Multiple Sclerosis Newsletter
Northern Colorado Edition

August - September 2003

Research Updates

Drink more fluids (non alcoholic),regardless of your activity level. Don't wait until you're thirsty to drink. Warning: If your doctor generally limits the amount of fluid you drink or has you on water pills, ask him how much you should drink while the weather is hot.

Don't drink liquids that contain caffeine, alcohol, or large amounts of sugar - these actually cause you to lose more body fluid. Also, avoid very cold drinks, because the can cause stomach cramps.

Stay indoors and if at all possible, stay in an air-conditioned place. If your home does not have air conditioning, go to the shopping mall or public library - even a few hours spent in air conditioning can help your body stay cooler when you go back into the heat. Call your local health department to see if there are any heat-relief shelters in your area.

Electric fans may provide comfort, but when the temperature is in the high 90's fans will not prevent heat-related illness. Taking a cool shower or bath, or moving to an air-conditioned place is a much better way to cool off.

Wear lightweight, light-colored loose fitting clothing.

NEVER leave anyone in a closed, parked vehicle.

Although any one at any time can suffer from heat-related illness, some people are at greater risk than others. Check regularly on:

Infants and small children
People age 65 or older
People who have a mental illness
Those who are physically ill, especially with heart disease or high blood pressure.

Visit adults at risk at least twice a day and closely watch them for signs of heat exhaustion or heat stroke. Infants and young children, of course, need much more frequent watching.

Limit your outdoor activity to morning and evening hours.

Cut down on exercise, If you must exercise, drink two to four glasses of cool, non alcoholic liquids every hour. A sports beverage can replace the salt and minerals you lose in sweat. WARNING: If you are on a low-salt diet, talk with your doctor before drinking a sports beverage. Remember the warning in the first "tip" (above), too.

Try to rest in shady areas

Protect yourself from the sun by wearing a wide-brimmed hat (also keeps you cooler) and sunglasses and by putting on sunscreen of SPF 15 or higher (the most effective products say "broad spectrum" or "UVA/UVB" protection on their labels.)

BIOLOGY OF BLOOD & MARROW TRANSPLANTATION
(Feb. 2003, Vol. 9, No. 2)

148 IMMUNOBLATIVE THERAPY WITH PURIFIED AUTOLOGOUS STEM CELLS RESCUE FOR THE TREATMENT OF POOR PROGNOSIS MS. CHRONIC IMMUNE MODULATION IS PARTIALLY EFFECTIVE IN SLOWING THE PROGRESSION OF MULTIPLE SCLEROSIS

Intensive conditioning regimens ablate host immunity. Stringent depletion of immune cells in the graft eliminate GvH reactions and hematopoietic stem cells (HSC) reconstitute a naive graft-derived immune system. As autoimmunity is an acquired defect of the immune system, purified stem cells from patients with autoimmune diseases should reconstitute an immune system free of autoreactivity. We are testing these hypotheses in a phase II study of 24 MS patients. Patients are chosen on the basis of rapid aggressive early disease and failure to respond to approved disease-modifying drugs. Following baseline evaluations and a back-up bone marrow harvest, HSC are mobilized using G-CSF. Decadron and Cyclophosphamid and collected by leukopheresis. Autologous HSC are purified on a ClinicMACS. Reinfusion of highly purified HSC follows treatment with Busulphan (-16 mg/kg dose adjusted to AUC of the first dose). Cyclophosphamide (20 mg/kg) and rabbit antithymocyte globulin (5 mg/kg). Five patients have been treated. Peripheral blood stem cells (PBSC) were mobilized and collected with nominal toxicity. Immune cell contamination of the purified HSC's were below the level of detection by FACS. The mobilization regimen did not cause worsening of MS by clinical or MRI exam. The expected regimen related toxicities were minimal following peripheral blood stem cell transplant. The MS has remained stable in all patients (3-12 months past transplant). Signs of central nervous system inflammation on MRI have resolved following treatment. All patients remain profoundly deficient in T lymphocytes. Although only early follow-up is available, complete immune ablation with stem cell rescue for MS appears to be well tolerated and no sign of active disease can be detected providing preliminary support for the role of immunoablative therapy in autoimmunity.

