Objective: To evaluate effects of NPT200-11 on Parkinson’s disease (PD)-relevant outcomes including alpha-synuclein pathology, neurodegenerative markers and motor performance in transgenic mouse models of PD.

Background: Accumulation of alpha-synuclein (ASYN) in neuronal and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Moreover, aberrant and progressive accumulation of alpha-synuclein (ASYN) pathology correlates with motor and non-motor dysfunction in PD patients. Targeted therapeutics that interfere with the ASYN pathogenic pathway could prevent, stop or slow the neurodegenerative processes in PD and other synucleinopathies.

Methods: NPT200-11, a new generation ASYN misfolding inhibitor, was evaluated in studies with pharmacokinetic, behavioral, neuropathological and in vivo imaging endpoints utilizing wildtype and multiple alpha-synuclein transgenic mouse models of PD.

Results: The bioavailability and brain uptake of NPT200-11 were confirmed in mouse pharmacokinetic studies. Efficacy evaluations in the Line 61 ASYN transgenic mouse model of PD demonstrated benefits of 3 months of 5 mg/kg NPT200-11 treatment on ASYN brain levels, multiple motor endpoints, and downstream neuropathology (including preserved striatal DAT – a potentially translatable finding for clinical development). Longitudinal and repeated in vivo retinal imaging of GFP-tagged ASYN in PDNG78 ASYN transgenic mice over the course of a 3 month study revealed time-dependent reductions in retinal ASYN pathology in 5 mg/kg NPT200-11-treated transgenic mice.

Conclusions: Taken together, these studies provide pre-clinical proof of pharmacological activity and support continued development of NPT200-11 as a disease-modifying treatment for Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-small-molecule-alpha-synuclein-misfolding-inhibitor-npt200-11-produces-multiple-benefits-in-an-animal-model-of-parkinsons-disease/