ALS Community Exchanges Ideas At AAN Meeting

At the 58th meeting of the American Academy of Neurology, held in April in San Diego, the ALS research community learned of a number of intriguing studies. Here are some highlights.

ALS-Affected Mice Benefit From Transplants Of Stem Cells

Neural stem cells taken from mouse brain tissue and transplanted into the lumbar spinal cords of mice with genetic ALS developed characteristics of motor neurons (the muscle-controlling nerve cells affected in ALS), produced nerve cell fibers (axons) and protected existing motor neurons, said researchers at the University of Milan in Italy.

Stefania Corti at the University of Milan and colleagues found the treated mice had a slower than expected disease course and lived longer than ALS-affected mice usually do.

“The results [show] that the right stem cell may indeed reach a specific area of the central nervous system and acquire morphological [structural] and functional properties of mature, ‘normal’ neurons,” said Giacomo Comi, an associate professor of neurology at the University of Milan, who was on the study team.

Trophos Seeks To Stop Cell Death Before It Starts

Trophos (www.trophos.com), a company based in Marseille, France, plans to test its experimental compound TRO19622 in people with ALS later this year, after finding the compound safe in healthy volunteers.

TRO19622 appears to work by stopping a cell death program known as apoptosis, a goal of many investigational drugs for ALS. An early step in apoptosis is the opening of pores in the membrane-enclosed “mini-organs” inside cells known as mitochondria. When these pores open, fluid rushes in, and a membrane surrounding the mitochondrion can rupture, allowing a chemical trigger for cell death to leak out.

TRO10622, which was discovered by Trophos as part of a screening program to find chemicals that keep nerve cells alive, has a cholesterol-like structure and apparently interferes with the opening of mitochondrial pores.

Blocking AChE Helps Mice Destined to Get ALS

EN101, a compound developed by Ester Biosciences (www.esterneuro.com) of Herzlia Pituach, Israel, apparently blocks the synthesis of the enzyme acetylcholinesterase (AChE), thereby providing a modest life extension and delay in symptom onset for mice destined to develop genetic ALS.

Marc Gotkine of Hadassah University Hospital in Jerusalem and colleagues reported that their results support a role for AChE in exacerbating ALS and suggest that blocking it may be worth pursuing.

ALS May Increase Blood Clot Risk

Researchers in Massachusetts studied 501 people with ALS between 1998 and 2004 and reported they had a higher than average incidence of deep vein thrombosis (DVT), a type of blood clot known to form in people who are immobile (even during a long plane flight) and have other risk factors.

DVTs are extremely dangerous, because they can break off and travel to the lungs, causing a life-threatening event known as a pulmonary embolism.

In addition to prolonged immobility with pressure on blood vessels, dehydration and a low-oxygen environment contribute to DVT development. (DVTs associated with long-distance air travel in a cramped seat have been dubbed “economy class syndrome.”)

In the general population, about 0.1 percent of people experience a DVT in a year, while in hospitalized patients, the yearly incidence is between 0.8 percent and 1.3 percent. In the ALS group, the annual incidence was found to be 2.7 percent.

The research team, which included neurologist Merit Cudkowicz, who sees patients at the MDA/ALS Center at Massachusetts General Hospital in Boston, recommended that doctors and patients be alert to the increased DVT risk and that they consider DVT preventive measures. (These usually include anticoagulant medications and/or elastic stockings.)

IV Gene Transfer Without Virus Helps ALS-Affected Mice

A team that included MDA grantees Gyula Acsadi at Wayne State University in Detroit and Jon Wolff at the University of Wisconsin-Madison reported they had improved life span and sustained motor function in ALS-affected mice by injecting growth factor genes without a viral transporter.

The researchers injected “naked” DNA for insulin-like growth factor 1 (IGF1) into leg veins under pressure, and found that mice receiving these injections lived an average of 28 days (25 percent) longer than untreated mice.

Acsadi later said he believes the IGF1 protein was either transported to nerve cells from nerve endings or that IGF1’s presence caused the transmission of neuroprotective signals.

The investigators concluded that IGF1 may be beneficial in ALS and that it may be possible to deliver it without using viruses, a strategy that would improve safety.

Two Groups Find Variations in Detox Enzymes in ALS Patients

Two independent groups, one of which included Denise Figlewicz, an MDA grantee at the University of Michigan, and the other Teepu Siddique, an MDA clinic co-director at Northwestern Memorial Hospital in Chicago, reported that variations in paraoxonase enzymes may be a risk factor for ALS.

Paraoxonase enzymes help detoxify pesticides, insecticides and nerve gases. Both groups found some versions of the PON genes, which instruct for these enzymes, were more common in people with ALS than in unaffected people. The PON gene variations may help explain the increased risk of ALS in Gulf War veterans. More data are expected this summer.

Is ALS Becoming Less Aggressive?

Patients whose ALS was diagnosed at the MDA/ALS Center at Methodist Neurological Institute (MNI) or at Baylor College of Medicine in Houston between 1999 and 2004 survived an average of four years, while those whose disease was diagnosed between 1984 and 1998 lived only three.

The increase in survival time and slower disease progression appear to be independent of all known factors, reported Stan Appel, director of the MDA/ALS Center at MNI, and other investigators on this MDA-supported study.

They found no differences between the two groups with respect to use of noninvasive ventilation, gastrostomy tubes or riluzole. Nor were there differences in age, gender the part of the body where symptoms began, the time between symptoms and diagnosis, or baseline respiratory function.

The investigators concluded that the slower progression and longer survival are either due to unmeasured aspects of care, or that possibly the disease itself may have become less aggressive over time.