ProMIS Neurosciences Inc., a biotechnology company specializing in the development of antibody therapeutics for neurodegenerative diseases, has recently published two significant papers that shed light on the role of misfolded
superoxide dismutase-1 (SOD1) aggregates in the development of
amyotrophic lateral sclerosis (ALS). These findings hold promise for advancing therapeutic strategies not only for ALS but potentially for other neurodegenerative conditions.
ALS is a fatal disease characterized by the degeneration of motor neurons, where the accumulation of toxic protein aggregates, specifically SOD1 and
TAR DNA-binding protein 43 (TDP-43), plays a crucial role. ProMIS Neurosciences is developing PMN267, a humanized IgG1 antibody targeting the misfolded TDP-43, which has shown potential as a therapeutic intervention for ALS.
The first study, published in
Acta Neuropathologica, has made a groundbreaking discovery by identifying the presence of aggregated SOD1 seeds in neural tissues from ALS patients. This includes not only those with SOD1 mutations but also those with the more common sporadic form of the disease. This finding underscores the importance of targeting misfolded SOD1 as a therapeutic strategy and highlights its potential as a biomarker for ALS.
The second study, available in the online journal Open Biology, focuses on the amyloidogenic regions in β-strands II and III of the SOD1 protein. These regions were found to significantly influence the aggregation and toxicity of SOD1 in ALS mutants. This discovery points to β-strands II and III as promising targets for developing new therapies aimed at
SOD1-linked ALS.
Neil R. Cashman, M.D., Chief Scientific Officer and Co-Founder of ProMIS Neurosciences, emphasized the importance of these findings in enhancing the understanding of ALS pathogenesis. He noted that the studies validate the broader therapeutic approach of targeting misfolded proteins in ALS and other neurodegenerative diseases characterized by toxic protein aggregates.
The Acta Neuropathologica paper utilized a real-time quaking-induced conversion (RT-QuIC) seed amplification assay adapted for SOD1 to measure the seeding activity of misfolded SOD1 aggregates in ALS neural tissues. This method confirmed the presence of measurable SOD1 seeds across various forms of ALS. Additionally, it was observed that the seeding activity diminished upon the removal of misfolded SOD1 using specific antibodies, supporting the therapeutic potential of targeting SOD1 aggregates.
ProMIS Neurosciences employs a proprietary platform designed to identify target epitopes that are restricted to pathogenic forms of proteins, including SOD1. The Open Biology study utilized in silico tools to predict amyloidogenic regions in the ALS-associated SOD1-G85R mutant, identifying seven critical regions. Modifying these regions reduced the aggregation propensity and toxicity of SOD1-G85R, highlighting their potential as therapeutic targets.
In summary, these research findings represent significant progress in the understanding of ALS disease mechanisms and the development of targeted therapies. By focusing on the misfolding and aggregation of SOD1, ProMIS Neurosciences aims to develop novel treatments that could potentially benefit patients suffering from ALS and other neurodegenerative disorders.
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