Two UC Riverside researchers say they have synthesized a molecule that may delay the symptoms of amyotrophic lateral sclerosis and increase the life expectancy of ALS patients.

Maurizio Pellecchia and Iryna Ethell, both biomedical researchers with the UCR School of Medicine, discovered a way to interrupt one of the pathways by which ALS, commonly known as Lou Gehrig’s disease, progresses.

One of the challenges in battling ALS, Pellecchia said, is that it seems to involve a number of mechanisms in the body.

So far, no single culprit has been found that is responsible for the disease in which the body attacks the neurons that control voluntary muscle movement. Muscles atrophy and people with the disease lose the ability to walk, use their arms, swallow and even breathe. Most die of respiratory failure within three to five years of the disease’s onset.

“Motor neurons get the disease by oxidative stress,” Pellecchia said. “The (ALS) drugs out there are generally antioxidants.”

But those drugs don’t target a specific type of cell or mechanism.

Pellecchia and Ethell’s work focused on a specific gene, EphA4, that has been shown to have a relation to ALS. One of the things known is that if one of the two genes is removed in ALS-affected mice at the embryonic stage the mice live longer. (Removing both would kill the animal.)

“Until EphA4, there was no direct target for this disease,” Pellecchia said. “That’s what makes this so exciting, because it’s something we can address with a specific drug.”

Both he and Ethell have been researching the gene and its interactions for years, even before they came to UCR, when both of them worked at the Sanford-Burnham-Prebys Medical Discovery Institute in La Jolla.

EphA4 expresses itself by anchoring a portion of its molecular structure to the exterior cell wall of motor neurons. Part of that structure includes a receptor site. In ALS patients, when a particular protein, ephrin-B2, binds to that receptor, it signals nearby astrocytes – nervous system cells – to attack the motor neurons.

Scientists still don’t know what causes the astrocytes to attack, but they might not need to if they can effectively interrupt the process.

The two researchers set out to find a chemical that would do that.

Painstaking Process

Using a computer program and lots of work hours, they narrowed down candidates mostly by trial and error. Pellecchia said hundreds of thousands of compounds were analyzed.

They ended up with a molecule, comprised mostly of hydrogen and nitrogen, that they dubbed 123C4.

Pellecchia said 123C4 binds very tightly to the receptor on EphA4, keeping ephrin-B2 from doing so. The astrocytes never get the signal to attack the motor neurons.

A study using laboratory mice with ALS, found that those receiving the synthetic blocker had delayed symptoms of the disease and lived longer than control mice.

If the results are similar in humans, Pellecchia and Ethell said, it could double the current 3- to 5-year life expectancy after the onset of ALS.

Pellecchia said a company is working to develop a drug that will deliver the molecule to the nervous system of ALS patients. Assuming that process is successful, human trials would still be a few years away.

“It’s a new drug, so it has to be tested to see how well does it get into the spinal cord and (if it has) any side effects,” Ethell said.

Pellecchia said he feels an urgency to move the process along as quickly as possible.

“We are working night and day on this,” he said.

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