ALS TDI and Asklepios collaborating on gene therapy development

The MDA-supported ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass., and Asklepios BioPharmaceutical in Chapel Hill, N.C., which also receives MDA support, are working together to develop viral delivery vehicles (vectors) that could be used to deliver therapeutic genes in ALS.

Potentially therapeutic genes under consideration in ALS include those that carry instructions for neuroprotective proteins or for blockers of harmful proteins.

The project will use custom-constructed “biological nanoparticle” (BNP) vectors, designed by Asklepios. These vectors are known for their ability to penetrate tissues without eliciting a strong unwanted immune response.

The ALS TDI will evaluate the BNP vectors in a tightly managed mouse colony in which the animals have a mutation in the SOD1 gene known to cause a familial form of ALS in humans and a similar disease in mice. Scientists there will analyze samples from animals treated with BNP vectors to determine the cells and tissues in which these vectors localize.

The partnership combines the extensive experience of Asklepios in developing gene-delivery technology with the expertise of the ALS TDI in screening ALS therapeutic leads.

The project is part of a three-year, $36 million funding and scientific collaboration involving MDA’s Augie’s Quest initiative and the ALS TDI.

FDA approves embryonic stem cells for use in study of spinal cord injury

The U.S. Food and Drug Administration (FDA) has said yes to a small safety trial of nervous system stem cells in people with recently sustained injuries to the middle (thoracic) part of the spinal cord, the biopharmaceutical company Geron Corporation of Menlo Park, Calif., announced Jan. 23.

Although this trial has no immediate implications for ALS patients, it’s seen as a major step toward developing stem cell treatments for conditions that damage the spinal cord, including ALS.

In a news release Geron said it will move forward with the “world’s first study of human embryonic stem cellbased therapy in man.” Although the primary goal of the study is to test safety, the investigators will also test for any functional improvement as a result of the treatment.

The cells used by Geron were derived from a single early-stage embryo a decade ago. They are treated in the laboratory to become an immature form of the cells that produce myelin, a coating that surrounds nerve fibers and is needed for their normal function, and they’ll be tested in this trial for their ability to repair damaged nerves in the spine of people injured seven to 14 days prior to treatment.

Although the myelin-producing cells to be used in the Geron trial are probably not the cells that might ultimately be tested in ALS, they and the processes used to produce them are similar to those under development for this disease.

“Embryonic stem cell treatments have been widely praised for their potential application in the repair and restoration of disease or injury damaged tissues and organs,” said Chris Airriess, chief operating officer at California Stem Cell (CSC) in Irvine, Calif., where he has MDA support to develop stem cell-based therapies for ALS. “This huge milestone reached by Geron is a watershed in the development of the field of regenerative medicine.”

CSC Scientific Advisory Board Chairman Hans Keirstead and member Gabriel Nistor are co-inventors of Geron’s experimental treatment for spinal cord injury.

Dogs found with SOD1 mutations and ALS-like disease

Researchers at several institutions in the United States and Sweden have found that a mutation in the gene for superoxide dismutase 1 (SOD1), known to cause ALS in 1 percent to 3 percent of human cases and to cause an ALS-like disease in rodents, also can cause an ALS-like disease in dogs.

The investigators, coordinated by Gary Johnson and Joan Coates at the University of Missouri in Columbia, analyzed DNA samples from 38 Pembroke Welsh corgi dogs with an ALS-like disease and 17 related, clinically normal dogs and found a mutation in the SOD1 gene that was significantly associated with the illness.

Unlike most human cases, however, this SOD1-related disease is recessive, not dominant, meaning an animal must have a mutation in both its two SOD1 genes in order to show symptoms. Humans generally only need one SOD1 mutation to show disease symptoms.

The investigators went on to identify a similar disease caused by the same SOD1 mutation in boxers, Rhodesian ridgebacks, German shepherds and Chesapeake Bay retrievers.

The dogs showed clinical signs of degenerating upper (brain) and lower (spinal cord) motor nerve cells (motor neurons), as in human ALS. When the dogs’ spinal cords were examined microscopically, they revealed loss of nerve fibers and SOD1-containing clumps in their nerve cells, which are also seen in ALS patients.

The dogs are the first spontaneously occurring animal model of ALS discovered, the researchers say in their paper, published online Feb. 2 in Proceedings of the National Academy of Sciences.

