[BobbyB]

Quebec researchers develop ALS vaccine

CHARLIE FIDLMAN, Montreal Gazette
Published: Monday, January 29, 2007

There’s glimmer of hope for people with ALS or Lou Gehrig’s disease.
A Quebec team of researchers is the first to develop a vaccine for an inherited form of amyotrophic lateral sclerosis (ALS), a progressive disease of the central nervous system that remains incurable.

Tested in mice, the study led by Laval University neuroscientist Jean-Pierre Julien, is a completely new approach to finding therapies for Lou Gehrig’s disease which affects two to five per cent of all ALS cases.

The vaccine delayed the onset of the disease, and also prolonged the life of the sick mice by about one month, or 10 per cent longer.

Scientists are cautiously optimistic about the discovery , published Monday in the online version of The Proceedings of the National Academy of Sciences journal.

The vaccine is based on mouse models of ALS and it remains to be seen whether it could work in people, said Philip Wong, professor of neuropathology and neuroscience at Johns Hopkins University.

"But it’s a very, very intriguing finding that could provide us with a novel therapeutic strategy," said Wong, a director at the university’s Robert Packard Centre for ALS, which funded some of the research.

The inherited form of ALS is caused by a mutant gene, SOD1, which produces a toxic protein.

Mice carrying the mutant SOD1 gene develop ALS and die. Those with normal SOD1 are fine, Julien said.

It’s yet not known how, but the excreted protein contributes to the death of the nerves that enable muscle movement. That idea – the protein – became an attractive research target, Julien said.

"Let’s try to have the immune system attack and neutralize the toxic protein," he said.

Animals engineered with a mutant human gene responsible for a familial form the disease but inoculated before the usual onset of symptoms survived disease-free much longer.

They also lived longer.

"It’s a terrible neurological disease," Julien said. Most people die within two to five years of diagnosis, usually of respiratory problems.

Many drugs have been tried for the treatment of ALS. Only one was found to have a modest effect, Rilutek (riluzole); it seems to prolong patients survival by about three months.

The fact that immunization makes a difference in the familial form of ALS paves the way similar approaches in other forms the illness, said Jeffrey Rothstein, professor of neurology and neuroscience at Johns Hopkins University and head of Packard.

"It gives us a different way of thinking about the disease... of trying to discover mechanisms for how the disease occurs, and that’s very important," Rothstein said.

The non-profit Robert Packard Centre for ALS is part of the Johns Hopkins School of Medicine in Baltimore, MD.

cfidelman@thegazette.canwest.com

[Agios]

From: alscenter@jhmi.edu

To: The ALS Community

Date: January 29, 2007

Subject: Robert Packard Center ALS News Network


View this article online at: http://www.alscenter.org/news/briefs/070129.cfm

First Vaccine for Familial ALS Shows Potential in Model Mice

A new study with ALS mouse models suggests a completely new, vaccine-based approach to treating the inherited form of amyotrophic lateral sclerosis, also known as Lou Gehrig's disease. The work led by Packard Center neuroscientist Jean-Pierre Julien, of Quebec's Laval University, shows that ALS model mice immunized before the disease's usual onset time had significantly less motor neuron damage. (Motor neurons are the disease's major target.) The animals also lived, on average, a month longer, an increased survival that Julien says is "remarkable" in that field of study.

"The encouraging results we've seen make us eager to refine this immune-based approach," he says, "to see if it will ultimately help familial ALS patients."

An article describing the research has just appeared in the online version of The Proceedings of the National Academy of Sciences.

The work adds ALS to the company of Alzheimer's and Parkinson's as neurodegenerative diseases in which buildup of an abnormal protein provides a basis for an immune-based approach to therapy. (In Alzheimer's, immune attack is directed at the beta-amyloid molecule. In Parkinson's it's alpha-synuclein and now, in ALS, a vaccine is aimed at dismantling the misfolded SOD1 protein.)

The familial form of ALS that comes from having an abnormal SOD1 gene isn't the most common. It affects only 1 to 2 percent of those with the disease. But the fact that immunization makes such a difference in that type * the one the models mimic * paves the way for trying a similar approach to common sporadic ALS, should a target protein be found.

"What made us feel hope for a vaccine was our earlier work that showed the abnormal SOD1 protein is secreted by cells and is, thus, 'out there' where the immune system can attack it," Julien explains. Evidence has accumulated to show that abnormal SOD1 can be toxic just by being in the environment of nervous system cells. The molecule triggers death in cultures of motor neurons and produces disease-linked changes in neighboring nervous system cells.

In the study, the researchers aimed to see if reducing the extracellular "bad" SOD1 would slow progress and/or lessen symptoms of inherited ALS.

They prepared a vaccine containing small amounts of mutant SOD1 protein engineered in bacterial sources. Then they vaccinated two strains of model ALS mice that overproduce the mutant SOD1 protein that's tied to the disease. One strain is a mild overproducer; the second generates some 20 times usual levels. The animals received several inoculations and a final booster injection before six months of age.

In both studies, control model mice got "blank" injections without the immune-provoking SOD1.

Onset of movement difficulties in the first strain came some 20 days after the control animals. Those vaccinated mice also lived a month longer, on average. And followup labwork showed 42 percent more of their motor neurons survived than the controls.

Eventually, all the mice * both strains and controls * sickened and died for a combination of reasons, Julien says. "It's not like a vaccine for a viral illness, for example, where you kill the invading organism and that's that. In this case, the animals' cells continue to manufacture the mutant protein." Also, Julien adds, it's difficult for antibodies to penetrate into the brain and spinal cord where the mutant protein exists.

As expected, vaccinated mice of the second strain, the one with overwhelming amounts of mutant SOD1, weren't helped by the vaccine. However, a trial "passive" immune approach that used a mini-pump to directly inject human antibodies against SOD1 into the spinal fluid of the potently overproducing animals modestly increased their lifespan.

"The fact that we have proof the principle works is heartening," Julien says. "It encourages our ultimately looking into this approach for patients, especially because human production of mutant SOD1 is far lower than in the model mice."

Using antibodies directly to bypass the vaccine * where the body's immune system is nudged to manufacture antibodies * may get around the worries of encephalitis. Vaccines against the Alzheimer's protein sparked that dangerous brain inflammation in human trials. The team is also hoping to use more specific antibodies to lessen undesirable side-effects.

Support for this study came from the Robert Packard Center for ALS Research at Johns Hopkins and from the Canadian Institute of Health and Research. Other members of the research team were Makoto Urushitani and Samer Abou Ezzi, both with Laval University in Quebec.