November 05, 2007
Scientists Use Immune System to Target ALS Protein
Targeting misfolded SOD1 protein molecules with immunologic strategies developed by Amorfix Life Sciences of Toronto improved survival and slowed gait deterioration in mice with a type of familial (genetic) amyotrophic lateral sclerosis (ALS) caused by mutated SOD1 genes, says Neil Cashman of Amorfix and the University of British Columbia (Canada) in Vancouver.
Cashman, who presented the findings at the 132nd annual meeting of the American Neurological Association in October in Washington, said his research team created “monoclonal antibodies” (immune-system proteins) that specifically targeted two of the abnormal parts of an SOD1 molecule while leaving normal SOD1 alone. The targeted parts are exposed when the protein is misfolded.
When Cashman and colleagues infused the antibodies into the abdomen or brain in the ALS-affected mice, using a strategy known as “passive immunization,” the proteins attacked the misfolded SOD1, slowing the disease and slowing the deterioration of gait that occurs when the mice become ill.
Using a strategy known as “active immunization,” the researchers then injected ALS-affected mice intra-abdominally with pieces of misfolded SOD1 protein molecules carrying a molecular flag designed to attract the immune system’s attention.
The mice created their own antibodies to the misfolded SOD1 components and survived an average of 20 percent to 30 percent longer than untreated mice.
Cashman says his group also detected misfolded SOD1 in humans with ALS not related to SOD1 gene mutations.
In contrast to some in the ALS research community, he has long believed that abnormally formed SOD1 protein molecules underlie not only the type of ALS that results from mutated SOD1 genes but also other types of ALS, and that therefore targeting misfolded SOD1 has implications for treating nonfamilial (sporadic) ALS and non-SOD1 familial ALS.
“We’re optimistic that we’re on a good path to specifically destroy misfolded SOD1 in all types of ALS, while sparing the normally folded molecules,” Cashman said. He also noted that Amorfix and its partner, Biogen Idec in Cambridge, Mass., are currently collaborating to develop effective therapeutics for ALS patients.
