Objective: To develop novel, small molecular weight compounds, that can interfere with the aggregation process of alpha-synuclein (aSyn), as disease modifying agents.

Background: The aggregation of aSyn within certain susceptible neuronal populations is a common pathological feature of Parkinson’s disease (PD) and other neurodegenerative synucleinopathies. It is well established that aSyn aggregates play a key role in disease pathogenesis even if the exact molecular mechanisms that mediate neurodegeneration and the conformational state of the toxic forms of aSyn are not well defined. Nevertheless, an increasing amount of evidence from cellular and animal models indicates that the active processes of aggregation and fibril growth of aSyn are actually contributing to neuronal toxicity. Therefore, agents that may target these processes and either disaggregate or inhibit the formation of β-sheet rich aggregates would have therapeutic effects by rescuing neurons from toxicity.

Methods: We have generated small molecular weight compounds based on the rationale of the Morphomer™ technology platform developed by AC Immune. Morphomers™ designed to interact with β-sheet-rich structures of aSyn, were evaluated first in vitro for their ability to reduce or inhibit aSyn aggregation monitored by the Thioflavin T and sedimentation assays. The compounds were further characterized by their ability to rescue neuroblastoma cells from aSyn-mediated toxicity. The compounds’ binding affinities to aSyn aggregates were assessed by Back-Scattering Interferometry. The efficacy of selected compounds was evaluated in transgenic (Tg) mice overexpressing aSyn by behavioral, biochemical and histological analyses.

Results: We have identified Morphomers™ that have high affinity for aSyn pathological structures and importantly that can potently reduce the content of β-sheet structures of aSyn in vitro while rescuing cells from aSyn-mediated toxicity. Moreover, aSyn Tg mice that were treated with Morphomers™ show improvements in motor deficits as well as reduction of intracellularly aggregated aSyn.

Conclusions: These data indicate that Morphomers™ which are selected through different in vitro assays to target aSyn aggregates also show therapeutic efficacy in a transgenic model of synucleinopathies. These results support the concept that prevention of aSyn aggregation process can provide therapeutic benefit in PD and related synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-small-molecules-targeting-alpha-synuclein-aggregation-for-the-treatment-of-parkinsons-disease/