Objective: To characterize the effects of a computationally identified small molecule in rat and primate models of Parkinson’s disease-associated motor deficits and treatment-associated complications.
Background: Levodopa plus carbidopa (L/C) represents the most effective treatment for motor deficits of Parkinson’s disease (PD). However, the efficacy of L/C diminishes with PD progression and its chronic use often leads to the debilitating side effect termed levodopa-induced dyskinesia (LID), which is not treated well with available drugs. Thus, clinical management of PD requires a monotherapy that can reduce the motor symptoms without inducing dyskinesia or an add-on therapy to reduce LID severity.
Method: Using a machine learning approach trained on gene expression data from striatonigral neurons of 6-OHDA lesioned mice exposed to various levels of L-DOPA, we identified a repurposable small molecule drug, SB-0107 (trapidil). SB-0107 induced a gene expression pattern similar to that associated with LC’s motoric efficacy while reversing the pattern associated with LID. SB-0107 selectively potentiates protein kinase A II, a kinase downstream of dopamine receptors. We investigated its effects in two highly translatable models of PD disability and LID.
Results: In 6-OHDA lesioned rats, the combination of SB-0107 and sub-therapeutic doses of L-DOPA resulted in anti-parkinsonian effects that are equivalent to or greater than high doses of L-DOPA alone, while not inducing LID-like behavior after repeated dosing. More importantly, in the MPTP-lesioned macaques, SB-0107 showed a dual benefit; it significantly enhanced L/C’s effects on PD disability, while also significantly decreasing LID by ~50%.
Conclusion: SB-0107 demonstrates potent enhancement of anti-parkinsonian effects of L/C in rodents without inducing LID. In primates, SB-0107 has enhances the anti-parkinsonian actions of L/C while reducing LID. The unique mechanism of action and preclinical results warrant further development of SB-0107 for PD.
To cite this abstract in AMA style:
A. Bordbar, K. Merchant, D. Weiner, M. Hill, J. Brotchie, T. Johnston, I. Famili. SB-0107, a drug repurposing opportunity identified through machine learning, shows the potential to treat Parkinson’s disease motor disability and levodopa-induced dyskinesia in rat and primate models [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/sb-0107-a-drug-repurposing-opportunity-identified-through-machine-learning-shows-the-potential-to-treat-parkinsons-disease-motor-disability-and-levodopa-induced-dyskinesia-in-rat-and-primat/. Accessed May 13, 2025.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/sb-0107-a-drug-repurposing-opportunity-identified-through-machine-learning-shows-the-potential-to-treat-parkinsons-disease-motor-disability-and-levodopa-induced-dyskinesia-in-rat-and-primat/