Dogs may be better predictors of human responses to experimental ALS treatments than mice, because they’re closer in size to humans than rodents are, their nervous systems are more similar to humans in structure and complexity, and they’re unlikely to possess the very high levels of mutated SOD1 protein found in some mice but not in humans with the disease.

Type B botulinum toxin improves ALS-related drooling for four weeks

Injections of type B botulinum toxin, derived from Clostridium botulinum bacteria, seem to reduce the severity of drooling in people with ALS for up to a month in a recent, small study. There were no significant adverse events.

Carlayne Jackson, director of the MDA ALS Center at the University of Texas Health Science Center in San Antonio, with investigators at the University if Kansas Medical Center in Kansas City and Carolinas Medical Center in Charlotte, N.C., studied 20 ALS patients whose drooling was not responding to medical therapy.

Study participants were randomly assigned to receive one set of injections of either type B botulinum toxin, which is known to reduce saliva production, or a placebo (inactive substance), into two salivary glands (the parotids and submandibulars) on each side of the face.

Two weeks after the injections, 82 percent of the participants treated with botulinum toxin reported improvement in their drooling, compared to 38 percent of those who received a placebo. At four weeks post-treatment, 90 percent of the toxin-treated participants reported improvement, while 44 percent of the placebo-treated patients felt they had improved.

At eight and 12 weeks after the injections, study participants in the botulinum toxin group continued to report improvement more often than those in the placebo group, but these differences were not statistically significant.

“We conclude from these results that it is likely that BTxb [type B botulinum toxin] is effective in improving sialorrhea [drooling] in patients with ALS, although these results need to be confirmed in a larger study,” the authors report in the February 2009 issue of Muscle & Nerve. They say higher doses may be needed to sustain the beneficial effect.

Investigators are looking for an ALS-specific “profile” in blood and spinal-fluid samples.

When investigators coordinated by James Connor at Pennsylvania State University College of Medicine in Hershey compared spinal fluid samples from 41 people with ALS to samples from 33 people with other neurologic diseases to see whether they could develop an ALS-specific “profile,” they found several proteins that were more abundant in the ALS than the non-ALS group.

The investigators, who published their report in the Jan. 6, 2009, issue of Neurology, also found some evidence that ALS may be associated with variations in a gene called HFE, which affects inflammation, immunity and iron regulation.

Such profiles, made up of various biological indicators, or “biomarkers,” may not sound like exciting research, but they’re crucial for accurate diagnosis and tracking responses to treatment. They may also yield insights into disease causation and suggest new possibilities for therapy.

The spinal fluid, also known as cerebrospinal fluid (CSF), which bathes the brain and spinal cord, is believed to be a good source of ALS biomarkers because of its close proximity to the sites of injury in this disease.

The five protein biomarkers that were the most significantly different in the ALS group’s CSF compared to the non-ALS neurologic disease group were interleukins 2, 6, 10 and 15, and granulocyte-monocyte colony stimulating factor. All were found at higher levels in the ALS group, and all either augment or counter inflammation or other activities of the immune system.

The authors say their findings don’t clarify whether inflammatory processes precede disease onset or result from it, but they do reveal inflammatory activity early in the disease process. Their results, they say, are “consistent with the overall concept that microglia [immune cells of the nervous system] recruitment and activation are key components of ALS pathogenesis.”

They note that their data expand those of previous studies and show promise that a biomarker profile of ALS can be developed. Future studies, they suggest, should involve larger numbers of ALS patients with HFE gene variations and patients with ALSlike diseases that aren’t ALS; and they suggest analyzing CSF samples from various time points in the disease to see what changes may correlate with progression.

The MDA-supported ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass., has analyzed some 250 human blood samples in search of ALS-specific biomarkers and hasidentified some preliminary candidates. To ask about participation, contact Beth Levine of ALS TDI at (617) 441-7200 or blevine@als.net

A multicenter study to identify differences in blood and CSF biomarkers between people with ALS and those with other neurological diseases is also seeking participants. Samples will be part of a large repository available to researchers studying ALS, and the samples also will help better understand the cause of these different disorders.

