20th International ALS Symposium Held in Berlin

Although electronic communications allow rapid transmission of information among laboratories around the world, face-to-face meetings still play an important role in research. Many new collaborations, contracts, grants and ideas have begun during a coffee break or over dinner when researchers get together.

St. Nicholas Quarter, along the Spree River, is in the historical heart of Berlin.

More than 850 ALS researchers, clinicians and representatives of ALS groups from around the world gathered in Berlin Dec. 8-10, 2009, for the 20th International Symposium on Amyotrophic Lateral Sclerosis/Motor Neuron Disease, organized by the Motor Neurone Disease Association, based in England, Wales and Northern Ireland.

Below are a few highlights from the many reports given at the symposium. Symposium summaries are available online at the Web sites of the Motor Neurone Disease Association (www.mndassociation.org) and the MDA-supported ALS Therapy Development Institute (ALS TDI, www.als.net).

ALSTDI 00846 hits inflammation-related biological targets

Steve Perrin, chief scientific officer at the ALS TDI, presented encouraging results for the experimental drug ALSTDI 00846, being developed by the Institute with funding from MDA.

According to Perrin, who reported on results in mice with an ALS-like disease caused by mutated SOD1 genes, the drug changes a number of markers of inflammation, which is believed to contribute to ALS.

MDA supports the Massachusetts-based ALS Therapy Development Institute through its Augie’s Quest initiative.

The drug improved survival when administered before symptom onset, but not after, which may sound a bit discouraging. However, Perrin noted that this SOD1 mouse has far more copies of the mutated SOD1 genes per cell than do humans with the SOD1 form of ALS (who have only one copy), so seeing any positive results in this mouse model of the disease is extremely encouraging.

ALS TDI and MDA are planning to carry out further studies of this potential drug.

KNS760704 shows safety, ‘trends’ toward benefit

The experimental drug KNS760704 was reported to be safe and well tolerated, and there were indications of possible benefit, in 92 people with ALS who took it for nine months.

KNS760704 is being developed by Knopp Neurosciences (www. knoppneurosciences.com), a Pittsburgh drug discovery company.

Merit Cudkowicz, an investigator on the study who directs the MDA/ALS Center at Massachusetts General Hospital in Boston, announced results of a phase 2 trial of KNS760704. Although she did not receive MDA support for this trial, Cudkowicz has received and continues to receive MDA funding for other ALS research.

According to Knopp, KNS760704 may protect nerve cells under stress. The experimental drug is a molecular mirror image of pramipexole, a prescription medication approved for the treatment of Parkinson’s disease and restless legs syndrome under the trade names Mirapex and Sifrol. The company says these mirror-image molecules have very different properties.

In part 1 of this study, 102 people with ALS were randomly assigned to receive daily doses of 50, 150 or 300 milligrams of KNS760704 or a placebo for three months. There was a trend toward a slowing in the rate of disease progression, as measured by the ALS Functional Rating Scale, across all treatment groups, with greater benefit correlated with higher dosage levels. (“Trends” are results that suggest an effect but can’t be called “significant,” because they don’t reach mathematical criteria for statistical significance.)

In part 2 of the study, which followed a one-month “washout” period, 92 of the original trial participants were randomly assigned to receive either 50 or 300 milligrams per day of KNS760704 for an additional six months. There was a dose-related trend toward a slowed rate of disease progression, and there also was a trend toward a survival benefit in the 300-milligram group compared to the 50-milligram group.

Cudkowicz said the safety results and the trends toward improved functional and survival outcomes observed in this study provide preliminary evidence supporting the ongoing evaluation of KNS760704 in phase 3 clinical trials.

SB509 modestly improves muscle strength

Strength testing is part of many ALS treatment trials.

According to another report given at the symposium, the experimental compound SB509 appears safe and well-tolerated and may have a positive effect on function in people with ALS.

SB509 is being developed by Sangamo BioSciences (www.sangamo.com), a Richmond, Calif., biotechnology company, which funded this phase 2 trial.

The compound contains the gene for an activator of a protein called vascular endothelial growth factor A (VEGF A). VEGF A protein increases production of blood vessels and may protect or nourish nerve cells.

