A report of recent research progress in MS
When Jean-Martin Charcot first described multiple sclerosis in 1868, he realized that the disease involved not only damage to myelin, the substance that insulates nerve fibers, but damage to nerve cells (neurons) as well. Researchers now recognize that damage to neurons may occur early in the course of MS, and may be a major contributor to progressive disability.
In March 2001, the National MS Society invited nearly 100 top experts in MS research and other nervous system disorders to New Orleans to discuss how neurons and nerve fibers (axons – extensions of nerve cells that allow them to transmit electrical impulses, Figure 1) are damaged or disrupted in MS. This international workshop, “Neuronal Injury in MS and Related Disorders: Mechanisms and Prevention,” was chaired by Stephen G. Waxman, MD, PhD (Yale University Medical School, New Haven, CT) and W. Ian McDonald, MB, ChB, PhD (Royal College of Physicians, London). Here we present highlights of the meeting (see also page 5), and discuss Society-funded research in this area.
Caught in the Crossfire
Most damage to axons appears in active, inflammatory MS lesions, that is, areas of brain tissue where the immune system is attacking myelin. Therefore, it is possible that a molecule involved in the immune attack may damage neurons. Kenneth J. Smith, PhD (Guy’s, King’s and St. Thomas’ School of Medicine, London) presented data on one such molecule, nitric oxide (NO).
“Nitric oxide is produced by inflammatory cells and it is present in raised concentrations in active lesions in MS,” said Smith. “In such concentrations it can have a range of effects, including some that are harmful, such as impairing cell metabolism. We believe that NO may play a role in the loss of axons in multiple sclerosis, particularly if axons are electrically active while they are exposed to NO.”
Smith and his colleagues exposed axons to NO while they were conducting nerve impulses, and found clear evidence that the axons degenerated. Smith’s team then tested whether, in low doses, agents such as the local anesthetic lidocaine (which reduces pain by blocking nerve conduction) might be able to protect axons from damage.
“Our preliminary results indicate that these agents are effective in axonal protection, even when used at concentrations sufficiently low that they do not block conduction,” said Smith. “They may be of particular value when there is active inflammation in the nervous system.” Further research is ongoing to evaluate the potential therapeutic use of these agents.
Peter Werner, PhD (Albert Einstein College of Medicine, New York) recently completed a Society-funded pilot project in which he investigated the role of glutamate (a molecule released by immune cells that stimulates rapid signaling by neurons) in myelin and axonal loss. Werner and his colleagues administered a compound that inhibits glutamate to mice with EAE, an MS-like disease. The agent, known as an “AMPA/kinate antagonist,” improved EAE substantially, increasing the survival of myelin-making cells and reducing damage to axons.
Werner and colleagues concluded that glutamate may overly stimulate nerve cells and kill them, contributing to tissue damage in the MS lesion. They also noted that AMPA/kinate antagonists, which are currently being tested in people who have strokes, may be a promising therapy for MS.
Changing Sodium Channels
Waxman presented exciting results
from Society-funded* studies of how sodium channel abnormalities disrupt
nerve cells. Sodium channels are tiny pores along the axon that are essential
for nerve conduction (Figure 1).
Figure 1. This is a neuron
(nerve cell). The axon is an extension of the main cell body that allows
it to transmit electrical impulses. Sodium channels are tiny pores along
the lining of the axon that are essential for nerve conduction. The axoglial
junction (inset) contains sections of the axon without myelin. Flanking
these are the regions where myelin is attached to the axon with the help
of various proteins, such as those in the Caspr family. Researchers are
recognizing that these proteins are crucial to the formation of the axoglial
junction and to nerve conduction.
“Sodium channels contribute to the electrical function of neurons, and can help restore conduction to axons that have lost myelin,” said Waxman. “We have found that the genes controlling production of these channels can change in association with damage to axons. There are several types of sodium channels, and if the wrong types are produced, it is like having the wrong type of battery in your radio. It can cause problems.”