Sites are in California, Florida, Georgia, Illinois, Maryland, Massachusetts, Missouri, New Jersey, New York, New Hampshire, North Carolina, Oregon, Pennsylvania and Utah. Merit Cudkowicz, who heads up the MDA ALS Center at Massachusetts General Hospital in Boston, and Swati Aggarwal, also at Mass General, are the principal investigators.

The study involves blood draws, a lumbar puncture (needle inserted into fluid around spinal cord) to obtain CSF, and collection of disease-related information.

If interested, call the toll-free number at (877) 458-0631.

The Eyegaze Communication system from LC Technologies enables people with ALS to use their eyes to generate speech, create Word documents, surf the Web, send emails, control their environment and stay on the job.

Currently, LC Technologies offers two options — the Eyegaze Edge basic system ($8,700) and the new Eyegaze Edge Tablet ($10,500), which is smaller, has fewer wires and cables, and is more accurate. Both systems serve as speech-generating devices, and typical users average 20 words per minute.

The Eyegaze Edge camera and software also can be purchased separately ($7,250) and attached to a number of computers, including tablets, laptops or desktops, to make your own Eyegaze system.

According to the reports of two users with ALS, the Eyegaze system can be a portal to greater creativity and social connection.

Tell your story

Jack Orchard of St. Louis, Mo., relies on the Eyegaze system for much more than generating speech. Paralyzed from the neck down, Orchard wrote his 192-page autobiography using the Eyegaze and said the technology made the process “incredibly easy.”

For Jack Orchard of St. Louis, Mo., the basic Eyegaze communication system has been a blessing in many ways, not least of which was his ability to write and publish his autobiography, Extra Hands — Grasping for a Meaningful Life.

Paralyzed from the neck down, Orchard, 41, wrote the entire book using his Eyegaze system, which he’s had since 2005. It took about three months to produce a first draft and another 15 months to get it ready for publishing. (Extra Hands for ALS is an organization Orchard started in 2002 to provide helpers to families coping with ALS. The group disbanded in December 2008.)

Writing his book was “incredibly easy, almost effortless, thanks to the sophistication of the technology,” Orchard wrote via e-mail. “When you lose your natural connections to other people and replace them with a special tool like Eyegaze, you come to rely very heavily on it and using it becomes almost as natural as using the capabilities you’ve lost.”

Orchard uses the system at least 12 hours a day. A former venture capitalist with a degree in economics from Harvard and an MBA from Stanford, he says the learning curve isn’t very steep but does take some practice.

To use the system, a person stares at a letter on the screen for a certain “dwell” period (which is adjustable). Orchard says this may sound simple, but normally people aren’t accustomed to staring at a letter while typing.

“As we press keys with our fingers, we scan ahead with our eyes looking for the next letter,” Orchard explained. “But when you type with your eyes, you have to get away from scanning ahead and focus your glance only on the letter you want.”

It also took time for Orchard to get used to Eyegaze’s different screens for mouse control, environmental controls, text reader, common phrase reader and games. He currently uses the speed onscreen keyboard because the letters are arranged around the space bar according to how frequently they’re used in the English language, making it easier for him to type quickly with very little eye movement. With a dwell rate set at .18 seconds, Orchard types about 30 to 35 words a minute.

“That’s fast enough that it doesn’t even feel like ‘dwelling’ on a letter,” Orchard said. “I just look at anything on the screen, and the system instantly accepts my choice. It took many months to be able to use it effectively at this dwell duration, in the same way that it takes a lot of practice to type on a keyboard without looking at the keys.”

Orchard says the initial calibration of the system to his gaze was done in 10 seconds, but he typically recalibrates a few times a day to adjust to changing light in his office.

Orchard has connected his system to a separate PC which runs several software programs simultaneously. The Eyegaze system sits to the left of his PC, which is directly in front of him; since Eyegaze only tracks one eye, it doesn’t have to sit directly in front of the user.

One downside of having separate pieces is that it’s difficult to move the system to and from his desk and wheelchair. But Orchard says it’s safer to keep them separate because it “keeps the eye-tracking software insulated from the garbage you pick up by browsing the Web and e-mail like viruses, spyware, cookies, etc. If something causes your system to crash, at least your communication capability is never in jeopardy.”

New connections

In Castleton, Va., the Eyegaze Edge has changed John Singleton’s life in only six short months. Singleton, who received a diagnosis of ALS in 1991, had never been on the Internet before September when he received the Eyegaze Edge. Since then, Singleton has discovered ALS chat groups and communicated with people all over the globe.

