By Bruce Lieberman
SAN DIEGO UNION-TRIBUNE STAFF WRITER
October 27, 2004

In the fight against Lou Gehrig's disease, a relentless affliction that paralyzes its victims before killing them, scientists now believe they are developing powerful weapons to conquer it.

At the Society for Neuroscience meeting this week in San Diego, scientists have discussed three new approaches that have shown some success in animals. Scientists hope to begin preliminary human clinical trials involving two of the approaches next year.

Amyotrophic lateral sclerosis, or ALS, is an insidious killer, disconnecting the brain from the body but leaving the mind aware enough to follow the rapid descent into paralysis.

The disease kills the body's motor neurons, the long nerve cells that sprout from the spinal cord and extend toward the limbs like branches on a tree. Without them, the brain loses control of the body. Patients lose their ability to move, to speak and eventually to breathe.

About 5,600 Americans are diagnosed with ALS each year. Four in five will be dead within five years.

In the mid-1990s, scientists identified one gene whose mutated form contributes to the death of motor neurons. The protein the gene produces, called superoxide dismutase, or SOD1, is found to be involved in about 20 percent of inherited forms of the disease.

Only about 5 percent of all ALS cases are inherited, however. The cause of the vast majority of total ALS cases remains a mystery.

Even so, scientists have intensively studied SOD1, hoping that what they learn about the small percentage of cases involving this gene will help them understand ALS in general.

So far, success has been elusive. More than 100 drugs have been tested on animals, but only one has shown any success in humans, and even it has limited efficacy.

"We've cranked through a fair number of drugs quickly . . . (but) I don't think any of us are dissuaded by failures," said Jeffrey Rothstein, an ALS researcher at Johns Hopkins University in Baltimore.

The SOD1 gene undermines not only motor neurons but also the supporting cells surrounding them called astrocytes and microglial cells. For years, scientists have studied how they might silence the SOD1 gene in motor neurons. But UCSD researcher Don Cleveland has found that motor neurons in mice can be protected – even when they have the mutated SOD1 gene – if astrocytes and microglial cells surrounding them are kept healthy.

Both are critical to the health of motor neurons: Astrocytes nourish motor neurons, while microglial cells scavenge toxins from the cellular environment around motor neurons.

"You don't need to target the neurons; you need to target the neighboring cells," Cleveland said.

One way to protect astrocytes and microglial cells would be to change their genetic code so their DNA no longer makes SOD1. Injecting a benign virus that carries new genetic instructions into those cells – gene therapy – would be one option.

Another way could be to engineer stem cells in the lab to grow into healthy astrocytes and microglial cells, then transplant the replacement cells into a patient, Cleveland said.

In a separate presentation Monday, Swiss researcher Patrick Aebischer spoke of a technique called RNA interference to shut off the mutant gene that produces SOD1 – before the protein is even made inside the cell.

RNA interference disrupts the action of ribonucleic acid, a molecule that acts as an intermediary between DNA and the proteins it encodes.

Fragments of RNA or DNA, designed to disrupt RNA action inside cells, could be delivered to a patient by a modified – and therefore benign – form of the HIV virus, Aebischer said. The engineered virus would infect astrocytes, microglial cells and motor neurons, shutting down the production of SOD1 in all three.

"The goal is to silence the gene not just in motor neurons but also in the cells around it – the neighborhood," said Aebischer, who works at the Swiss Federal Institute of Technology in Lausanne.

Cleveland said a clinical trial is planned for next year that will combine his approach, protecting astrocytes and microglial cells to safeguard motor neurons, and Aebischer's approach, RNA interference to shut down the SOD1 gene.

In the trial, involving Carlsbad biotechnology company Isis Pharmaceuticals, researchers will use synthetic fragments of DNA, called anti-sense oligonucleotides, and inject them directly into the brains of patients. The molecules will then flow from the brain down through the spinal cord, where researchers hope they will be taken up by astrocytes, microglial cells and motor neurons, disrupting their production of the mutated SOD1 protein.

Getting new treatments into patients so SOD1 can be shut down will be the biggest challenge as researchers move from animal studies to human clinical trials, Cleveland said.

"The issue is not that we can't identify strategies that are effective," he said. "It's, 'Can we deliver them in an effective way?' "