Waxman’s team first examined the activity of sodium channels in rodents. “After damage to axons, the genes for some sodium channels were ‘turned off’ and one previously inactive sodium channel gene was ‘turned on,’” he explained. “These kind of molecular changes result in altered nerve conduction, and can lead to neuropathic pain” (pain resulting from a disturbance of nerve function).
The team wondered further whether sodium channels may act abnormally in people with MS and how this may affect the function of neurons. To test this idea, the team studied “sensory neuron specific” (SNS), a type of sodium channel normally found outside the brain and spinal cord.
“We found that SNS channels are present in neurons from the brains of both mice with EAE and people with MS,” said Waxman. “In people with MS, the presence of these channels in the brain, where they are not normally found, may cause neurons to fire signals abnormally, leading to symptoms such as loss of coordination. If these findings can be confirmed, the next step would be to see whether drugs could be developed to block SNS channels in people with these symptoms.”
Where Myelin Meets Axon
The relationship of neurons and myelin may be a key factor in how neurons are disrupted in MS. “Many neuroscientists think of myelin only as supportive – the ‘insulation’ that allows for nerve conduction,” said Scott Brady, PhD (University of Southwestern Medical Center, Dallas) at the New Orleans workshop. “But the relationship between neurons and myelin-making cells is more extensive – it may be the most extensive interaction between any two cell types. The loss of one section of myelin can profoundly affect the very structure and function of the neuron.”
Efforts to understand this relationship focus on the “axoglial junction,” the spots along the axon where myelin connects to the axon (Figure 1). A path-breaking study focusing on the axoglial junction was recently published by Manzoor A. Bhat, PhD (Mount Sinai School of Medicine, New York) and colleagues, including Society grantee Jack Rosenbluth, MD.
Bhat’s team found that one protein in particular is crucial to the formation of the axoglial junction. They developed a mouse in which this protein, called “Caspr/Paranodin” (NCP1), is deleted. In the absence of NCP1, the axoglial junction did not form normally. Myelin peeled away from the axon and nerve conduction was reduced, leading to tremors and paralysis. This shows that NCP1 is critical to the formation of the axoglial junction, and suggests that it may be involved in diseases such as MS. These findings are reported in the May 2001 issue of Neuron).
Jeffrey Dupree, PhD (University of North Carolina, Chapel Hill) studied proteins from the same “Caspr” family during a successful Society-sponsored postdoctoral fellowship. ** Dupree found that in mice lacking fat-like lipid molecules in myelin, nerve conduction is impaired and the mice develop tremor and hind-limb paralysis.
Dupree examined these effects further, and determined that the lack of these lipids caused an abnormal distribution of Caspr proteins at the axoglial junction. These abnormalities disrupted nerve conduction, resulting in the mice’s neurologic symptoms — a finding similar to Bhat’s using different experiments. Dupree now has a Society-funded pilot project to investigate whether abnormalities in the axoglial junction lead to the death of neurons.
The New Orleans workshop on neuronal injury provided a stimulating forum for top researchers to discuss this important topic. The meeting raised several therapeutic possibilities (see also page 5), and the Society is planning a follow-up workshop to focus on methods of nerve cell repair. Several Society grantees are tackling the question of how nerve cells are damaged or disrupted and how to protect them. These efforts bring to the fore the progression of nerve damage and disability in MS, and bring us closer to understanding and devising therapeutic strategies to prevent this devastating effect of multiple sclerosis.
*funded in part by the Gerald J. and Dorothy R. Friedman New York Foundation for Medical Research through the NMSS New York City Chapter, in honor of Susan Thomases.
**funded in full with support from the NMSS Central North Carolina, Eastern North Carolina, and Mid-Atlantic chapters.
Visit the Research section of the Society’s Web site for the latest research news, ongoing clinical trials, and progress of Society-funded grantees: http://www.nationalmssociety.org/research.asp
Replacing Cells Lost in MS
“The ultimate goal is to find safe cells that can be used for safe transplantation.”
