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-André Delambre
Scientifique Research Committee
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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 NationalAcademy 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.


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