John Singleton of Castleton, Va., proved a quick study with the new Eyegaze Edge system. Singleton logged on to the Internet for the first time when he received the system six months ago and has made numerous online connections.

The 47-year-old grandfather uses the system an average of 10 hours a day, sending e-mails, surfing the Internet and generating speech.

“I have a big family, and when we get together, it gets pretty loud. Before I got my Eyegaze, it was very hard for anyone to hear me. But now, I can say what’s on my mind, and everyone can understand me.”

He admits that the system was a bit challenging in the beginning, but that he caught on fairly quickly and continues to improve. At first his eyes would get dry after using it for a while, but he doesn’t have a problem now that his eyes have acclimated to the system.

Singleton’s one suggestion for improvement would be making the Edge easier to transport on his wheelchair. The Eyegaze Edge must be plugged in, making it difficult to transport the 15-inch flat-screen monitor. (The latest version, the Eyegaze Edge Tablet runs off its own battery and mounts to a wheelchair or table, making it easier to transport.)

The original Eyegaze communication system cost $32,000, but in the years since its development, the system has undergone several improvements and upgrades — making it more portable and affordable.

“All I used to do is watch television all day long, but now I have something to do of my own,” he said. “I get to communicate with people that have ALS in an online forum, and they tell me I’m helping them with what I say.”

Singleton even reconnected with his first love from 30 years ago. Although their lives went in different directions, Singleton always thought of her fondly. He managed to locate her online, and they’ve been “connected” ever since.

“I get to communicate with people online, and I’ve never been able to do that before in my life,” Singleton says of his Eyegaze Edge system. “I wouldn’t know what to do without it.”

Medicare will cover up to 80 percent of the cost for a communication device, and MDA offers a one-time $2,000 grant for devices prescribed through its clinics. MDA also will provide $500 annually for repairs and modifications. To learn more about the new Eyegaze Edge tablet system and other options, visit www.eyegaze.com, or call (800) 393-4293.

Entering sweepstakes via the Internet is a “lifeline to sanity” for David N. Gresh of Honeoye Falls, N.Y.

Gresh, 55, received an ALS diagnosis in 2002, and two years later retired from his career as a kitchen and bathroom designer for a small design company called Bright Ideas.

Introduced to the Web site Sweepstakes Advantage (www.sweepsadvantage.com) by his live-in caregiver, Trish Gannon, he gave it a try and has been hooked ever since.

Launched in 1997 as a “free online directory of sweepstakes, freebies and contests,” Sweepstakes Advantage lists thousands of contests by category (daily, monthly, instant win, etc.); by prize (cash, travel, electronics, automobiles, etc.); and by destination (fishing, Disney, etc.).

Registering with the site (free) gives members access to more than 5,000 onlinecontests, as well as tools for keeping track of what they’ve entered and forums to chat with other contestants. In exchange, the site collects certain personal information from users, who then receive targeted ads and offers.

Gresh “sweeps” using a wireless mouse, an onscreen keyboard and a software program called Roboform that makes it easier to fill out online forms.

Sweeping four to six hours each day, he has entered thousands of contests and won some 75 prizes, including cash, gift cards, movie tickets, DVDs, tickets to Six Flags, an iPod and a guitar signed by Faith Hill and Tim McGraw. The site also pays for the completion of product marketing surveys.

Giving it away

Occasionally, Gresh will win a prize that he can’t use, such as the all-expenses-paid trip for two to Los Angeles, (he gave it to Gannon and her 16-year-old son), and the “skis that don’t seem to fit my power chair.” If neither Gresh nor his friends can use a prize, he’ll donate it to a good cause or sell it on eBay.

The one prize that he really wants to win is a trip into space on a suborbital flight.

“That’s one up on Stephen Hawking,” he jokes.

In addition to earning money by completing surveys on products and services through Sweepstakes Advantage, he also visits Web sites that only offer survey completion such as www.greenfieldonline.com, www.zoompanel.com and www.socraticforum.com.

Another place Gresh frequents is www.mypoints.com, where he earns points that can be redeemed for gift cards by reading e-mails and buying from the sponsors.

Passing the Torch

Gresh says he wants to share information about these sites even though it decreases his chances of winning.