MULTIPLE SCLEROSIS
Mayo Clinic (2003)

Interviewing Moses Rodriguez, M.D. researching exciting development for multiple sclerosis treatment.

What is the focus of your current research?
Our work is primarily in multiple sclerosis (MS), which affects about 350,000 people in the United States. MS is a chronic disease of the central nervous system It can be a very disabling disease.

MS results from injury to the myelin sheath with the nerves (axons) remaining relatively intact. Myelin is the fatty insulation that surrounds most nerves in the brain and spinal cord. As a result of destruction of this sheath, the function of the nerves is impaired, resulting in neurologic deficits. Our goal is to devise strategies to re-grow the myelin on the nerves in the central nervous system.

People used to say that was impossible, but we have shown that it can occur in animals. Our laboratory has discovered that antibodies may play a critical role in repair of the myelin sheath. Antibodies directed against the cells that make the myelin sheath (oligodendrocytes) appear to induce new formation of myelin in the central nervous system.

We recently discovered a series of human antibodies that promote repair in the central nervous system. This is an exciting new development for the treatment of multiple sclerosis. New formation of myelin is the ultimate therapeutic goal in multiple sclerosis. the use of monoclonal antibodies appears to be a practical and feasible approach to accomplish this.

Why is it that a patient develops weakness of the leg or numbness in the foot or loss of vision?
What we have found is that in these cases not only is the sheath damaged but the nerve also is damaged. We are very actively investigating why that happens. We also have found that plasma exchange works for some individuals with severe cases of multiple sclerosis. We found that if you remove the plasma from patients with certain types of MS with very dramatic injury, you get dramatic recovery.

Are there broader applications for your research?
We think that some of the same concepts could be applied to diseases like spinal-cord injury. We think that potentially we could promote and repair using different kinds of antibodies. What are the implications for patient care? My focus is very practical because I also see patients. The beauty of our approach is that it will be non-invasive. Other research is focusing on stem cells and transplantation - all of which is very invasive. We are saying you don't need to do all that. The cells already are there. If you just stimulate them to do the right thing then you can get the process going.

How has being at May Clinic contributed to your research?
The most important thing for me has been having dual appointments in both a basic science and a clinical department - Immunology and Neurology. This allows me to bridge the gap between basic science and patient care. There is a tendency for basic scientists and clinicians to go about their work and not talk to each other. One important aspect of having appointments in both places is the ability to recruit students, postdoctoral students and clinicians who come from both disciplines. This provides an interesting mix of people in the lat - people who normally wouldn't interact.

The joint appointment also means I am thinking about our research when I am seeing patients. For example, we initiated the plasma-exchange trial based on our observations in the laboratory, so we are able to take what we learn in the laboratory and apply it simultaneously to patients.

How do you see your research as fitting into the bigger picture of Mayo Clinic?
Mayo's vision of "the needs of the patient come first" is something I strongly believe in. I think it is very different in most other institutions. Most other institutions major missions are to advance knowledge or to write papers. I think the mission of helping patients has driven my focus toward research that ultimately will benefit patients. I strongly support basic science. But to me the basic science has to have a focus toward patient care. Just doing basic science is great, but it is not what I do. I've been at Mayo since 1983. It has been a very good experience academically and professionally.

ANOTHER WAY TO WIN?
Clinical Trials Often Lead to Breakthroughs,
But for Most Patients There is No Sure Bet
by Beth Baker AARP Bulletin (June 2003)

Ellen Berty of Arlington, Va., surprises or even shocks many people when she says "I used to have diabetes." Berty, not 55 was diagnosed at the age of 13 with type 1 diabetes - sometimes called juvenile diabetes. She estimates she took 22,000 shots of insulin over the years. But Berty has not had an insulin injection since June 24, 2001 - Just 10 days after she received an inset cell transplant in a clinical trial at the National Institutes of Health (NIH) "Those islet cells now live in my liver and produce insulin", she told the AARP Bulletin.

