues: Dr. Paola Leone of the University of Medicine and Dentistry of New Jersey and colleagues treated seven patients between April and August of this year. At our Annual Meeting, Dr. Leone reported that all patients responded well to the treatment, with no adverse events. Preliminary assessment of the latest treated group showed that the gene transfer was effective in normalizing brain metabolites and water content.
In Acqui Terme, Dr. Vollmer reviewed the Schwann Cell Transplantation Trial for MS at Yale University, which in 2002 was stopped after 3 of the planned 5 patients were treated because of lack of evidence that the approach led to myelin formation. (Two patients actually did have some remyelination, Dr. Vollmer revealed, but his team was not able to prove that it was due to the transplanted, rather than to endogenous, Schwann cells.) Dr. Vollmer has already submitted a paper describing the study to a major medical journal-which will hopefully spark the interest of other laboratories to repeat the experiment with Schwann or other cell types.
Dr. Vollmer himself is considering taking another shot at Schwann cell transplantation in patients with transverse myelitis, a disease characterized by a single lesion in the central nervous system (CNS), which makes functional repair more attainable than in a multifocal disease like MS.
Since its inception, The Myelin Project has given priority to transplantation of myelin-producing cells as the approach with the greatest potential for achieving our objective: regeneration of myelin in demyelinating diseases. We have thus financed over the years a series of experiments in rodents, cats and dogs. Two studies have recently graduated from lower-order animals to marmosets (a species of monkey native to South America), a significant development, since testing a therapy in non-human primates is the final step before initiating human trials.
With partial financing from The Myelin Project, Dr. Gianvito Martino and colleagues at San Raffaele Scientific Institute in September began a new study directed at testing the ability of transplanted human neural stem cells to repair myelin damage in marmosets with experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis-like condition. This experiment will seek to replicate in non-human primates the success Dr. Martino had in mice, the conclusions of which were published in the journal Nature in April (and summarized in our June 2003 newsletter). If the results of the new study are positive as well, the San Raffaele researchers intend to move expeditiously to a human trial.
Dr. Anne Baron-Van Evercooren and colleagues at SalpÍtriËre Hospital in Paris are continuing with their experiment involving transplantation of Schwann cells into the spinal cord of EAE marmosets. The Paris and Milan teams are conducting their studies in concert, exchanging information and sharing data. Both groups use the same animal model of MS, but are transplanting different types of cells, and targeting different areas of the CNS. Comparison of the two approaches is likely to yield more information than if the studies were conducted without coordination.
With the assistance of Dr. Abdelmadjid Belkadi, a recently hired neurobiologist, Dr. Ian Duncan of the University of Wisconsin-Madison has resumed work on a project originally begun in 1998 involving the transplantation of oligodendrocyte progenitor (OP) cells into the CNS of the myelin deficient (md) rat, a strain that is born without myelin. This study is not a repetition of Dr. Duncan's previous experiments in the shaking pup and md rat because in this new experiment remyelination is pursued by transplanting OPs into different sites of the CNS.
When transplanted into a single site in the spinal cord, OP cells migrated as far as 23 millimeters from the site of implant, and produced extensive myelination of dysmyelinated nerve tracts. By transplanting OP cells at two sites in the spinal cord, the researchers have been able to achieve the same amount of remyelination in half the time compared with transplantation at a single site. In an attempt to obtain greater remyelination, the researchers have as their next step begun transplanting OPs into four different sites, two in the brain and two in the spinal cord.
At the Acqui meeting, Dr. Andrea Ballabio of the Telethon Institute of Genetics and Medicine in Naples, Italy, presented his research on the discovery of the gene responsible for multiple sulfatase deficiency. The finding was published in the May 16 issue of the journal Cell. The gene identified by Dr. Ballabio does not produce the sulfatases themselves, but rather is an essential co-factor that greatly increases the sulfatases' activity. The discovery is likely to open new avenues to develop treatments for the eight sulfatase deficiencies, which include MLD.
III. Conclusion
Because of the weak economies in the U.S. and Europe over the past year, the influx of funds into our coffers has fallen off considerably as compared with previous years. We have sufficient reserves to honour our current obligations, but not nearly enough to assume new commitments. We count on your support to revive the inflow of our receipts, thus allowing us to finance all vital experiments included in our research program.
Please be generous with your donations, and help us continue to finance cutting-edge translational research that may produce effective therapies for you or your dear ones in not so distant a future.
Work Group meetings
Following the 14th Annual Meeting of The Myelin Project Work Group, held September 14-16 in Acqui Terme, Italy, The Myelin Project Headquarters and Le Projet Myéline decided to provide $300,000 toward this first phase of the trial, with additional funding to come from other sources.
Our distinguished international Task Force convenes at regular intervals to share and critique research results, long before publication in medical journals.
This assures a cooperative rather than a competitive approach and a common course toward the myelin solution.
Today, neurological science is on the brink of a great leap forward.
Dramatic new cell-transplant therapies are being tested that may induce the central nervous system to regenerate its missing myelin, repair damaged nerves and restore motion, sensation and vision.
Research - how fast are things moving?
Great strides are being made. Our research results have now allowed us to conduct our first human trial. Myelin forming cells were transplanted into the Central Nervous System of a woman suffering from the progressive form of multiple sclerosis.
The transplant was a Phase-1 study designed to prove the safety of the procedure. The team from Yale University Medical Center that performed the operation included among others:
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Schwann Cell transplantation update
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 thetrial 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.
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Transplantation of neural stem cells
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.
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Schwann Cell research proposal
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.
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Progestin study proposal
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.
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Simvastatin trial update
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, 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.
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Spinal chord lesions study update
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.
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Neural cells study update
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.
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Krabbe Disease study update
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.
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Leukodystrophies report
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 adrenoleukodystrophy (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 for FDA 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 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.