“I would suggest ‘sweeping’ for ALS survivors if they can use the computer because it’s a fun hobby, the thrill of winning is exhilarating, and imagining winning and enjoying the prizes gives me hope each day,” says Gresh.. “We all need a daily dose of hope.”

For more sweepstakes tips, contact Gresh at daveg0929@yahoo.com.

MDA’s “ALS: Anyone’s Life Story” campaign once again will be featured on its ALS Division Web site during national ALS Awareness Month this May.

This online series introduces individuals affected by ALS from across the nation, raising awareness of ALS by illustrating that it truly could be “Anyone’s Life Story.” MDA notifies local media whenever someone from their area is featured on the series, which often leads to additional media coverage.

A different individual will be featured each of the 31 days in May. To see those featured in 2008, visit the MDA ALS site (www.als-mda.org), click on Resources at the top, then Anyone’s Life Story.

Potential candidates for the series include people with ALS who are public speakers, leaders within local MDA support groups and outreach efforts, or anyone living with ALS who has an inspirational outlook on life.

If you’re interested in applying, contact your local MDA office by calling (800) 572-1717.

But hurry! The deadline for applications is March 10! Candidates must fill out a short questionnaire and provide a photo; call your local office for complete information.

In September 2006, Charlene DeMarco, a former doctor of osteopathy, and Elizabeth Lerner were convicted of 11 federal charges of trying to cheat people with ALS and their families.

The two had claimed they could treat ALS patients with stem cell therapy, going so far as to say DeMarco had received approval from the U.S. Food and Drug Administration (FDA).

Lerner and DeMarco’s scheme brought in tens of thousands of dollars from people with ALS hoping to benefit from a treatment they never did receive.

DeMarco was sentenced to 57 months in prison and Lerner to 33 months. They also were ordered to pay more than $82,000 in criminal fines and restitution to victims.

A serious problem

The sorts of claims made by DeMarco and Lerner are not new.

One day it’s stem cells in China; the next, chelation in South Carolina. It might be detoxification or a strict antioxidant regimen prescribed on the Internet, or South American herbal supplements. These treatments may be touted as “the answer” that will “drastically slow disease progression,” or sometimes even as “the cure.”

Safety and efficacy questions aside, the only guarantee when it comes to such claims is that there’s likely someone behind them who stands to make a healthy profit at the expense of families coping with ALS.

The dangers inherent in some of these “treatments” aren’t limited to loss of income. The possibility exists that they may exacerbate ALS symptoms; hasten the progression of the disease; interact negatively with other prescribed medications; or cause health problems such as liver or kidney failure.

Even if they cause no adverse effects, if they fail to slow or stop ALS as advertised, they may become the source of stress, disappointment and dashed hopes.

Learn to spot a scam

In the year since her ALS diagnosis, Sharon Caruthers of Mentone, Calif., has heard about a fair number of products and procedures she describes as “scams.”

One of the first clues, she says, is the inability to get straight answers about the product or service.

“All the talk from scammers kind of reminds me of people who say they talk to dead people,” she says. “Don’t you think if they really were talking to a ghost they’d just give you their name, not ‘I think I get a feeling for a name with a J, maybe Jim or John’?”

If the treatment in question were real, she says, reputable doctors would be “shouting it from the rooftops.”

Other signs of a scam include:

• claims backed by testimony from individuals, not scientific evidence;
• no rigorous, controlled trials;
• the treatment has not been published in a peer-reviewed scientific journal;
• the treatment is only available from the source that’s offering it;
• attempts to contact the person advertising the treatment are ignored; and
• product Web sites are forever “under construction,” forcing interested parties to make contact by phone.

Sharon Caruthers says the discovery of a legitimate therapy for ALS will be publicized by reputable physicians, not marketed by an unknown individual or group through an obscure Web site.

“There have been dozens of compounds that have been in large clinical trials for ALS that have all failed,” says neurologist Katalin Scherer, who directs the MDA/ALS Center at UPH Hospital in Tucson, Ariz.

“So someone’s claims that what they’re selling will cure ALS or prolong survival are highly unlikely to be true.”

Wanting to believe

People with ALS always are potentially vulnerable to misinformation on therapeutics, says John McCarty, director of therapeutic investigations at the ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass.