To Berty the transplant has been nothing short of a life-saving miracle. Shad been experiencing drops in her blood sugar levels so severe that on several occasions, while driving, she just managed to pull her car off the road and stop before losing consciousness. Berty's ticket to a new life was the trial that led to an experimental transplant under the direction of David Harlan, M.C. Chief of the transplantation and autoimmunity branch of the National Institute of Diabetes and Digestive & Kidney Diseases.

NO ADVANCE WITHOUT RISK
Like Berty, and estimated 1 million Americans each year are willing to put the potential rewards from enrolling in a clinical trail ahead of the possible risk. CenterWatch, a Boston-based company that tracks the clinical trials industry (and a subsidiary of Medical Economic Co, publisher of the "Physicians" Desk Reference"), expected some 80,000 clinical trials designed to assess the safety and effectiveness of new drugs, devices and medical procedures to be conducted in 2002 alone.

A website developed by NIH's National Library of Medicine lists more than 7,600 clinical trials sponsored by NIH, other federal agencies, pharmaceutical companies, and universities (Berty, in fact started her search at that site.)

With Pharmaceutical companies developing an ever-increasing number of new drugs, the reason for the proliferation of clinical trials is plain enough "Quite simply", says Andrew Kelahan, former vice president of the Coalition of National Cancer Cooperative Groups, " if we don't do the clinical trials, we can't develop new treatments."

TRIALS AND ERRORS
Not everyone, however, is as lucky as Ellen Berty. Although the vast majority of clinical trials are well-run, a number of high-profile tragedies, in which research subjects have died during trials at well-known institutions, have underscored the risks of volunteering for experimental therapies.

In September 1999, 18 year old Jesse Gelsinger, who had a rare liver disorder, died after undergoing experimental gene therapy at the University of Pennsylvania. Jesse's father, Paul Gelsinger, sued, alleging that the lead researcher concealed his financial interest in the company developing the treatment.

In July 2000 the Federal Government shut down all clinical trials at the University of Oklahoma Health Sciences Center when 26 cancer patients died after receiving an experimental vaccine for melanoma, a serious form of skin cancer.

In April of this year the Department of Veterans Affairs ordered a nationwide review of clinical trials at 115 veterans hospitals after investigators uncovered cases of falsified data and other serious violations of federal rules - some of which may have contributed to the deaths of patients enrolled in the trials.

"A lot of research is slipshod, dangerous or unnecessary"> says Peter Lurie, M.C. deputy director of Public Citizen's Health Research Group, a Washington-based watchdog organization.

Some of the experimental drugs or treatments that are being evaluated in clinical trials can have unpleasant or even life-threatening side effects. CenterWatch estimates that one of every 30 patients in clinical trials will experience a serious side effect and that one in 10,000 will die as a result of the experiment. "Those who participate in research are taking the risks for the rest of us," says Greg Koski, M.D. a former director for the Office for Human Research Protections at the U.S. Department of Health and Human Services."We have to put the interests of the subjects above and beyond our other considerations," he says "and that's not always easy to do."

Fortunately, the vast majority of patients in clinical trials receive top-flight care and are likely to be closely monitored and tested as part of the research. Even participants who are on a placebo - an inactive compound (typically a sugar pill) that looks like the medication being tested - often show significant improvement because they are, sometimes for the first time, getting regular attention from highly skilled medical professionals.

AGE, ACCESS, OPPORTUNITY
After years of being excluded from virtually all clinical trials, older Americans are, in increasing numbers, finally finding their way into such trials. And little owner,: more than 700 of the 1,000 or so drugs now being evaluated in clinical trials are aimed at treating diseases or conditions associated with aging, according to the Pharmaceutical Research and Manufacturers of America, the drug industry's Washington-based trade group.