One of the most exciting areas of MS research is the effort to transplant myelin-making cells into the central nervous system. These cells may be able to repair damage to myelin, regenerate injured axons and restore nerve signal conduction. Jeffery Kocsis, PhD (Yale University, New Haven, CT) is funded by the Society* to explore the possibilities of cell transplantation in rats, and he discussed this research at “Neuronal Injury in MS and Related Disorders: Mechanisms and Prevention,” a Society-funded workshop held in New Orleans in March 2001 (see also p. 1). Thanks in part to his findings, this research will soon enter early clinical trials in people with MS.
“Therapies that regulate the immune attack on the central nervous system in MS will continue to develop,” said Kocsis. “But other approaches may be necessary to improve nerve conduction in brain tissue where myelin and axons have already been damaged.”
The key to cell replacement therapies is finding the right cells – not an easy task. “This is a major effort right now, with researchers investigating a variety of cell types,” said Kocsis. “First, we need to show that the cell can survive – transplanting any organ or cell carries the risk of rejection, in which the immune system attacks the new tissue. We also need to make sure that the cell will develop without abnormalities. Finally, we need to determine if the cell can migrate to areas of myelin damage and form new tissue.”
One promising prospect is Schwann cells, myelin-making cells from the peripheral nervous system (the network of nerves outside the brain and spinal cord), about which Kocsis published findings in the February 1, 2001 issue of The Journal of Neuroscience. “We took Schwann cells from adult human nerves, froze them, and stored them for weeks to months,” he said. “The frozen cells were then injected into lesions in the spinal cords of rats.
“We found that the human Schwann cells formed relatively extensive myelin and that previously obstructed nerve impulse conduction improved. This was an important preclinical study, because it showed that Schwann cells from relatively older humans could migrate to areas of myelin damage and form working myelin.”
Based on this research, Kocsis’s Yale colleague Timothy Vollmer, MD, is planning a small trial of Schwann cell transplantation in 5 people with secondary-progressive MS. Kocsis’s laboratory will provide technical support, and has developed highly efficient ways of harvesting these cells from individuals who enroll in the study. Schwann cells will be taken from nerves in the participants’ feet, and transplanted into areas of myelin damage in the brain.
“This trial is being designed to determine if these cells can survive, and to make sure treatment is safe,” noted Kocsis. “We will attempt the procedure in one person at a time, and if there are any problems, we will stop the study. It is important to understand that we are not yet evaluating the effectiveness of this therapy.” If safety and tolerability of this invasive procedure can be shown, clinical trials to test its effectiveness will be planned which involve larger numbers of people and a well-controlled design.
Enrollment information for the initial study is available on the Society’s Web site, at http://www.nationalmssociety.org/Research-trialsrecruiting.asp, or via email, at firstname.lastname@example.org.
Kocsis is investigating another cell type that might be useful in replacement therapies – olfactory ensheathing cells (OECs) – in collaboration with Alexion Pharmaceuticals, Inc. (Cheshire, CT). OECs form the myelin sheath on nerve fibers in the nose.
“OECs have unique properties that make them good candidates for transplant,” said Kocsis. “They can replicate themselves and can grow into other types of nerve cells. Also, we are taking these cells from the snouts of pigs that are genetically programmed to inhibit immune-system rejection. They may prove to be a rich source for cell therapies.”
Kocsis’s team found that these OECs retain their potential to repair myelin after transplantation into rats (Nature Biotechnology, September 2000). “Using advanced techniques to record nerve conduction, we found that transplanting OECs improved the speed and distance of nerve conduction,” said Kocsis. “Our findings are important prerequisites for considering therapy in humans.”
The promise of cell-based therapies is evident, but Kocsis emphasizes the need to proceed carefully. “The ultimate goal is to find safe cells that can be used for safe transplantation.”
