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In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson's disease.

ABSTRACT: Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson's disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson's disease. Herein the results of preclinical evaluations of minzasolmin that formed the basis for subsequent clinical development are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson's disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020-003265).

SUBMITTER: Price DL

PROVIDER: S-EPMC10352257 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson's disease.

Price Diana L DL Khan Asma A Angers Rachel R Cardenas Alvaro A Prato Maria Key MK Bani Massimo M Bonhaus Douglas W DW Citron Martin M Biere Anja-Leona AL

NPJ Parkinson's disease 20230717 1

Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson's disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson's disease. Herein the results of preclinical evaluations of minzasolmin that formed the ...[more]

PMID: 37460603

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Project description:BackgroundAccumulating α-synuclein (α-syn) aggregates in neurons and glial cells are the staples of many synucleinopathy disorders, such as Parkinson's disease (PD). Since brain adenosine becomes greatly elevated in ageing brains and chronic adenosine A1 receptor (A1R) stimulation leads to neurodegeneration, we determined whether adenosine or A1R receptor ligands mimic the action of known compounds that promote α-syn aggregation (e.g., the amphetamine analogue 2-aminoindan) or inhibit α-syn aggregation (e.g., Rasagiline metabolite 1-aminoindan). In the present study, we determined whether adenosine, A1R receptor agonist N6-Cyclopentyladenosine (CPA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) could directly interact with α-syn to modulate α-syn aggregation and neurodegeneration of dopaminergic neurons in the substantia nigra (SN).MethodsNanopore analysis and molecular docking were used to test the binding properties of CPA and DPCPX with α-syn in vitro. Sprague-Dawley rats were administered with 7-day intraperitoneal injections of the A1R ligands and 1- and 2-aminoindan, and levels of α-syn aggregation and neurodegeneration were examined in the SN pars compacta and hippocampal regions using confocal imaging and Western blotting.ResultsUsing nanopore analysis, we showed that the A1R agonists (CPA and adenosine) interacted with the N-terminus of α-syn, similar to 2-aminoindan, which is expected to promote a "knot" conformation and α-syn misfolding. In contrast, the A1R antagonist DPCPX interacted with the N- and C-termini of α-syn, similar to 1-aminoindan, which is expected to promote a "loop" conformation that prevents α-syn misfolding. Molecular docking studies revealed that adenosine, CPA and 2-aminoindan interacted with the hydrophobic core of α-syn N-terminus, whereas DPCPX and 1-aminoindan showed direct binding to the N- and C-terminal hydrophobic pockets. Confocal imaging and Western blot analyses revealed that chronic treatments with CPA alone or in combination with 2-aminoindan increased α-syn expression/aggregation and neurodegeneration in both SN pars compacta and hippocampus. In contrast, DPCPX and 1-aminoindan attenuated the CPA-induced α-syn expression/aggregation and neurodegeneration in SN and hippocampus.ConclusionsThe results indicate that A1R agonists and drugs promoting a "knot" conformation of α-syn can cause α-synucleinopathy and increase neuronal degeneration, whereas A1R antagonists and drugs promoting a "loop" conformation of α-syn can be harnessed for possible neuroprotective therapies to decrease α-synucleinopathy in PD.

Project description:BackgroundParkinson's disease (PD) and its progression are thought to be caused and driven by misfolding of α-synuclein (ASYN). UCB0599 is an oral, small-molecule inhibitor of ASYN misfolding, aimed at slowing disease progression.ObjectiveThe aim was to investigate safety/tolerability and pharmacokinetics (PK) of single and multiple doses of UCB0599.MethodsSafety/tolerability and PK of single and multiple doses of UCB0599 and its metabolites were investigated in two phase 1 studies in healthy participants (HPs), where food effect and possible interaction with itraconazole (ITZ) were assessed (UP0030 [randomized, placebo-controlled, dose-escalation, crossover study, N = 65] and UP0078 [open-label study, N = 22]). Safety/tolerability and multi-dose PK of UCB0599 were subsequently investigated in a phase 1b randomized, double-blind, placebo-controlled study of participants with PD (UP0077 [NCT04875962], N = 31).ResultsAcross all studies, UCB0599 displayed rapid absorption with linear, time-independent PK properties; PK of multiple doses of UCB0599 were predictable from single-dose exposures. No notable food-effect was observed; co-administration with ITZ affected UCB0599 disposition (maximum plasma concentration and area under the curve increased ~1.3- and ~2 to 3-fold, respectively) however, this did not impact the safety profile. Hypersensitivity reactions were reported in UP0030 (n = 2) and UP0077 (n = 2). Treatment-related adverse events occurred in 43% (UCB0599), and 30% (placebo) of participants with PD were predominantly mild-to-moderate in intensity and were not dose related.ConclusionsSeventy-three HPs and 21 participants with PD received UCB0599 doses; an acceptable safety/tolerability profile and predictable PK support continued development of UCB0599 for the slowing of PD progression. A phase 2 study in early-stage PD is underway (NCT04658186). © 2022 UCB Pharma. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson's disease.

Publications

In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson's disease.

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