Neurodegenerative protein-misfolding diseases, like Parkinson’s and Alzheimer’s disease (AD), are driven by prion-like self-replicating and propagating protein assemblies of Aβ, α-synuclein, and many more. The conformation of these proteins in the aggregated state is thermodynamically more stable than their physiological monomer conformation. Therefore, we have developed all-D-enantiomeric peptide ligands that are specific for the respective target protein and bind the monomeric protein of interest with high affinity, thereby stabilizing them in their native conformation. This leads to the disassembly of oligomers and fibrils into monomers, and allows re-installation of homeostasis.
The ligand for α-synuclein, SVD-1a, disassembled preformed α-synuclein fibrils (PFF) as shown by AFM and DLS. SPR and NMR demonstrated picomolar affinity of SVD-1a to α-synuclein monomers, while keeping them in their physiological IDP conformation.
The ligand for Aβ, RD2, demonstrated ex vivo target engagement and disassembled Aβ oligomers obtained from brain tissue of former AD patients (Kass et al., Cell Rep. Med. 3, 100630, 2022). A clinical phase Ib, double-bind, placebo-controlled study with 20 mild cognitively impaired (MCI) and mild AD patients treated once daily orally with RD2 for four weeks with an additional four weeks follow-up period yielded good safety and tolerability. Also, as demonstrated and published before with four different animal models in four different laboratories, 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 placebo controlled double-blind proof-of-concept phase II study with 270 patients treated orally over 12 to 24 months with RD2 at two different doses or placebo is approaching end of patient recruitment.
I will also acknowledge the many contributors of both developments that are too many to be included here in the abstract.