In people with ALS, VEGF A levels in the spinal fluid are lower than normal, and receptors (docking sites) for VEGF are increased in blood vessels and in the spinal cord, perhaps because the body attempts to compensate for the lower VEGF protein levels.

Forty-five people with ALS are enrolled in the partially completed phase 2 trial, and the symposium report included data from 22 of them.

All trial participants are being treated with SB509. They’re being compared to a “historical” control group — untreated ALS patients who may have been in a placebo group in other trials but are not enrolled in this trial.

Four months after treatment with SB509, six out of 19 people (32 percent) showed improvement on manual muscle testing scores. These trial participants each received two sets of SB509 injections into the muscles of the neck, arms and legs, three months apart.

In the historical control group, 26 out of 153 (17 percent) showed improvement on manual muscle tests.
Five of the six people treated with SB509 who showed improvement with manual muscle testing also improved on the ALS Functional Rating Scale, which assesses physical abilities, and/or a respiratory measurement called forced vital capacity.

The trial took place at California Pacific Medical Center in San Francisco, the University of Kansas Medical Center in Kansas City, and Johns Hopkins University in Baltimore. All three institutions are sites for MDA/ALS centers, from which study participants were drawn (although MDA did not directly support this study).

Jeffrey Rothstein, who directs the MDA/ALS Center at Johns Hopkins University in Baltimore, said the ability to maintain muscle strength or delay its deterioration could have a significant impact on quality of life for people with ALS.

ALS Research Roundup

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Soil bacteria implicated in ALS-Gulf War connection

In 2001, a government-funded study showed that military personnel serving in the Gulf War in 1990-1991 were nearly twice as likely to have developed ALS as were military personnel who had not served in that war.

The study analyzed the records of nearly 700,000 U.S. soldiers deployed between Aug. 2, 1990, and July 31, 1991, to fight in the Persian Gulf War against Iraq. Of those, 40 eventually developed ALS, which is roughly twice the rate of ALS cases found in 1.8 million veterans who weren’t deployed to that region during the same period.

Since then, epidemiologists and biologists have speculated that some combination of genetic susceptibility and environmental factors, such as toxins, pollutants or viral infections, may have converged to cause the unusually high rate of ALS cases in the Gulf War group (even though the absolute numbers remained small).

In a study published online Nov. 10, 2009, in the journal Amyotrophic Lateral Sclerosis, Paul Cox of the Institute for EthnoMedicine in Jackson, Wyo., and colleagues, implicate desert dust containing microorganisms called “cyanobacteria” as a possible cause of the increase in cases.

The dry, crusty landscape of the region is rich in cyanobacterial crusts and mats, which help bind the desert sands, the study’s authors say. When these are disturbed by vehicles or other military activiies, they can produce significant dust, which contain known neurotoxins BMAA and DAB. “If dust containing cyanobacteria is inhaled,” they write, “significant exposure to BMAA and other cyanotoxins may occur. We suggest that inhalation of BMAA, DAB, and other aerosolized cyanotoxins may constitute a significant risk factor for the development of ALS and other neurodegenerative diseases.”

They also note that a major criticism of the initial reports of an increased incidence of ALS among Gulf War veterans was the lack of evidence for a “biologically plausible” environmental factor that could contribute to such an increase. The authors, which include former MDA research grantee Walter Bradley at the University of Miami, say cyanobacterial exposure is such a factor.

Smoking is a risk factor for ALS

A new analysis says that smoking, already suspected of being a risk factor for ALS, definitely is one.

Carmel Armon, professor of neurology at Tufts University School of Medicine in Boston and chief of neurology at Baystate Medical Center in Springfield, Mass., analyzed the medical literature published on smoking and ALS between 2003 and April 2009.

He initially identified 28 studies, only two of which were considered reliable enough to be included in the final results, which were announced Nov. 17, 2009, in the journal Neurology.

The first paper Armon references was published in 2007 in Neurology. It reports on the occupation, education and smoking habits of 364 people with ALS and 392 without the disease in the Netherlands. Smoking was the only factor the researchers studied that, by itself, increased the chance of developing ALS. It raised the risk of the disease 1.6 times over average.