“There seems to be a time, associated with coming to grips with the diagnosis and the implications, where many folks simply can’t believe that at least some of these various claims aren’t true,” he says. “After all, most of us are inclined to assume the best of people and intentions, and are used to believing what we read.”

McCarty notes that problems sometimes arise when people with ALS seek out research publications, perhaps for the first time in their lives, and try to make sense of them.

This “may set up folks for frustration and exposure to quack therapists,” he says.

Also complicating matters is the very nature of the claims themselves.

“Many of the unlikely-to-benefit therapies have a kernel of real, possible science at the core — or at least something that was considered as possible by scientists at some point,” McCarty explains. “Thus, many of these quack therapies are like pearls — attractive in that a clinic, for example, can build lustrous promises over a grain of rough science. But the proven clinical effectiveness is simply not there.”

The right to try something

With the exception of riluzole (the only FDA-approved drug for ALS, which provides modest benefits for some with the disease), people with ALS “have no options,” Caruthers says, adding that it makes sense that they “should be able to try something” as opposed to simply dying.

Katalin Scherer recommends that anyone who chooses to try an unproven therapeutic should talk to their doctor about it.

Scherer acknowledges that this sentiment is often at the heart of an individual’s decision to try unproven therapeutics.

“They want to know, ‘If I’m going to die anyway, why can’t I try this, that or the other?’”

Scherer reminds her patients that, although death may come earlier because of ALS, “there’s no guarantee and no predicting for them or for any of us.”

She emphasizes that ethical and moral obligations don’t permit physicians to encourage patients’ use of untested therapeutics. Importantly, she notes, some compounds which have been effective in animal trials have not worked in humans — and a handful actually have proved harmful to humans.

“The first oath we take when we become physicians is ‘Do no harm,’” she says. “If someone has an incurable disease, it doesn’t give us license to try whatever we want in hopes of making it better, because ultimately it could be harmful.”

McCarty suggests that patients consider “whether to embark on a particular unproven therapeutic route, or how one can best contribute to the research efforts and thus ensure this is the last generation of patients with the untenable situation of facing a fatal disease with no obvious therapeutic options.”

Information and misinformation

When it comes to avoiding scams, the main thing to remember is, the more information, the better. Good information often can be distinguished from bad by assessing the quality and reliability of the source.

“If you Google things [do an Internet search], be wary of where the search results come from,” Scherer advises. Start research at Web sites of bona fide authorities, such as MDA, the National Institutes of Health and the FDA. These often yield references to other credible sites.

Caruthers also advises talking with long-term survivors of ALS who are familiar with the ways of scam artists. “Old-timers” can be contacted online at sites such as:

• MDA’s chats
  www.mda.org/chat/calendar.html
• ALS TDI’s Forum
  www.als.net/forum
• Patients Like Me
  www.patientslikeme.com
• The ALS Forums
  www.alsforums.com
• Living with ALS
  http://health.dir.groups.yahoo.com/group/living-with-als/

Tell your doctor

Scherer recommends that those who’ve decided to try an unproven therapy talk to their physician about it.

Although some might be skeptical about revealing such information to their doctors, she says, “In my experience, we’re very open to these discussions. In order to maximize our patients’ safety, we need to know if there’s any potential for hazardous interaction with the prescribed medications they’re taking.”

Sharing their experiences with others in the ALS community is important as well.

McCarty hopes that those who try unproven therapeutic routes “communicate as objectively as possible on the experience. We know as researchers and clinicians that the chance for most of these interventions to help in slowing ALS is essentially null; thus, it’s crucial that those who take that risk communicate their experience.”

“Share,” he urges, “so that others can learn.”

Catherine Lomen-Hoerth says some abnormal behaviors in people with ALS may be reaction to the disease; others may be something more.

Jean-Pierre Julien says immunization strategies may prove beneficial in some cases of familial ALS.

Induced pluripotent stem cells (iPS) hold promise both for modeling of disease progression and as therapy, notes Clive Svendsen.

Nearly 600 conferees gathered in Las Vegas Jan. 25-28 for the 2009 MDA National Clinic Directors’ Conference, where a number of speakers presented a broad range of ALS-related topics. Here are some highlights.

Abnormal behavior in ALS may deserve closer look

Catherine Lomen-Hoerth, who directs the MDA clinic at the University of California at San Francisco (UCSF), reported on fronto-temporal dementia (FTD) and ALS.

