Body of work supports targeting misfolded proteins as a therapeutic strategy for ALS with the potential to translate across multiple neurodegenerative diseases
CAMBRIDGE, Massachusetts and TORONTO, Ontario , Aug. 06, 2024 (GLOBE NEWSWIRE) -- ProMIS Neurosciences Inc. (Nasdaq: PMN), a biotechnology company focused on the generation and development of antibody therapeutics targeting toxic misfolded proteins in neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA), today announced the publication of two papers highlighting the role of toxic misfolded superoxide dismutase-1 (SOD1) aggregates in the pathogenesis of ALS. One paper published in Acta Neuropathologica is titled, “Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion,” and the other publication in the online journal Open Biology is titled, “Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells.”
ALS is a fatal neurodegenerative disease of motor neurons. Toxic aggregates of SOD1 and TAR DNA-binding protein 43 (TDP-43) in motor neurons are characteristic of ALS. As recently reported by ProMIS, these two proteins interact such that misfolding of TDP-43 leads to misfolding and aggregation of SOD1. ProMIS is currently developing PMN267, a humanized IgG1 antibody directed against toxic misfolded TDP-43 as a potential therapeutic for ALS.
The newly published research in Acta Neuropathologica reports on the seminal finding that aggregated SOD1 seeds are present in ALS neural tissues, not only in patients with SOD1 mutations, but also in patients with the most common sporadic form of the disease, which supports the relevance of misfolded SOD1 as a therapeutic target and as a potential biomarker of disease. The Open Biology publication highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II and III to the aggregation and toxicity of SOD1 in ALS mutants, suggesting that β-strands II and III are potential targets for the development of SOD1-associated ALS therapies.
“This body of work advances the understanding of ALS disease biology and the importance of misfolded SOD1 aggregates in the pathogenesis of the disease. Furthermore, these studies reinforce the broader therapeutic strategy of targeting misfolded proteins in ALS and other neurodegenerative diseases driven by toxic protein aggregates,” stated Neil R. Cashman, M.D., Chief Scientific Officer and Co-Founder of ProMIS Neurosciences and an author on both publications.
As described in Acta Neuropathologica, the seeding activity of misfolded SOD1 aggregates in ALS neural tissues was measured using a real-time quaking-induced conversion (RT-QuIC) seed amplification assay system newly adapted to SOD1. Confirmation of the existence of measurable SOD1 seeds across different forms of ALS is an impactful contribution to the fundamental understanding of the disease. In addition, the observation that seeding activity was reduced after removal of misfolded SOD1from ALS tissue preparations with antibodies supports targeting SOD1 aggregates as a therapeutic approach.
The ProMIS platform is designed to identify target epitopes restricted to pathogenic forms of proteins including SOD1 and, as reported in Open Biology, in silico tools used to predict amyloidogenic regions in the ALS-associated SOD1-G85R mutant led to the identification of seven regions throughout the structure. Modifying the structure of these regions showed a reduction in the aggregation propensity and toxicity of SOD1-G85R, which supports their potential as a target for therapeutic intervention.
The complete articles can be accessed online here (Acta Neuropathologica) and here (Open Biology).
About ProMIS Neurosciences Inc.
ProMIS Neurosciences Inc. is a clinical stage biotechnology company focused on generating and developing antibody therapeutics selectively targeting toxic misfolded proteins in neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA). The Company’s proprietary target discovery engine applies a thermodynamic, computational discovery platform - ProMIS™ and Collective Coordinates - to predict novel targets known as Disease Specific Epitopes on the molecular surface of misfolded proteins. Using this unique approach, the Company is developing novel antibody therapeutics for AD, ALS and MSA. ProMIS has offices in Toronto, Ontario and Cambridge, Massachusetts.
Forward-Looking Statements
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