Although medical researchers have long pointed to age-related differences in how drugs are absorbed, metabolize, and excreted, it wasn't until 1989 that the Food and Drug Administration (FDA) published guidelines for including older patients in clinical trials. Today, according to the FDA roughly 15-20% of participants in drug trials are over 65.

Dennis DeRosia, former Chairman of the Association of Clinical Research Professionals, a nonprofit organization that accredits clinical trials, says that in many cases it makes sense to recruit older patients for drug trials.

"The only way we ever are going to know if medication is good or bad for a particular age group" DeRosia told the Bulletin, "is by testing it on that age group." In a recent study researchers at Duke University found that older people tend to be more willing than younger people to participate in clinical trials. Eric Peterson, M.D., associate professor of medicine at Duke, says that older people generally have fewer time constraints and a greater desire to help the next generation by advancing medical research.

Nontheless, older Americans may still be underrepresented in clinical trials. In a study published in 2001 in the Journal of the American Medical Association, Peterson and his colleagues found that only nine percent of heart disease trials included patients 75 years or older - even though 37% of all heart attack victims in the United States are in that age group. They also found that more than half the trials did not enroll a single patient over 75, nearly a third of them specifically excluded older persons.

"It's not the fault of the elderly that they're underrepresented," Peterson told the Bulletin. He says that researchers often seek subjects who don't take other medications or have other conditions that might lead to "adverse events" - medical problems arising during the clinical trials that must be reported to the FDA.

Robert N. Butler, M.D. founding director of NIH's National Institute on Aging, and President of the New York-based International Longevity Center - USA, says that even today older people are "woefully under-represented or even excluded from clinical trials". the resulting lack of knowledge, Butler says, leads to "adverse reactions, inappropriate dosages and treatments and the misperceptions that older people cannot tolerate or benefit from new drugs and procedures."

IS ANYONE WATCHING?
The rights and interests of patients in clinical trials are supposed to be protected by Institution Review Boards (IRB's) committees of physicians and scientists assembled by NIH or by the university, pharmaceutical company or other sponsor conducting the research. IRB's are charged with making sure that clinical trials are conducted safely and ethically. They are expected to halt trials if protocols are not followed or when significant adverse reactions occur. But, says Public Citizen's Lurie, "There's a kind of arrogance that has suffused the ethical review system," In some cases overzealous researchers or unscrupulous physicians have played down risks or exaggerated the benefits of the trial. "There can be a problem," he says,"comparing a new drug with a placebo rather than with a proven effective drug."

Adil E. Shamoo, professor at the University of Maryland School of Medicine and founder of Citizens for Responsible Care and Research, a Baltimore based watchdog group, says the rush to bring new drugs to market has led to shoddy monitoring by IRB's, "The failure is systemic" Shamoo told the Bulletin. Federal oversight is not strong enough.

Judy Salerno, M.C. deputy director of the National Institute on Aging, says that ethical treatment in clinical trials is of particular concern for patients with Alzheimer's and other neurodegerative diseases, who may not understand what is being asked of them. "With cognitively impaired persons we really have to do everything we can do to make sure the research is ethical" Salerno says "and that is protects the rights and welfare of each individual subject.

RESEARCH AND RESULTS
Despite the potential downsides of clinical trials, they generally get high marks from participants. A 2000 survey by CenterWatch, for example, found that most participants in clinical trials felt they had received excellent care and would participate in a trial again. And for some, like Ellen Berty participating in a clinical trial represents an opportunity to be a small but nontheless significant part of medical history in the making - in this case, a potential cure for type 1 diabetes. In 2002 researchers reported that 80% of patients who had received sufficient islet cells through transplantation no longer needed insulin injections a year later - and, most important, were metabolically stable. That's no small miracle, for Berty and for medical research