Preclinical Data Demonstrates Potential of Small-Molecule Inhibitors of α-Synuclein Toxic Oligomers for Parkinson Disease

Bart Henderson

Recently, findings from preclinical data on Wren Therapeutic’s first-in-class, oral inhibitors of α-synuclein oligomer generation demonstrated a significant reduction of both oligomers and aggregates in vitro, cellular, and in vivo models of Parkinson disease (PD). The data suggests that the treatment approach is network-centric, enabling the detection of small molecules that can block oligomer generation with specificity and precision.¹

Using the small-molecule inhibitors, researchers observed a critical reduction of both α-synuclein oligomer levels and α-synuclein aggregates in a dose-dependent manner in iPSC dopaminergic cells and in Line 61 transgenic mouse models. Notably, the small-molecule compounds inhibited both molecular mechanisms of α-synuclein oligomer formation in the assays at low drug concentrations, with high specificity, without inhibiting either amyloid-ß or Tau aggregation.

The two data sets were presented in poster and oral presentations at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28-April 1, in Gothenburg, Sweden.^2,3 Researchers measured kinetic rates of oligomer generation with high accuracy using proprietary in vitro biochemical assays to optimize the small-molecule oligomer inhibitors. This resulted in an enhancement of potency and oral pharmacokinetics for positive brain penetration.

"α-Synuclein oligomers are fleeting protein intermediates implicated in the molecular damage and cellular destruction that decimate dopaminergic neurons in Parkinson's disease and other α-synucleinopathies. Unfortunately, their elusive, ephemeral physical nature makes them difficult to target using conventional drug discovery approaches, as well as to develop biomarkers to support clinical development," Bart Henderson, CEO of Wren Therapeutics, said in a statement.¹

The two different biomarker detection assays—a Sandwich ELISA assay and a Proximity Ligitation Assay—used homotypic antibodies with high affinity and high specificity for α-synuclein oligomers. Also, the Line 61 transgenic mouse models were measured with ELISA and pS129.

"We are taking a different approach to drug discovery, using biophysics to design landmark therapeutics that can address the urgent need for effective drugs for this rapidly expanding neurodegenerative disease. In parallel, we are advancing the latest biomarker technologies to guide preclinical and clinical development to increase the probability of clinical success," Henderson said in a statement.¹

Additionally, recent research on α-synuclein oligomers have shown that these are a result from errant protein folding, and are considered the toxic entities responsible directly for neurotoxicity in PD. Thus, the new treatment approach from Wren aims to treat the central molecular cause of neurodegeneration in PD.¹ One of the most challenging problems in drug discovery for researchers is characterizing and suppressing transient protein intermediates when working with protein assembly reactions. It is a challenge because the proteins are highly transient, and are unable to be analyzed in isolation.

“We are excited about our progress and the promising initial data we presented today for several oral, small-molecule oligomer inhibitors and for the biomarker technologies we are deploying to measure on-target efficacy in both preclinical and clinical studies,” Henderson added in a statement.¹

Wren noted that in PD research, targeting the process of α-synuclein formation requires a specific method in measuring, assaying, and analyzing the proteins. Thus, the company concluded that more research is needed that targets a network of interactions in the progression of PD, that has a different structured approach from the conventional single-target drug investigations.

REFERENCES
1. Wren Presents Preclinical Data at AD/PD 2023 Demonstrating Potential of its First-in-Class, Small-Molecule Inhibitors of α-Synuclein Toxic Oligomers for the Treatment of Parkinson's Disease. News Release. Wren Therapeutics. March 29, 2023. Accessed March April 7, 2023. http://www.wrentherapeutics.com/wren-presents-preclinical-data-at-ad-pd-2023-demonstrating-potential-of-its-first-in-class-small-molecule-inhibitors-of-%ce%b1-synuclein-toxic-oligomers-for-the-treatment-of-parkinsons-disea/
2. Pandey S, Staats R, Pullein M, et al. The selective detection of alpha-synuclein oligomers to analyze small molecule inhibitors of their formation for the treatment of Parkinson's disease. Presented at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28-April 1, in Gothenburg, Sweden. Abstract Poster 825.
3. Cridland A, Ball S, Teng X, et al. Reducing toxic alpha-synuclein oligomers in PD through precise targeting of the molecular mechanisms of oligomer formation with small molecule inhibitors. Presented at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28-April 1, in Gothenburg, Sweden. Abstract Poster 729.