ProMIS Neurosciences Announces Data on the Pathogenic Role of Toxic Misfolded SOD1 Aggregates in ALS Published in Acta Neuropathologica and Open Biology
06 Agosto 2024 - 8:00AM
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.
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