Objective: To develop a disease-modifying therapy for Parkinson’s disease (PD) and related synucleinopathies by eliminating intracellular, toxic, and seeding-competent aggregate species of α-synuclein (α-syn).

Background: Aggregation of the IDP protein α-syn is a pathological hallmark of synucleinopathies such as PD and MSA. Soluble α-syn aggregates are considered key mediators of neurotoxicity and prion-like cell-to-cell propagation. We developed the all-D-enantiomeric peptide PRI-101, which binds α-syn monomers with high affinity, stabilizes their IDP conformation, prevents spontaneous aggregation, and disassembles pre-formed fibrils into monomers¹. PRI-002 (RD2), an all-D-peptide developed for Alzheimer’s disease is currently being evaluated in a Phase II clinical trial².

Method: Binding affinity of PRI-101 to α-syn monomers was determined by surface plasmon resonance. Inhibition of aggregation and disassembly of pre-formed fibrils were assessed using biochemical in vitro assays and α-syn biosensor cells. PRI-101 was further evaluated in a human iPSC-derived 3×SNCA PD organoid model. In vivo efficacy was investigated in fibril-inoculated hemizygous TgM83^+/− mice following continuous subcutaneous administration and in the spontaneous α-syn aggregation model LINE61 after oral dosing. Outcome measures included survival, α-syn pathology in disease-relevant brain regions, and behavioral performance.

Results: PRI-101 bound α-synuclein monomers with low nanomolar affinity. In vitro, it rendered pre-formed fibrils seeding-incompetent, with an EC₅₀ of 1.4 µM that further decreased upon extended co-incubation and disassembled PFFs (DLS). PRI-101 inhibited intracellular seeded aggregation. When added to the culture medium of 3×SNCA organoids, PRI-101 reduced α-syn aggregation in a concentration-dependent manner. In single- and multiple-dose pharmacokinetic studies, PRI-101  demonstrated robust CNS penetration. In TgM83^+/− mice, s.c. administered PRI-101 significantly prolonged median survival. In LINE61 mice, oral treatment reduced α-syn pathology, particularly in the substantia nigra.

Conclusion: PRI-101 inhibits α-syn aggregation and actively disassembles fibrils across biochemical, cellular, organoid, and in vivo PD models. These data support PRI-101 as a first-in-class therapeutic candidate with disease-modifying potential for PD and related synucleinopathies.

PRI-101 mode of action.

References: 1 Sevenich, M., Gering, I., Kass, B. et al. Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide. npj Parkinsons Dis. 11, 271 (2025). https://doi.org/10.1038/s41531-025-01132-7

2 Jürgens D, Tischler G, Brener A et al. PRImus‐AD study: Design of the phase 2 study treating patients with MCI or mild dementia due to Alzheimer’s disease (AD) with the orally available PRI‐002. Alzheimers Dement. 2025 Dec 25;21(Suppl 5):e103102. doi: 10.1002/alz70859_103102. PMCID: PMC12741198.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/disassembly-of-%ce%b1-synuclein-aggregates-by-the-all-d-peptide-pri-101-preclinical-efficacy-in-vitro-and-in-vivo/