ALS Alert Newsletter | July

Vaccine Delays ALS in Mice

Immunotherapy may help postpone or delay motor neuron disease, according to a new study.

Mice immunized against misfolded SOD1 had delayed onset of ALS symptoms.

Vaccines protect against a variety of infectious diseases, from measles to the flu. A new study published in the Journal of Neuroscience shows that vaccines may one day treat and even prevent ALS. By immunizing mice that carried a mutant, misfolded form of the SOD1 protein, scientists were able to delay both disease onset and end-stage disease.

In its normal, healthy state, the SOD1 protein looks like a butterfly: two identical wings tethered in the center. In some cases of ALS, however, SOD1 misfolds and causes other SOD1 proteins to misfold as well. These SOD1 proteins stick together and form large clumps, which researchers have linked to ALS disease. Previous studies have shown that these aggregates may injure motor neurons by damaging their mitochondria, which provide energy to cells.

Janice Robertson, a neuroscientist at the University of Toronto, took advantage of the misfolded SOD1's altered shape. A variety of mutations linked to familial ALS can cause SOD1 misfolding, and each mutation results in a protein with a slightly different shape. Common to all of these misfolded proteins, however, is an exposed section of SOD1 that is normally buried in the middle of the healthy protein and forms the "body" of the butterfly. Since all misfolded SOD1 proteins have this region in common, and since this region is not normally accessible on healthy SOD1, Robertson and colleagues were able to create a small protein that would stimulate the body into making antibodies recognizing this region. The antibody that resulted from this peptide, known as SEDI, bound to misfolded SOD1 proteins in mice, but not to normal SOD1.

Similar immunotherapy approaches have been tested in other neurodegenerative diseases like Alzheimer's and Parkinson's diseases, as well as for SOD1 in ALS, Robertson pointed out. "What makes this study different is that the SEDI protein used in our immunization corresponds to a region in SOD1 that is buried in the protein's normally folded state. In ALS, this region of the protein becomes exposed, and we have immunized with a peptide that corresponds to this exposed region," Robertson said. "This sends the immune system into action, which will remove the misfolded SOD1 proteins but leave the normally folded ones."

Testing the vaccine

In her latest study for the Journal of Neuroscience, Robertson used the SEDI peptides to immunize mice that overexpressed a mutant version of SOD1. The SEDI antibody elicited by this immunization would attach to the misfolded SOD1 and signal the body to remove and degrade the clumps of toxic proteins. Since these clumps had been linked to ALS disease, the researchers anticipated that clearing the SOD1 aggregates would delay disease onset and lessen severity.

Beginning when the mice were six weeks old, Robertson and colleagues gave them a series of injections of the SEDI peptide or placebo into their abdomens for the next five months. Immunization with SEDI peptide significantly decreased the amount of aggregated SOD1 in the spinal fluid and spinal cords of the mice, and also decreased the extent of neuroinflammation typically associated with the disease.

The researchers then compared the amount of time to both disease onset and end-stage disease in mice receiving peptide or placebo. The mutant SOD1 mice that received placebo injections began to show motor weakness at approximately 11 months of age, compared to one year for mice receiving the SEDI peptide. The immunizations also significantly slowed disease progression, extending time to end-stage disease by nearly two weeks. Although this might not sound like much of a difference, even in an animal whose lifespan is only one or two years, the results of the study still indicate significant promise for ALS patients.

Although any potential human trials are a long way off, Robertson says that similar efforts may even one day prevent the onset of disease in people who carry the SOD1 mutation. If they are immunized before they show signs of motor neuron disease, then they may never develop symptoms. This type of immunotherapy may also be useful to patients who already show signs of ALS.

What's Next?

Before the SEDI antibody can be tried in humans, Robertson and colleagues want to test the treatment in mice who have already begun to show symptoms of ALS to see whether it can treat the disease. She also wants to test the antibody in dogs who have an SOD1 mutation that causes a canine form of ALS, since this is more closely related to the human disease than the transgenic mouse models because it occurs spontaneously.

The SEDI antibody is specific to SOD1 mutations, which means it may not be directly applicable to other forms of ALS caused by different mutations. Still, the research may help scientists develop other therapies and treatments for ALS linked to mutations in genes like TDP-43, FUS, and C9ORF72.

"Although it is argued that SOD1 mutations are causative of a minority of ALS cases, a treatment for any type of ALS would be a major breakthrough, and since currently we know more about SOD1 than any other protein involved in causing ALS, it should not be overlooked as an important disease target," Robertson said. "Indeed the general strategy of targeting misfolded regions of other disease causing proteins could be applied to the new and more prevalent types of ALS. The validation that we have provided of targeting misfolded SOD1 as a therapeutic strategy for ALS is just the start."

–– Carrie Arnold