Objective: Demonstration of the anti-prionic MoA for α-synuclein in vitro, PoC in vivo, as well as ex vivo.

Background: Neurodegenerative protein-misfolding diseases, like Alzheimer’s (AD) and Parkinson’s disease (PD), are driven by prion-like self-replicating and propagating protein assemblies of amyloid β (Aβ) or α-synuclein. The conformation these proteins have in the aggregated state is thermodynamically more stable than their physiological monomer conformation, which is often intrinsically disordered. Therefore, we have developed all-D-enantiomeric peptide ligands that bind the monomeric protein of interest with high affinity, thereby stabilizing the physiological intrinsically disordered monomer structure. These ligands are eliminating already existing aggregates by disassembling them into monomers. This purely thermodynamic driven mode of action (MoA) is truly “anti-prionic”, because it is eliminating already existing oligomers and fibrils.

Method: Atomic force microscopy (AFM), dynamic light scattering (DLS), size exclusion chromatography (SEC), surface plasmon resonance spectroscopy (SPR), nuclear magnetic resonance spectroscopy (NMR), and a clinical study with 20 patients in a single center, randomized, placebo-controlled, double-blind study.

Results: The all-D-enantiomeric ligand for α-synuclein, SVD-1a, disassembled preformed α-synuclein fibrils (PFF) as shown by AFM and DLS analysis. SPR and NMR demonstrated picomolar affinity of SVD-1a to α-synuclein monomers, while keeping them in their physiological IDP conformation. I will also present data from the respective Aβ related compound, which has entered a phase 2 clinical study with data from a clinical phase Ib, double-bind, placebo-controlled study with 20 mild cognitively impaired (MCI) due to AD and mild AD patients treated once daily orally with RD2 or placebo for 4 weeks with an additional 4 weeks follow up period. Patients treated with RD2 improved their short term memory abilities significantly, as shown with the Word List assay of the CERAD battery of neurocognitive testing. A phase II study has started. I will also acknowledge the many contributors of both developments that are too many to be included here in the abstract.

Conclusion: The unique anti-prionic mode of action for the treatment of AD, PD and other protein misfolding diseases is promising.

References: [1]: Kass et al., Cell Rep. Med. 3, 100630 (2022)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-purely-thermodynamic-anti-prionic-mode-of-action-for-the-treatment-of-parkinsons-disease-and-other-neurodegenerative-diseases/