COENZYME Q10 SAVES NERVE CELLS IN MICE WITH ALS

Researchers at Massachusetts General Hospital and Harvard Medical School in Boston have found that coenzyme Q10, a widely available over-the-counter compound, can combat nerve-cell degeneration in mice with ALS. The study is in the July 21 issue of Proceedings of the National Academy of Sciences.

MDA grantee M. Flint Beal of the Department of Neurology at Massachusetts General and also at Cornell University Medical Center in New York was part of the research team. "I'm not as yet recommending that people with ALS take coenzyme Q10," Beal said. "In order to make this recommendation, it will be necessary to do a clinical trial. I don't believe it would be harmful, but there is no evidence as yet that it will be beneficial."

Coenzyme Q10 acts in at least two ways in cells, the paper's authors say. One, it's an antioxidant, combating oxidation-reduction reactions that can damage cell membranes and other structures. Two, its activity is part of the chain of biochemical events that take place inside the cells' mitochondria, its energy-producing units.

"I do believe that more effective antioxidants may be beneficial for ALS patients," Beal said. "A number of these are under development, but further work needs to be done before these can be unequivocally recommended for ALS patients."

Oral coenzyme Q10 significantly prolonged the lives of mice with mutated SOD1 genes and a disorder that closely resembles human ALS (which also sometimes results from mutations in this gene). Coenzyme Q10, even when given by mouth, was found to penetrate into brain tissue in general and into the mitochondria of brain cells.

"Both antioxidant effects and preservation of mitochondrial function may contribute to the observed neuroprotection," the authors say. "Although vitamin E supplementation delays disease onset in [such] mice, it has no effect on survival," the report continues. "This finding suggests that coenzyme Q10 may be more effective than vitamin E in the treatment of neurodegenerative diseases."

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CALCIUM-BLOCKING COMPOUNDS FROM VITAMIN D MAY BECOME NEW TREATMENT

Theories differ on how it gets there and what it does, but almost all researchers in neurodegenerative diseases agree on one thing: Excess calcium is definitely a signpost on the road to nerve-cell death. Recent studies suggest calcium does its greatest harm when too much of it gets into the cells' mitochondria, their crucial energy-producing units.

MDA research grantee Stanley Appel of the Department of Neurology at Baylor College of Medicine in Houston is among researchers who say they may have a new lead on how to rid motor neurons of excess calcium. Appel, who directs the MDA/ALS Center at Baylor, says molecules that resemble vitamin D could probably be used to increase production of proteins that stick to calcium, change its actions in cells and decrease its ability to do harm.

Known as calcium-binding proteins, these have names like calbindin and parvalbumin, and they protect many of the body's cells from the dangers of too much calcium. Calcium-binding proteins are, however, sadly lacking in the motor neurons (muscle-controlling nerve cells) that degenerate in ALS, perhaps explaining just why these particular cells are singled out in this disorder in the first place.

The investigators found that the vitamin D molecule they were testing increased production of calcium-binding proteins and decreased calcium levels in motor neurons. However, vitamin D can also raise blood levels of calcium to dangerous levels.

Writing in the Jan. 1 issue of Neuroscience Research, Appel and co-authors caution that currently available vitamin D preparations have both effects and could be highly toxic. "People with ALS should not take extra vitamin D now," Appel says.

However, he says, modified versions of the vitamin D molecule that aren't yet available "may be useful tools in enhancing the expression of calcium-binding proteins in the motor system and may have possible therapeutic value in neurodegenerative disease."

Appel also notes that limiting dietary calcium will not help reduce calcium in motor neurons and may lead to loss of calcium from the bones.

Appel's laboratory has a grant from MDA to continue this work.

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MYOTROPHIN IN LIMBO BUT NOT YET GONE

The experimental ALS drug Myotrophin "appears likely to remain in scientific and regulatory limbo for at least another year," says Peter Doskoch, senior editor of Neurology Reviews, in the September issue of that publication.

That's not a surprise for this drug, whose history has been mired in difficulties since it was first brought before the Food and Drug Administration for market approval in 1996.

Conflicting Results

The crux of the matter seems to be the conflicting results of two large clinical trials, one conducted in North America and one in Europe. The North American trial suggested that Myotrophin, which is derived from the natural body chemical insulin-like growth factor 1, might have some benefits for people with ALS, but the trial in Europe suggested it would not. Both trials used the Appel rating scale that measures loss of function over time.

