VACCINE MAY SOMEDAY TREAT MG

Vaccinelike compounds could someday be used to treat the muscle disorder myasthenia gravis (MG), says MDA-supported immunologist J. Edwin Blalock at the University of Alabama at Birmingham.

Blalock was part of a team that developed two vaccines against MG, publishing their most recent results in the January issue of the FASEB (Federation of American Societies for Experimental Biology) Journal.

In MG, proteins produced by the immune system (antibodies) attack specialized docking sites (acetylcholine receptors) that normally receive a chemical signal (acetylcholine) from a nearby nerve cell ending. The acetylcholine signal is normally the first step in muscle contraction.

In MG, considered an autoimmune (self-immune) disease because the body's immune system attacks its own tissues, antibodies block or destroy acetylcholine receptors. The blockade and destruction lead to fluctuating weakness that can be severe.

	In myasthenia gravis, antibodies (A) attack docking sites on muscle cells that would normally receive chemical signals from nerve cell endigns. Activated T cells (T) and B cells (B) lead to antibody production.	MDA researchers created one vaccine (vt) that causes the immune system to attack activated T cells and another vaccine (vab) that causes it to attack activated B cells and the antibodies that destroy docking sites.

Blalock's strategy led to production of vaccine compounds that resemble, but don't look exactly like, the parts of immune-system cells that are activated during an autoimmune attack against muscle. These are the T-cell and B-cell receptors and the antibodies.

The vaccines make the immune system regard T-cell receptors, B-cell receptors and antibodies against muscle docking sites as foreign invaders and, therefore, worthy targets of destruction. The immune system then turns against its own mistakes, and nerve-to-muscle transmission is restored, animal experiments show.

The vaccines have prevented MG or made it milder in rats that would otherwise have developed full-blown MG symptoms when given the disease, Blalock says. He's also treated both rats and dogs that already have MG with such vaccines and has seen improvement. One dog has been free of the disease for three years and another for five.

Vaccine strategies may be the wave of the future in treating several autoimmune disorders.

PROGRESS IN UTROPHIN THERAPY FOR DMD

MDA-funded researchers are exploring a number of different strategies to develop therapies for Duchenne and Becker muscular dystrophies (DMD and BMD), the degenerative muscle diseases caused by a lack or shortage of the dystrophin protein.

Now Kay Davies of the University of Oxford in England reports that her group has found a second way to activate the production of utrophin, a protein that may be able to stand in for dystrophin in the muscles of people with DMD or BMD.

Utrophin is a sort of molecular cousin to dystrophin that only is found at specialized areas on the surfaces of muscle cells called synapses. Dystrophin, in contrast, is usually found over the entire surface of the muscle cells. Previously, Davies' group found that utrophin can compensate for the missing dystrophin in the muscles of mice with muscular dystrophy if enough of it can be made to cover the whole surface of the muscle cells.

Although mice can be genetically programmed to make more utrophin from birth, this approach will not work in humans. Instead, Davies is interested in identifying the switches that normally regulate the amount of utrophin produced in the muscle so that ways can be found for increasing utrophin production at any time by manipulating these switches.

Her group identified one such switch, known as a promoter, for the utrophin gene last year. Unfortunately, this first promoter acted more like a master control switch and had the potential to turn on a lot of other genes whose products are normally only found at the muscle synapse. The researchers worried that changing the activity, or expression, of a large number of genes might harm the muscle. What was needed was a more specific switch.

Now, the researchers have found a second switch to turn on the utrophin gene that doesn't seem to regulate other synapse-specific genes.

"We now plan to search for chemicals that can activate this second promoter," Davies says. "We know this approach works because we've done this with the first promoter, working with OSI Pharmaceuticals, and have found some compounds that look promising. Many drugs upregulate (increase the activity of) genes, so we are hopeful of finding one with minimal side effects."

Ultimately, this research could lead to a drug treatment for DMD and BMD, an approach that may be easier than trying to replace the defective dystrophin gene in trillions of muscle cells.

