A Therapeutic Vaccine for ALS Directed Against Misfolding Specific Epitopes of Cu/Zn Superoxide Dismutase 1
University of British Columbia, University of Saskatchewan
Amyotrophic lateral sclerosis (ALS), aka Lou Gehrig’s disease, is one of the most common motor neuron diseases affecting 4-8 out of 100,000 people worldwide each year. 2,500 – 3,000 Canadians currently live with this disease. 80% of the patients die within 2-5 years of diagnosis due to progressive loss of motor neurons and paralysis. To date, there is no cure or effective treatments. The causes for ALS are yet fully understood. Both genetic and environmental factors have been shown to contribute. The first known gene for ALS, superoxide dismutase 1 (SOD1), was identified in 1993. The SOD1 protein acts to scavenge toxic free radicals in the cell. Mutations in SOD1 contribute to ~20% of hereditary ALS likely due to the propensity of mutant SOD1 proteins to misfold and clump, ultimately leading to an overload of “trash” in the cell. Interestingly, misfolded SOD1 has also been observed in ALS without family history. Studies on other neurodegenerative disorders, such as Alzheimer’s disease, have suggested vaccination to be a promising treatment by absorbing misfolded target proteins. However, a central challenge for this strategy is immunological tolerance associated with native molecules. To circumvent this obstacle, we have devised a strategy to development vaccines that specifically target misfolded SOD1. In collaboration with Dr. Scott Napper from the Vaccine and Infectious Disease Organization (VIDO), we will utilize a transgenic mouse model of motor neuron disease to screen the best vaccine candidates in order to eventually advance to Phase I clinical trials.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
The largest impact of this program would be the development of an effective preventative/therapeutic vaccine against ALS for the individuals who are currently suffering from or at high risk of ALS. Because our vaccine strategy only targets the toxic species of SOD1 molecules, with minimal interference with their normal counterpart, we expect our vaccines to possess an enhanced safety and efficacy profile. In addition to improving patient’s quality of life, success with this program will also provide a cost-effective approach to alleviate the economic burden on patients, their families, caregivers, and the healthcare system. In a broader sense, our success will imply that similar vaccination strategy could also be extended to other neurological disorders associated with spreading of misfolded proteins, such as Alzheimer’s and Parkinson’s diseases.
In order to develop a safe and effective vaccine, the specificity, composition, and dosage are among the most critical factors that must be carefully optimized. Failure at any of these can lead to undesirable or even detrimental consequences. In our case, the specificity of our vaccines requires even greater stringency, because they must only target the pathogenic species of SOD1 while sparing its normal form. Our experimental strategy was designed to characterize each of these key factors. Our data will give us a better understanding of the 3-D information of SOD1 valuable for therapeutic interventions, and the optimal vaccine formulation and dosage for efficient absorption and immune response. In addition, our preclinical studies will predict the potential of our vaccines in the prevention and/or treatment of ALS, and therefore provide the necessary rationales for eventual Phase I clinical trials.