The second study, published in Annals of Neurology in 2009, looked at people who were part of the European Prospective Investigation into Cancer and Nutrition (EPIC) database. Out of 517,890 initially healthy subjects, 118 ultimately died of ALS.

Those who reported they were currently smoking at the time they entered the study had almost twice the risk of dying from ALS (1.89 times greater than average) compared to those who never smoked.

Those who classified themselves as “former smokers” at the time of study enrollment had 1.48 times the risk of dying from ALS compared with those who had never smoked.

Italian study adds to uncertainty about serum lipids and ALS

In 2008, a French research group published a somewhat surprising study that suggested high levels of lipids (fats, such as cholesterol and triglycerides) in blood serum might be more common in people with ALS than in the general population but at the same time might actually improve survival time once the disease develops. (See “Does a high serum cholesterol level increase survival time in ALS?” in the May 2008 ALS Newsmagazine.)

Now, adding to the uncertainty are results of a study conducted in Italy and published Nov. 17, 2009, in Neurology. These investigators found no differences between serum lipid levels in 658 people with ALS and 658 without the disease. Nor did they find that high serum lipids were related to longer survival in those with ALS. However, they did find that respiratory impairment was correlated with lower blood lipid levels in the ALS group.

The researchers say one explanation for the observation is that, as respiratory muscles decline in strength, more energy expenditure is needed for breathing, which in turn may lower blood lipid levels.

They say their findings do not support the French researchers’ conclusion that people with ALS have a tendency to have high serum lipids or that high serum lipid levels in this population are related to longer survival.

The jury is still out on whether or not there is any relationship between serum lipid levels and ALS, and MDA researchers are studying this question.

Lorene Nelson at Stanford University in California has received MDA funding to study whether cholesterol-lowering medication increases the risk of developing ALS or influences its rate of progression after it develops.

FDA says ALS arimoclomol study can reopen

A multicenter clinical trial of arimoclomol, an experimental compound being developed by CytRx Corp. (www.cytrx.com) of Los Angeles, will resume, with a revised protocol, the company announced Dec. 2, 2009. The trial is funded by CytRx.

Arimoclomol is designed to activate molecules called “chaperones,” which help regulate cellular repair. According to CytRx, arimoclomol can detect proteins that are misfolded and potentially toxic and refold them into their correct, nontoxic shapes.

The U.S. Food and Drug Administration (FDA) placed a hold on this phase 2b trial of arimoclomol in January 2008, saying it wanted to see more toxicity data from previously completed animal studies.

The new trial, which has not yet officially opened, will test arimoclomol in groups of 20 to 30 people with ALS at a time, starting with a dosage level of 100 milligrams three times a day and increasing the dosage level by 75 milligrams per dose up to a maximum of 400 milligrams three times daily. An independent safety monitoring board will review results before each dosage increase.

Each group will receive arimoclomol for three months. Fifteen people will receive a combination of arimoclomol at various dose levels plus riluzole (Rilutek), an established treatment for ALS, at a fixed dose of 50 milligrams twice daily; and another five to 15 people will receive a placebo plus 50 milligrams of riluzole twice a day.

The two principal investigators are Merit Cudkowicz, director of the MDA/ALS Center at Massachusetts General Hospital in Boston; and Jeremy Shefner, director of the MDA/ALS Center at the State University of New York Upstate Medical University in Syracuse.

In addition to looking at safety, the investigators will evaluate participants’ scores on the revised ALS Functional Rating Scale, as well as their vital capacity (a respiratory measurement) results. However, the trial is designed only to note extreme responses in these two categories.

For information about this trial as it becomes available, see the clinical trials section of MDA’s Web site.

For information about a separate trial of arimoclomol in the SOD1 form of familial ALS, see the clinical trials section of MDA’s Web site. Or contact Darlene Pulley at dpulley@partners.org for the Boston site; or write to sod1@emory.edu for the Atlanta site.

Editor's Note: Contact information for the phase 2b arimoclomol trial was removed on Feb. 6, 2010, because the trial is not yet recruiting participants.