FA LINKED TO DECREASE IN CELLULAR ENERGY

Friedreich's ataxia (FA) is a progressive neurodegenerative disorder that causes uncoordinated movements and, frequently, cardiomyopathy. In recent years, evidence has accumulated that the disorder is triggered by problems within the tiny energy-producing centers in cells known as mitochondria.

Now researchers in England have demonstrated that energy production is reduced in the cells of people with FA.

In 1996, researchers identified genetic defects in the form of extra copies of a repeated DNA sequence (GAA repeat) as the most common cause of the disease. These extra GAA repeats hindered the production of the mitochondrial protein frataxin, but the normal role of frataxin in the cell wasn't understood.

Some clues to the function of frataxin were found the next year when several laboratories genetically manipulated yeast cells to remove the frataxin protein. The groups found that production of the energy molecule ATP was disrupted in the manipulated cells. Closer inspection revealed that the mitochondria of the yeast cells were filled with iron and the cells lacked mitochondrial DNA (mitochondria normally have their own DNA, or genetic material).

These observations led researchers to suggest that the normal role of frataxin is to remove iron from the mitochondria. When frataxin is missing or decreased, iron accumulates in the mitochondria, where it sets off a chain of toxic chemical reactions leading to the destruction of the mitochondrial DNA. Without their DNA, the mitochondria are unable to make all of the proteins needed to manufacture ATP.

Last year, two groups of researchers studying cultured cells from humans with FA found some similar problems in the mitochondria of those cells, suggesting that the yeast findings are probably relevant to human FA.

Now, researchers led by Raffaele Lodi of Oxford University and Anthony Schapira of University College in London have used a noninvasive chemical detection technique called phosphorus magnetic resonance spectroscopy to measure the amount of ATP produced in the muscle cells of people with FA during rest and exercise. The researchers found that people with FA have a "profound deficit" in ATP production and that this deficit is greater in those people with more copies of the GAA repeat.

This finding demonstrates conclusively that FA is a mitochondrial disorder and suggests that treatments for FA should be designed, as are treatments for many other mitochondrial diseases, to increase mitochondrial function and decrease production of toxins.

POSSIBLE ALS, VIRAL INFECTION LINK FOUND

A group of researchers led by Martina Berger of the University of California, Irvine, have uncovered what may be the strongest link yet between the neurodegenerative disorder amyotrophic lateral sclerosis (ALS) and viral infection.

The disorder, which usually affects older adults, is characterized by the progressive loss of the nerve cells that control muscle movement.

The noninheritable "sporadic" form of ALS is most common and, although theories abound, no cause for it has been identified.

Berger's group was able to identify viral nucleic acid sequences in nerve tissue samples from 88 percent of people with ALS (15 of 17 examined), compared to only 3 percent from people who died of other causes (1 in 29).

The detected virus belongs to a family called the enteroviruses, which includes the virus responsible for poliomyelitis (another neurodegenerative disease).

However, the virus detected in the ALS samples most closely resembles another enterovirus, echovirus-7, which causes meningitis and sometimes encephalitis.

Although the study provides a strong correlation between viral infection and ALS, researchers caution that it can't be determined whether the virus actually causes the disease or whether the disease simply leaves people particularly susceptible to the virus. Much more work will be needed to demonstrate a cause and effect connection.

If a viral cause of ALS can be confirmed, however, it should open the door to treatments based on anti-enteroviral medications already in existence.

The study is published in the January issue of Neurology.

PIONEER RESEARCHER MASSIMILIANO ALOISI DIES

Longtime MDA researcher Massimiliano Aloisi died in Rome in October. He was 91.

A pioneer of muscle research in Italy, Aloisi was the first Italian researcher to receive funding from MDA.

His studies of myopathy due to vitamin E deficiency earned Aloisi recognition as an international leader in the fields of myology and neuromuscular disorders.

In addition to valuable research that spanned four decades, Aloisi was also instrumental in the creation of the Italian Muscular Dystrophy Associ-ation, an organization largely modeled after MDA.

"He was a charismatic teacher and a wonderful role model, not only as a scientist, but as a true academic," said Robert Ross, MDA senior vice president and executive director.