*funded in part through gifts from the NMSS Western Connecticut Chapter and the Dan Family through the NMSS Greater Illinois Chapter.
—Jeffery Kocsis, PhD
Sexuality and Intimacy in MS: Asking the Right Questions
Surveys suggest as many as 91% of men and 80% of women with MS may be affected by sexual problems. However, people and their physicians may hesitate to talk about these problems. To bridge this gap, Audrey Sanders, PhD, and Frederick Foley, PhD (Ferkauf Graduate School of Psychology, Yeshiva University, New York) and colleagues developed a questionnaire to help researchers and clinicians to assess the effects of MS on intimacy and sexuality. Sanders was funded by a fellowship from the Society’s Health Care Delivery and Policy Research Program.
The “MS Intimacy and Sexuality Questionnaire-19” (MSISQ-19) contains 19 questions that address virtually all areas of sexual dysfunction that may occur in people with MS: the primary effects of the disease on sexual functioning, such as impaired genital sensation or decreased sexual drive; the secondary effects of MS symptoms on sexuality, such as fatigue, muscle tightness or bladder dysfunction; and other effects of MS, such as depression and negative self-image.
To design the MSISQ-19, Sanders and colleagues consulted with health professionals and people with MS. The team then administered the questionnaire to 215 people with MS recruited from the MS Comprehensive Care Center at St. Agnes Hospital, White Plains, NY. The questionnaire demonstrated its usefulness in measuring aspects of marital satisfaction (including communication and sexual function), sexual impairment, psychological distress and well-being, and other factors affecting intimacy (Sexuality and Disability, Vol. 18, No. 1, 2000).
Highlighting specific areas of sexual difficulty makes it easier for people with MS to recognize and describe their own particular problems, says Sanders. The MSISQ-19 can open a dialogue between people with MS and their health care providers concerning MS and sexuality, and help both to address issues affecting intimate relationships. In addition, this tool can help researchers understand and devise strategies to treat sexual dysfunction in MS.
The National MS Society is proud to be a source of information about MS. Our comments are based on professional advice, published experience and expert opinion, but do not represent individual therapeutic recommendation or prescription. For specific information and advice, consult your personal physician. For more information about MS research, call: 1-800-FIGHT MS, or visit our Web site: http://www.nationalmssociety.org.
Vaccinations and MS: No Link
Whether or not vaccinations can cause MS or trigger attacks of MS has been a matter of some concern. Recent publications demonstrate that there is no cause for concern, and may reassure people with MS and their physicians about the safety of vaccines.
Albert Ascherio, MD, DrPH (Harvard School of Public Health, Boston) and colleagues compared the history of hepatitis B immunization among 192 women who had developed MS and 645 who had not. Those who received hepatitis B vaccination were no more likely to develop MS than those who had not. Christian Confavreux, MD (Hôpital Neurologique, Lyon, France) and colleagues found no connection between tetanus, hepatitis B and influenza vaccinations and relapses of MS in reviewing records of 643 people with MS. (Both studies appear in The New England Journal of Medicine, February 1, 2001).
Neville F. Moriabadi, MD (University of Regensburg, Germany) and colleagues administered flu shots to 12 people with relapsing-remitting or secondary-progressive MS and 28 people without MS. Neither group showed an increase in immune cells that may launch the attack in MS, and flu shots did not worsen MS symptoms (Neurology, April 10, 2001). These findings support a Society-funded study by Aaron Miller, MD (Maimonides Medical Center, Brooklyn, NY) and colleagues, who found that flu shots were not associated with exacerbations of MS in 104 people with relapsing-remitting MS (Neurology, February 1997).
“The results of these studies should provide reassurance to recipients of these vaccines, to patients with multiple sclerosis, and to their physicians,” note Bruce G. Gellin, MD, MPH, and William Schaffner, MD (Vanderbilt University School of Medicine, Nashville) in an editorial accompanying the NEJM studies.