Normally, nerve cells signal muscle fibers through a chemical called acetylcholine. In ALS, as nerve cells are damaged, these connections are disrupted. New findings suggest microRNA 206 participates in restoring these connections after inquiry.

Scientists say microRNA 206 could have therapeutic potential

A molecule called microRNA 206, produced by muscle fibers after an injury to nerve cells, helps rebuild crucial nerve-muscle communications, say scientists at the University of Texas Southwestern Medical Center in Dallas and Harvard University. Loss of such connections is an aspect of ALS in mice and humans.

After finding that mice with an ALS-like disease fared worse without microRNA 206 than with it, researchers said raising levels of this compound or amplifying its effects in some other way could become a new therapeutic avenue.

Eric Olson at the University of Texas Southwestern Medical Center in Dallas, with colleagues there and at Harvard University, reported the new findings in the Dec. 11, 2009, issue of the journal Science.

When the scientists genetically engineered mice to develop an ALS-like disease and also to lack microRNA 206, they found the mice had faster disease progression and died earlier than mice with the same disease that had normal microRNA 206. However, mice with and without microRNA 206 developed their first disease symptoms at about the same time.

That and other experimental results led the investigators to the conclusion that microRNA 206, which comes from muscle fibers, acts in response to injury to nerve tissue and becomes important only after such injury occurs. The compound appears to help compensate for the ALS-related nerve injury, albeit incompletely.

While there are no immediate implications for people with ALS, investigators Eric Olson and Andrew Williams, both at UT Southwestern, have filed patent applications related to these results, indicating they may believe it has potential for drug development.

New MDA/ALS Center Opens in Chicago

MDA’s ALS Division has designated the MDA clinic at the University of Illinois at Chicago as an MDA/ALS center. This brings the total number of these specialized clinics to 36.

The University of Illinois at Chicago is the site of a new MDA/ALS center.

MDA/ALS centers offer a multidisciplinary team approach for people with ALS, focusing on service and research, and offering the latest therapies. The centers also help people learn to better cope with the disease, and participate in ALS research projects.

The director of the new center in Chicago is neurologist Julie Rowin, associate professor in the Department of Neurology and Rehabilitation and director of the Electromyography Laboratory at the University of Illinois. Rowin conducts extensive research in the areas of ALS and myasthenia gravis.

MDA’s New Site, myMuscleTeam, Helps You Keep in Touch and Coordinate Volunteers

In the journey with ALS, a good support network is essential. Friends, family and willing volunteers make life easier and sweeter in so many ways.  

But coordinating such a network can seem like one more job on an overflowing “to do” list.  It takes time and effort to keep people informed and to connect vague offers of help to actual tasks.

To address this problem, MDA has launched myMuscleTeam, a free online service that helps MDA families experience the strength and support that comes from their community — or “Muscle Team” — of friends and family. 

Available at mymuscleteam.lotsahelpinghands.com, myMuscleTeam allows individuals with ALS and their family/caregivers to create private and secure Web pages that serve two primary functions: communication and care coordination. 

Communication: On myMuscleTeam, users can post photos and journal entries that keep their support network updated on medical matters and life in general. Users only have to post once to reach multiple recipients, as opposed to telling and retelling the latest news to separate individuals. Because the site automatically sends out a notice whenever an update is posted, it also is helpful to those who worry about “bothering you” with questions, but who want to stay up-to-date and aware of your changing circumstances.  The end result: Your support network grows stronger with less effort on your part.

Care coordination: A care coordination calendar enables users to post items for which assistance is needed — such as transportation to medical appointments, meal preparation, shopping, household chores and more — so family, friends and others from your personal “Muscle Team” can sign up to help. Privacy and security settings ensure that you control which people are permitted access to the calendar. An automatic reminder e-mail is sent to those who have signed up to help. This calendar is the perfect answer to the oft-asked question “What can I do to help?”

As you look ahead to the new year, take a moment to check out myMuscleTeam and put it to work
for you!

Not Gloom and Doom: Demystifying Hospice

by Bill Norman

For some, “hospice” is a vague idea whose connection to death leads to outright rejection before the true facts are known.

In fact, hospice neither prolongs life nor hastens death. Instead, it offers practical care and support at a difficult and sometimes traumatic time.