An FDA advisory panel has refused to approve Myotrophin twice, in 1996 and again in 1997, citing insufficient evidence that the drug helps people with ALS. The 1997 panel agreed with the sponsoring drug companies (Cephalon and Chiron) that Myotrophin appears safe.

'Potentially Approvable'

On May 12 of this year, cautious optimism prevailed among Myotrophin's supporters, which include not only Cephalon and Chiron but many patients and some doctors, when the FDA stated that the drug was "potentially approvable" subject to review of additional information. (Supporters say the drug extends strength and functional abilities.)

The requested additional information includes either results from patients now taking the drug under Cephalon's "expanded access program," in which people selected by a random access process receive Myotrophin for free, or results from an ongoing trial of Myotrophin in Japan, Cephalon spokesman Jason Rubin said on Sept. 28.

Rubin said Cephalon has provided all the available information from the expanded access program and that the Japanese trial results won't be ready until next year.

European Bid Withdrawn

Meanwhile, Cephalon issued a Sept. 15 press release saying that it and Chiron have withdrawn an application to market Myotrophin in Europe. "This decision was based on difficulties in resolving issues raised by the Rapporteurs [reviewers] concerning the differences in response seen in the two pivotal studies, and whether a benefit measured by slowing disease progression, using a functional rating scale, is considered clinically relevant," the press release states.

Benefits for Some?

A ray of hope for Myotrophin may lie in the view of some researchers who say ALS probably has many causes and that there may be some types of ALS that would benefit from this drug and others that wouldn't. Statistics showing benefit to an as-yet-unidentified group of ALS patients could be lost in those from the larger group, supporters of this view say. Whether a search for a subgroup of "Myotrophin responders" will be undertaken remains to be seen.

Access Continues

Between 300 and 400 patients are now receiving Myotrophin through the expanded access program, Rubin said, adding that the program remains in operation but isn't selecting new patients at this time.

* * *

To keep up with Myotrophin's progress, check Cephalon's Web site at www.cephalon.com, where the company's press releases and other information are frequently updated. The company's main phone number is (610) 344-0200, and the toll-free number for the expanded access program is (800) 896-5855.

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GOLDBERG REMEMBERED

Members of MDA's ALS support group in the Dallas/Fort Worth area wanted to remember their friend Barry Goldberg in a special way on the 1998 MDA Telethon. They established the Barry Goldberg Award and selected Douglas Adams, president and general manager of KXAS-TV in Dallas/Fort Worth, to receive the first annual award.

Goldberg was a Plano, Texas, resident and MDA leader who died in January after eight years with ALS.

Along with the plaque, Adams was given an Energizer bunny. Goldberg often compared himself to the toy, which "keeps going and going." The award was underwritten by the Everready Battery Company.

Adams is also an MDA vice president.

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MATTINGLY FAMILY FEATURED IN LIFE MAGAZINE

Maryland resident Andrew Mattingly Jackson Jr. spent years encouraging scientists to study the debilitating, long-term disorder that has affected his family for generations.

As a result, leading researchers made progress earlier this year in narrowing the location of the gene that underlies the disease, a juvenile-onset form of ALS which seems to be compatible with a normal life span. On Oct. 5, Life magazine published an issue highlighting the Mattingly family saga.

The condition, sometimes referred to as Mattingly's disease after the main branch of Jackson's family, has in the past been diagnosed as Charcot-Marie-Tooth disease (CMT), a peripheral neuropathy.

But Jackson, who has the disease, as did his father and as does his 48-year-old son, long suspected it had nothing to do with CMT.

"Every time I was with someone who had that disease (CMT), I could see a decided difference between me and them," Jackson says. For example, Jackson realized he wasn't experiencing the loss of sensation associated with CMT.

Jackson, who is 70 and a widower, has about 50 relatives affected by the disorder. Dozens more stand a good chance of developing it.

Jackson first noticed symptoms in 1947 when he was in his late teens, although he believes there may have been earlier indications. The disease progressed at a gradual rate.

He worked for Black and Decker for 40 years and retired only when he felt that the disease made it hard for him to fulfill practical functions of the job.

He now lives in a retirement community, and although he was able to drive a van up until about four years ago, he can no longer bathe or feed himself or perform other personal tasks without caregiver assistance. He can write by picking out one letter at a time via a computer device. His powers of speech are undiminished.

His history is fairly typical of the familial disorder. Average age of onset is 17. Difficulty walking is usually noticed first. By the 30s or 40s an affected individual is likely to require a wheelchair and, by the 50s, useful hand function is generally lost.

Despite the early appearance of symptoms and slow progression over a normal life span, leading researchers now believe the condition falls within the ALS family and refer to it as a juvenile-onset form of disease.

