Objective: To assess efficacy and potency of our proprietary lead compound OT-003, an orally bioavailable small molecule Tropomyosin receptor kinase B (TrkB) modulator, in preclinical Parkinson’s disease (PD) models.

Background: Pangea Bio is developing OT-003, a small molecule TrkB modulator for neurological disorders including PD. The endogenous ligand of the TrkB receptor is BDNF. Physiological BDNF/TrkB signaling is crucial for neuronal development, survival, and plasticity. Aberrantly reduced BDNF/TrkB signaling is a hallmark of various neurodegenerative diseases, including PD, where BDNF protein and mRNA levels are reduced in the substantia nigra. OT-003 binds and activates the TrkB receptor promoting neuronal survival, enhancing neuronal and synaptic plasticity, and reducing pathological protein aggregates such as α-synuclein (α-syn).

Method: OT-003 was tested in separate experiments on primary rat dopaminergic neuronal cell cultures either injured with MPP+ or α-syn preformed fibrils (PFF). In both experiments, OT-003 and positive controls were pre-incubated on day 6 of culture for 1h before MPP+ or α-syn PFF exposure, respectively. The number of TH-positive neurons, complexity of the neurite network, mitochondrial ROS and α-syn levels were assessed using immunostaining and quantified using automated image analysis. Statistical significance was tested using one-way ANOVA followed by Fisher’s LSD test. p<0.05 was considered significant.

Results: In the MPP+ assay, OT-003 reduced mitochondrial ROS generation in dopaminergic neurons after 4h of MPP+ application. After 48h of MPP+ application, OT-003 increased the survival of TH-positive neurons, protected the neurite network and reduced α-syn aggregation. In the α-syn PFF study, OT-003 concentration-dependently reduced TH-positive neuronal cell loss, loss of neurite network and α-syn aggregation 96h after PFF addition. This positive cellular data was reproduced in a PD mouse model in vivo, where 5-week daily oral dosing of OT-003 reduced PD pathologies, including ps129-a-syn aggregates, and improved motor function.

Conclusion: These results in combination with additional compelling in vitro and in vivo data are supportive of OT-003’s potential to be a novel disease-modifying therapy for patients suffering from Parkinson’s disease.

This work has been presented at ADPD in Lisbon in March 2024.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/trkb-modulator-ot-003-reduces-dopaminergic-cell-loss-mitochondrial-stress-alpha-synuclein-aggregation-and-motor-dysfunction-in-parkinsons-disease-models/