“People should think about hospice as a comfort measure, not gloom and doom,” says Janet Neigh, executive director of the Hospice Association of America (HAA).  “There’s a misconception that hospice is a place. It’s actually a concept, an approach to care for people who have a terminal illness.”

Hospice care helps those with a limited life expectancy — and their caregivers — live each remaining day to the fullest possible, says Neigh. 

Supportive care

Hospice care is palliative — focused on making the patient as comfortable as possible — not an effort at major medical intervention.

Hospice provides a combination of physicians, registered nurses, home health aides, counselors, social workers and trained volunteers who meet the physical, emotional and spiritual needs of patients, their loved ones and caregivers. 

Care can include providing pain relief, bathing and dressing, preparing meals, running errands, doing household chores and providing informed answers to questions. Specialized equipment, such as alternating pressure mattresses, can be made available at the person’s home.

Hospice also provides services for family members, such as bereavement counseling and support groups, for up to a full year after a loved one passes on.

Eligibility and payment

Generally, a person must be certified by a medical doctor as having a terminal illness and probably having six months or less to live, in order to receive two consecutive 90-day periods of hospice benefits.  However, coverage can be extended — for years in some cases — so long as the doctor’s prognosis of six months or less to live is regularly renewed.

People with ALS also may become eligible for hospice care if a doctor certifies they have “rapid functional decline,” whether or not they demonstrate specific declining health characteristics.

Hospice policies vary from facility to facility. Most hospices accept people with pre-existing feeding tubes and some programs also accept patients who already are vented. In a few cases, hospices have rejected people with ALS who are taking Rilutek, a drug that prolongs survival. The local MDA clinic doctor is a good resource when considering hospice.

The great majority of hospice patients have their expenses covered by Medicare Part A. Most private insurances also cover hospice expenses. Less than 1 percent of hospice patients pay out of their own pockets. Other sources of coverage include Medicaid and charitable assistance. (Note: Get expensive equipment such as power wheelchairs and communication devices before entering hospice, as insurance won’t pay for these items afterward.)

Where is care provided?

Far and away the most common setting for hospice care is the person’s own home or that of a family member. Hospice facilities, acute care facilities, nursing facilities and hospitals are utilized to a much smaller extent.

Hospice patients may receive different levels of care in different settings and may move from one setting to another depending on the level of care required. The goal is to ensure that neither patients nor families have to confront a crisis situation on their own.

Routine home care

More than 95 percent of hospice patients — those whose symptoms are under control — receive this type of in-home care, which can include the following:

• Registered nurse visits
• Physician and specialist services
• Home health aide visits
• Medications
• Medical equipment and supplies
• Lab and diagnostic studies
• Counseling (dietary, spiritual, bereavement)
• Therapy (speech, physical)
• A hospice nurse on call 24 hours a day
  

Inpatient care

Patients whose symptoms aren’t being controlled at home may temporarily go to an acute care facility where their condition can be monitored continuously and medications prescribed. When symptoms are brought under control or an acceptable comfort level has been achieved, they can return to routine home care.

Continuous home care

Similar to inpatient care, this level of care differs in that the patient whose symptoms are proving troublesome chooses to stay at home under the continuous care of a hospice nurse. Continuous care is usually considered a short-term situation, and its need is evaluated every 24 hours.

Respite care

Family caregivers, especially in end-of-life circumstances, are under tremendous physical and emotional strain. When they need a break, respite care allows their loved one to stay in an around-the-clock care facility for up to five days at a time before returning home.

No matter the level of care, if a person’s health improves significantly, hospice services can be discontinued. Hospice patients also can, for any reason, sign a revocation statement that cancels their hospice services.

Sooner is better than later

“One of our biggest challenges is getting families to recognize that hospice should be utilized earlier than the last two weeks of life,” says Neigh, of the Hospice Association of America. A minimum of 30 days is needed to really reap the benefits of the program, she says.

“The first week is spent just figuring out patient and family needs,” she says. “It’s a time to get things stabilized. Family and patient have time to adjust to the fact that this is nearing the end. It’s time to do a life review, perhaps to have family and friends come from other parts of the country. It’s an adaptive process. It’s a special time of life.”