Four years ago, some 150 Mattinglys gathered for a reunion on Solomon's Island, Md. The event served as a kickoff for the genetic study of the disease. Blood samples were taken to provide DNA of affected and unaffected family members.

Jackson coordinated the blood-taking and made sure samples made their way to the laboratory of Philip Chance, the MDA grantee who headed up the study. Chance, a neurologist and genetics researcher, was at the University of Pennsylvania at the time but is now at the University of Washington in Seattle.

Jackson also contributed extensive genealogical information.

David Cornblath, an MDA grantee and a neurologist at Johns Hopkins University in Baltimore, also participated in the study. The researchers credit the family in general and Jackson in particular for their success in mapping the gene to a small region of chromosome 9, a finding reported earlier this year in the American Journal of Human Genetics and The ALS Newsletter (Vol. 3, No. 2).

The disorder hasn't been recorded outside the Mattingly family, although Jackson has hopes that increased publicity will lead to the discovery of unrelated affected individuals.

Jackson says no clinical trials have been undertaken to test potential ALS drugs on this particular form of ALS, but he'd like to see that happen.

Like CMT, juvenile-onset ALS is an autosomal dominant disorder. If one parent carries the affected gene, any child has a 50 percent chance of inheriting the disease.

Further study will focus on pinpointing the gene and then on understanding the cellular processes it regulates. It's possible that this increased understanding could benefit all people with ALS, inherited or otherwise.

All members of the Mattingly family are descended from British colonist Thomas Mattingly, who died in 1664. The branch of the Mattingly family that carries the disease settled in Maryland. Descendants of Mattinglys who spread westward, including baseball player Don Mattingly, appear to be much less frequently affected by the illness.

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HELP FIGHT ALS TODAY AND TOMORROW

Many people who know the devastating effects of ALS are providing lasting support for MDA's battle against the disease. Through your will, you can designate a gift to MDA earmarked to support ALS research or services.

Bequests to MDA can be made with cash, securities, real estate, or other property. You can bequeath a percentage of the entire estate to MDA or make a bequest of the residue, donating property remaining after all bequests to family and others have been satisfied. You may also name a memorial gift in honor of a family or individual.

To give what remains of your estate after other bequests have been satisfied, just include the following language in your will:

"I give, devise and bequeath all (or a specified fraction of) the rest, residue and remainder of my estate, whether real or personal, of every kind and description, and wherever situated, to Muscular Dystrophy Association Inc., a New York not-for-profit corporation having its principal office at 3300 East Sunrise Drive, Tucson, Arizona, 85718-3208, for its program of research and services related to amyotrophic lateral sclerosis."

To give a dollar amount or percentage of your estate:

"I give, devise and bequeath the sum of $________ (or ________ percent of my estate) to Muscular Dystrophy Association Inc., a New York not-for-profit corporation having its principal office at 3300 East Sunrise Drive, Tucson, Arizona, 85718-3208, for its program of research and services related to amyotrophic lateral sclerosis."

Your attorney or financial adviser can help you work out the details of a bequest to MDA's ALS program. For more information, call MDA's Planned Giving Department at (800) 572-1717.

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FILM TO PORTRAY ALS

A new film made in England will throw the dramatic spotlight on ALS. "The Theory of Flight" stars Helena Bonham Carter as a woman with ALS and Kenneth Branagh as her friend and caregiver. The relationship between the two characters is designed to generate humorous and romantic moments as well as serious ones.

The film, directed by Paul Greengrass, is slated for U.S. release this December from Fine Line Features. To correctly portray ALS, which is known as motor neuron disease in England, the filmmakers solicited advice from England's Motor Neuron Disease Association.

Award-winning actress Bonham Carter said that playing someone who has lost mobility and speech due to ALS was a "life-changing experience" for her. But she acknowledged that she couldn't truly know the reality of living with ALS since she was able to walk away from the role and the wheelchair at the end of the shooting day.

Another film dealing with ALS, an independently produced feature called "Hugo Pool," opened to uneven reviews last year. The film, directed by Robert Downey Sr., featured a character with ALS played by Patrick Dempsey.

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The Association welcomes gifts for ALS research honoring significant occasions of achievement. These gifts may be made in tribute to special people or to mark such events as anniversaries, birthdays, weddings, graduations or retirements.

THE ALS NEWSLETTER
Muscular Dystrophy Association
National Headquarters
3300 East Sunrise Drive
Tucson, Arizona 85718-3208

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