FTD is the selective degeneration and atrophy in the parts of the brain known as the frontal and temporal lobes. Symptoms include personality changes, difficulty with language, and behavioral disturbances. It’s progressive and, as yet, irreversible.

Although cases of severe FTD are uncommon in ALS, Lomen-Hoerth said there’s likely a continuum of cognitive and emotional deficits, making it important to look at abnormal behaviors in people with ALS and determine whether they appear to be reactions to the disease or something more.

Importantly, studies have shown shorter survival time in patients with ALS-FTD than in those who have only ALS. One reason for this correlation may be that compliance with treatment recommendations, such as with noninvasive ventilation assistance and feeding tubes, has been shown to be significantly less than in those with ALS but without FTD. Also typical in ALS-FTD, according to Lomen-Hoerth, are lack of judgment, poor insight into the disease process and difficulty using equipment.

A 20-minute screening test currently being developed at UCSF validates cognitive diagnoses in people who have ALS with 80 percent accuracy. However, Lomen-Hoerth noted, a full neuropsychological battery of tests, which includes takes nearly three hours to complete, is more sensitive to identification of cognitive impairment.

Immunization strategies offer therapeutic potential in familial ALS

Jean-Pierre Julien from Laval University in Quebec discussed immunization as a means of clearing the harmful molecules of mutated superoxide dismutase 1 (SOD1) protein associated with 20 percent of cases in the familial (inherited) form of ALS (which in turn accounts for 1 percent to 3 percent of all cases of the disease). Such strategies are based on the idea that reduction or neutralization of toxic mutant SOD1 molecules would alleviate the disease.

As noted by Julien and colleagues in a paper published in the Feb. 13, 2007, issue of PNAS, vaccination with human mutated SOD1 delivered by subcutaneous (under the skin) injection delayed disease onset, slowed the rate of motor function loss, and extended survival by approximately 30 days in mice known by the designation G37R and engineered to moderately overproduce mutant SOD1.

However, in G93A mice, which are characterized by severe SOD1 overproduction, the same “active” approach (in which the animal is given a foreign substance to which it may make antibodies) failed to result in significant positive effects.

Researchers suggested the number of anti-SOD1 antibodies that entered the nervous system may have been insufficient to neutralize such extreme levels of mutant SOD1 in the nervous system tissue. They found a “passive” approach, entailing direct infusion of an antibody solution into the brain, did help ameliorate the disease in these mice.

Work is now in progress to derive antibodies against SOD1 that might be suitable for treatment of patients with familial ALS caused by SOD1 mutations.

Stem cells may have variety of roles in research and treatment

Clive Svendsen of the University of Wisconsin-Madison reported on stemcell therapy development in ALS.

One way to develop this type of therapy would be to turn stem cells into progenitors of motor neurons to replace those lost as a result of ALS. The greatest hurdle, however, may lie in figuring out how to get new motor neurons to connect to muscle.

Other approaches therefore may hold more promise, Svendsen said. They might involve decreasing levels of mutant SOD1 protein, preserving cells that protect neurons and aid their survival, and/or transplanting new non-neuronal support cells that release neuroprotective proteins.

Induced pluripotent stem cells (iPS) are adult cells “regressed” back to a stemlike stage of development from which they can be coaxed down a particular developmentalpath. They hold great promise for the modeling of disease progression. As therapy, they offer the tantalizing prospect that, when implanted back into the individual from whom they were first derived, they probably won’t elicit an immune response.

Numerous trials involving stem cells are in the planning stages. (See “FDA Approves Embryonic Stem Cells.")

Sean Scott, president of the MDA-supported ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass., died on Feb. 9, after a relatively short battle with ALS, which also took the life of his mother.

Scott, 39, came to the ALS TDI as a volunteer in 2000 and quickly took the helm in developing its program, particularly the software that tracks the Institute’s research pipeline and helps it allocate resources.

He and his mother both had the SOD1-related familial form of ALS, which affects from 1 percent to 3 percent of those with the disease.

“ALS is a hell of a disease,” Scott wrote in an e-mail message to close friends and relatives composed shortly before his death.

“I spent the last decade building an infrastructure to combat this disease. I had declared war on it, but in the end it got me first. At a minimum, I think I earned the right to be referred to as KIA [killed in action] and not a victim. I’d prefer that you remember me that way.”