People with ALS, family members or caregivers should talk to the ALS health care team about hospice well before they think it’s “the end.”

“Doctors at MDA clinics are very familiar with this issue, and often broach the subject on their own,” notes Scott Wiebe, MDA director of outreach initiatives and the MDA/ALS Division.

Jane Irvine’s mother died from complications of ALS 40 years ago, before hospice existed, and Irvine says that was a primary reason she went into hospice work. She is now the director of home health and extended care at Hospice of the Valley in Phoenix, Ariz., the country’s largest hospice facility.

“I still run through my mind how my mother’s decline and death could have been handled differently. I would have given anything for more support,” she says. “If only hospice had been available at that time, it would have been a lifeline for my mother and me. Though I regret what did not happen for us, I take solace in knowing that the support system offered by hospice is available now for others who walk the same journey."

Can People with ALS be Organ Donors?

by Bill Norman

The fact that many people have the altruistic desire to donate their organs upon their deaths points out the inherent goodness of humans.

But when a potential donor has ALS, can his or her good intentions still be honored?

The answer can be hard to determine. For example, one woman wrote in an online chat that the state of Montana wouldn’t accept the organs of her husband who had ALS, but she later learned that Massachusetts had accepted the kidneys of a man with ALS.

The reason for such discrepancies is that there are 58 regional organ procurement organizations (OPOs) around the United States, and each has slightly different organ acceptance policies, based on guidelines from federal agencies such as the Centers for Disease Control and Prevention, and the Food and Drug Administration.

In the event that the OPO in one region will not accept the organs of a person with ALS, it’s possible that a neighboring OPO will.

Organ acceptability

Beyond regional policy differences, many medical conditions also can preclude people from donating their organs, says Rich Laeng, a public health analyst with the federal Health Resources and Services Administration (HRSA), “but it mostly depends on the donor’s overall health status and what condition their organs are in at time of death.” The urgency of need of a potential recipient also may be taken into consideration.

A determination of organ suitability is usually made by the medical staff that recovers the organs or by the transplant team, which reviews all of the data about the donor.

Organs that can be donated include the heart, heart valves, lungs, liver, pancreas, kidneys, eyes/corneas, tendons, some veins, intestines, skin, bone and more.

The bottom line: “In general, we recommend that all individuals consider themselves potential organ and tissue donors,” says Laeng.

It’s possible to elect to be an organ donor at the last minute, simply by advising medical staff in attendance. Conversely, those who change their minds at the last minute need only advise medical personnel that they no longer wish to donate.

Potential donors should discuss their decision with family members and indicate their intent by signing a donor card, Laeng says, and when the time comes, transplant professionals will determine the suitability of particular organs or tissue. (See “Resources” for more information about organ donation.)

Donating to science

If organ donation proves unworkable, there is still the option of donating to science, as an assist to medical and scientific research.

Most organizations pay for all expenses involved with the process of donating a body to science.  This includes taking possession of a person’s remains, cremation after research is completed and return of the ashes to the family. This whole process typically takes several weeks. Some organizations also pay for the cost of a final ceremony.

The United Network for Organ Sharing, which focuses on donating organs to people in medical need, also has information about donating to research (see “Resources”).

Many educational institutions advertise their programs on the Internet under search terms such as “donate body to science.” 

Note: Paying donors for their organs or bodies is illegal in most countries, including the United States.

Donating for ALS research

Some people with ALS want to donate specifically to institutions doing research on ALS.

Two organizations that accept brains and spinal cords for ALS research are the Harvard Brain Tissue Resource Center and the University of Miami Brain Endowment Bank (see “Resources”).

Other donation organizations, such as MedCure of Portland, Ore., advise donors that their request to have their bodies used for ALS research will be honored if feasible, but not guaranteed. Donations also may be used to find cures for other debilitating conditions, develop new medicines, study human anatomy and perfect new surgical procedures, such as for hip or knee surgeries.

Whether used for ALS or other research, donating a body is a gift to “future generations,” says the company on its Web site. 

“There is no replacement for the human body when it comes to teaching and research.”